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 .
DETAILED ACTION
Claims 1-2, 4-15, 19-20, 23-31, 33-35, and 38 are pending in the instant application and being examined on the merit.
Note: No power of attorney has been filed.
Objections to the Claims
Claim 20 is objected to because of the following informalities: The claims is grammatically incorrect and missing ---the --- between “detect presence“ in line 7. Appropriate correction is required.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 9-10, 23, 25, 34, and 38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 5, it is unclear if the method of treatment is for treating only a solid tumor or a solid tumor that can also have a hematological cancer present. The method is claimed for treating a cancer that comprises a solid tumor, but further claims the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent is an amount effective to increase expression of NKG2DL on solid cancer or hematological cancer cells.
Regarding claims 9-10, the claims list a genus followed by the term “such as” “preferably” or “for example” then describes species of the genus. It is not clear whether the recitation of the species are an optionally preferred example — and therefore not limiting—or further limitations of the scope of the claim.
The genus with optional species described are: Claims 9-10) “a protein dose of less than 3 mg/kg subject body weight” such as recitation of species of the genus.
Regarding claims 23 and 34, a DOTA derivative is claimed, wherein DOTA was defined as p-SCN-Bn-DOTA, which has the structure
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. The claim and instant specification do not clearly define the meets and bounds of a “DOTA derivative” to a degree that a person having ordinary skill in the art would be able to envision the metes and bounds of the claim. The NCI dictionary defines a derivative as a compound produced from or related to another (NCI dictionary derivative https://web.archive.org/web/20200411194716/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/derivative 2020). It is unclear the degree of relatedness of a compound to DOTA to be a “DOTA derivative” or whether radiochemical chelators such as (4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A),
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, p-NH2-Bn-Oxo-DO3A
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, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA)
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, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or
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are considered DOTA derivative (radiochemical chelator structures present in Price EW et al. (Chem. Soc. Rev. (2014) 43 (1): 260–290, Tables 2-4) are considered to be “DOTA derivatives” that are encompassed by the instant claims.
Regarding instant claims 25 and 38, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 25 and 38 recite the broad recitation in a), d), g), i), and k) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3; and in b), c), e), h), and j) light or heavy chain variable region; and the claim also recites in parentheses a specific SEQ ID NO: which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claims 25 and 38, the content of the parentheses of (human MICA) does not define or equate to the preceding terminology and thus is exemplary claim language which is unclear. Claim language that would avoid the exemplary claim language rejection would exchange “ (human MICA)”… with “hMICA (human MICA)”...
Regarding claims 25 and 38, claim 25 and 38 recites the limitation "the NKG2D targeting agent" in line 2. There is insufficient antecedent basis for this limitation in the claim. Only an NKG2DL targeting agent has been introduced in claims 1 and 27.
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 7, 25, 31, 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.
Regarding claims 7 and 31, the NKG2DL targeting agent is claimed to bind an epitope of MICA on an alpha-3 domain and/or block cleavage at the alpha-3 domain of MICA and thus claims an NKG2DL targeting agent functionally without structure. The prediction of CDR binding to an epitope is difficult to predict for antibodies and the Applicant does not have possession of a structure activity relationship of species of antibodies or other agents that would be able to predict all NKG2DL targeting agents that bind an epitope of MICA on an alpha-3 domain and/or block cleavage at the alpha-3 domain of MICA.
Regarding instant claims 25 and 38, the disclosure does not have possession of a NKG2DL targeting agent that binds MICA with:
a) substitution of CDR residues in heavy chain antibodies comprising SEQ ID NO:10 that would permit any residue within the Kabat CDR defined region as X, wherein the VH Kabat CDR 1-3 definition would be TYAFX; GIVPIFGTLKYAQKFQD; AIQLEGRPFDH;
b) exchange of VH and VL sequences of separate antibodies wherein the CDR residues are different. The instant VL comprising instant SEQ ID NO:40 and VH comprising instant SEQ ID NO:41 are from separate antibodies, wherein the VL is from MICA antibody 16A8 comprising WO 2013/117647 SEQ ID NO:34 and the VH is from MICA antibody 19E9 comprising WO 2013/117647 SEQ ID NO:46, and wherein the CDR residues between the VH or VL of the MICA antibodies 16A8 and 19E9 are not the same;
c) an antibody comprising a VH comprising an HCDR1-3 of
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and a VL comprising an LCDR1-3 of
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wherein the VH and VL CDRs were not tested and defined by a non-standard definition that is not identified, or wherein an isoleucine has been deleted from the Kabat VH CDR2 definition of MICA antibody 1D5 of US 2020/0055939 SEQ ID NO:347 and an isoleucine has been deleted from the Martin VH CDR2 definition of MICA antibody 1D5 of US 2020/0055939 SEQ ID NO:348;
Regarding instant claims 25 and 38, the disclosure does not test a NKG2DL targeting agent that binds MICA wherein the antibody is not ---an antibody comprising a VH comprising a CDR-H1, CDR-H2, and CDR3-H3 and a VL comprising a CDR-L1, CDR-L2, and CDR3-L3---. The claims of (a), (d), (g), (i), and (k) do not identify that the CDRs are from separate variable heavy and light chain regions.
Scope of the claimed genus
Claims 7 and 31 claim a therapeutic composition or method for treating a cancer in a mammalian subject with a therapeutic composition, wherein the therapeutic composition comprises a radioconjugated NKG2DL targeting agent, wherein the NKG2DL targeting agent binds an epitope of MICA on an alpha-3 domain and/or blocks cleavage at the alpha-3 domain of MICA and thus claims an NKG2DL targeting agent functionally without structure.
Claims 25 and 38 claim a therapeutic composition or method for treating a cancer in a mammalian subject with a therapeutic composition, wherein the therapeutic composition comprises a radioconjugated NKG2DL targeting agent, wherein the NKG2DL targeting agent is a radiolabeled anti-(human MICA) antibody comprising sequence defined options, wherein: 2) a) changes in the CDR are allowed; b) exchange of a VH and VL of prior art antibodies is permitted; and c) long CDRs with deletions of prior art CDRs are permitted; and 3) ---an antibody comprising a VH comprising a CDR-H1, CDR-H2, and CDR3-H3 and a VL comprising a CDR-L1, CDR-L2, and CDR3-L3--- is not required in options (a), (d), (g), (i), and (k)
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
1)-3) The instant specification does not show any data of any species of a therapeutic composition for the treatment of an NKG2D-expressing solid cancer or hematological cancer in a mammalian subject, the composition comprising: a therapeutically effective amount of a radionuclide-labeled NKG2DL targeting agent and a pharmaceutically acceptable carrier, wherein the radioconjugated NKG2DL targeting agent comprises a radioconjugated anti-NKG2DL monoclonal antibody, a radioconjugated NKG2D L-binding fragment of a monoclonal antibody, or a soluble, recombinant NK2GD receptor. Thus, the Applicant was not in possession of the NKG2DL targeting agent as claimed in instant claims 7, 25, 31, and 38.
State of the Relevant Art
The prior art has identified antibodies that bind MICA.
WO 2018/217688 (FERRARI DE ANDRADE L et al.) taught a NKG2DL targeting agent of an anti-MICA antibody 7C6 that binds the α3 domain of MICA (Fig. 1A), wherein the anti-MICA antibody 7C6 inhibits MICA release from cancer cells and increases cancer cell MICA surface expression in vitro (page 11, [0044] and Fig. 1B-D) and in vivo (Fig. 2C), wherein the sequence of 7C6 is taught in Fig. 21 which comprises a VH comprising ‘688 SEQ ID NO:7 and a VL comprising ‘688 SEQ ID NO:8, wherein the dose of antibody in vivo was 200 μg/mouse (pages 93-94, [00298]).
Regarding 2a) above, US 2017/0022275 (WUCHERPFENNIG KW et al.) taught anti-MICA antibodies including CM33322 Ab28 comprising a VH comprising ‘275 SEQ ID NO:168 and a VL comprising ‘275 SEQ ID NO:170. ‘275 did not test exchange of VH residue 35 which is within the Kabat definition of CDR-H2.
Regarding 2b) above, WO 2013/117647 (BLERY M et al.) taught MICA antibodies including: i) 16A8 comprising a VH comprising ‘647 SEQ ID NO:33 and a VL comprising ‘647 SEQ ID NO:34; and ii) 19E9 comprising a VH comprising ‘647 SEQ ID NO:46 and a VL comprising ‘647 SEQ ID NO:47 (‘647 pages 82-83, Table B)
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Regarding 2c) above US 2020/0055939 (LOMBANA TN et al.) taught MICA antibodies including: 1D5 comprising a VH comprising ‘939 SEQ ID NO:347 and a VL comprising ‘939 SEQ ID NO:348
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(‘939 page 78, Variable Domain Sequences Table), wherein the CDR sequences were defined as
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(page 75, Hypervariable Region Sequences Table).
The prior art did not teach a structure activity relationship for an NKG2DL targeting agent that binds an epitope of MICA on an alpha-3 domain and/or blocks cleavage at the alpha-3 domain of MICA. As further detailed below, the prediction of CDR binding to an epitope is difficult to predict for antibodies.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Thus, the prior art has not shown: 1) a structure activity relationship of species of antibodies or other agents that would be able to predict all NKG2DL targeting agents that bind an epitope of MICA on an alpha-3 domain and/or block cleavage at the alpha-3 domain of MICA; 2) a NKG2DL targeting agent that binds MICA with: a) substitution of CDR residues in heavy chain antibodies comprising SEQ ID NO:10 that would permit any residue within the Kabat CDR defined region as X, wherein the VH Kabat CDR 1-3 definition would be TYAFX; GIVPIFGTLKYAQKFQD; AIQLEGRPFDH; b) exchange of VH and VL sequences of separate antibodies wherein the CDR residues are different, wherein and antibody comprising a VL comprising instant SEQ ID NO:40 and VH comprising instant SEQ ID NO:41 is able to bind MICA; and c) an antibody comprising a VH comprising an HCDR1-3 of
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and a VL comprising an LCDR1-3 of
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wherein the VH and VL CDRs were not tested and defined by a non-standard definition that is not identified, or wherein an isoleucine has been deleted from the Kabat VH CDR2 definition of MICA antibody 1D5 of US 2020/0055939 SEQ ID NO:347 and an isoleucine has been deleted from the Martin VH CDR2 definition of MICA antibody 1D5 of US 2020/0055939 SEQ ID NO:348.
Claim Rejections – 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 27-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li HK et al. (Biochem Biophys Res Comm 2018 506(4) 1078-1084) and evidenced by UnitConverters.net (https://www.unitconverters.net/radiation-activity/megabecquerel-to-curie.htm 2026), Quesenberry KE et al. (https://web.archive.org/web/20171213183832/https://www.merckvetmanual.com/all-other-pets/mice/description-and-physical-characteristics-of-mice 2017).
Regarding instant claims 27, 30, Li taught an effective method of treating a mammalian subject with colorectal cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an α-particle emitting astatine-211 (211At)-labeled antibody targeting MICA/B which is an NKG2DL targeting agent (instant claim 27) , wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC (Fig. 4). Regarding instant claim 28-29, Li taught the antibody concentration was 10 µg per mouse and 1 MBq (page 1080, Section 2.9, left to right bridging paragraph). UnitConverters evidences 1MBq is about 27 µCi per dose (UnitConverters page 1, Table). Quesenberry evidenced that adult mice weight about 28 g (page 1, first paragraph). Thus, the radio-immunotherapeutic dose of Li is about 0.4 mg/kg and 27 µCi per dose.
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4-7, 9-12, 19, 23-29, 30-31, 33-35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.), Li HK et al. (Biochem Biophys Res Comm 2018 506(4) 1078-1084), and Quesenberry KE et al. (https://web.archive.org/web/20171213183832/https://www.merckvetmanual.com/all-other-pets/mice/description-and-physical-characteristics-of-mice 2017).
‘688 taught a NKG2DL targeting agent of an anti-MICA antibody 7C6 that binds the α3 domain of MICA (Fig. 1A), wherein the anti-MICA antibody 7C6 inhibits MICA release from cancer cells and increases cancer cell MICA surface expression in vitro (page 11, [0044] and Fig. 1B-D) and in vivo (Fig. 2C), wherein the sequence of 7C6 is taught in Fig. 21 which comprises a VH comprising ‘688 SEQ ID NO:7 and a VL comprising ‘688 SEQ ID NO:8, wherein the dose of antibody in vivo was 200 μg/mouse (pages 93-94, [00298]). ‘688 taught a method of effectively treating a subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an NKG2DL targeting agent of an anti-MICA antibody of 7C6 (Fig. 2). ‘688 taught the antibody as an immune-conjugate comprising a monoclonal antibody linked to a cytotoxic agent, wherein the agent is a radioactive isotope (page 6, [0029]). ‘688 taught the monoclonal antibody which bind to MICA comprise heavy and light chain variable regions, the heavy chain CDR1, CDR2, and CDR3 sequences comprising ‘688 SEQ ID NOs: 1-3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences comprising ‘688 SEQ ID NOs: 4-6 (page 2, [008]). ‘688 taught combination the method described herein, further comprising administering to the subject an additional therapy of immunotherapy and checkpoint blockade (pages 9-10, [0041]). ‘688 taught a NKG2DL targeting agent of an anti-MICA antibody 7C6-hIgGl-DANA mutant lacked Fc receptor binding and had reduced NK killing capabilities (pages 12-13, [0046] and Fig 3), but still decreased MICA shedding (pages 19-20, [0059] and Fig. 16). ‘688 taught a method of treating a subject with a solid melanoma skin cancer comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an NKG2DL targeting agent of an anti-MICA antibody of 7C6-DANA with reduced NK cell killing capabilities decreased MICA shedding but had limited capacity to kill a solid melanoma skin cancer (Fig. 17). ‘688 taught the antibody could be humanized (pages 4-5, [0020]) wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins (page 32, [0094]), and treatment of a human subject with cancer (pages 9-10, [0041]).
‘688 taught diagnostic assays and methods for accurately classifying whether a biological sample expresses cell-restricted MICA or whether the levels of cell-restricted MICA are modulated thereby indicative of cancer, (page 69. [00224]). ‘688 taught In some instances, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection (page 79, [00248]). ‘688 taught a method of detecting MICA in a biological sample in vitro or in vivo, wherein in vivo techniques for detection of a MICA polypeptide include introducing into a subject a labeled anti-MICA antibody, wherein the antibody is labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques (pages 71-72, [00229]). ‘688 taught administration of the anti-MICA antibody every 4 weeks (page 82. [00259]).
‘688 did not teach a radioconjugated NKG2DL targeting agent of comprising a chemically conjugated chelator and the chelator chelates the radionuclide label of 225Ac, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC, but this is obvious in view of ‘931, Li, and Quesenberry.
‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with a single dose of 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA (page 5, [0026] and Fig. 9; page 4, [0020] and Fig. 3). ‘931 taught administering a dose of about 0.01 mg/kg to 1 mg/kg patient weight of antibody labeled with a radioisotope (pages 10-11, [0047]). ‘931 taught an effective amount of 225Ac-CD38 as 1 or 5 µCi/kg (page 10, [0046]). ‘931 taught the anti-CD38 antibody may be administered once every 4 weeks (page 23, [0098]). ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate (Fig. 10A).
Li taught an effective method of treating a mammalian subject with colorectal cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an α-particle emitting astatine-211 (211At)-labeled antibody targeting MICA/B which is an NKG2DL targeting agent, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC (Fig. 4).
Quesenberry taught adult mice weight about 28 g (page 1, first paragraph).
Regarding instant claims 1-2, 4-7, 9-12, 19, 23-29, 30-31, 33-35, and 38, it would have been obvious for a person having ordinary skill in the art to modify the effective method of treating a subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an NKG2DL targeting agent of an anti-MICA antibody of 7C6, wherein 7C6 binds the α3 domain of MICA of ‘688 – by:
1) conjugating the antibody to the radiochelating agent p-SCN-Bn-DOTA and administering 0.3 µg of 200 nCi 225Ac-DOTA-7C6
2) administering a dose of about 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg in view of ‘931 and Quesenberry;
3) treating a human subject with a humanized 7C6 antibody comprising heavy and light chain variable regions, the heavy chain CDR1, CDR2, and CDR3 sequences comprising ‘688 SEQ ID NOs: 1-3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences comprising ‘688 SEQ ID NOs: 4-6;
4) before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent in view of ‘688;
5) administering the radioconjugated MICA antibody every 28 days, which would include at least two doses in view of ‘688 and ‘931;
This is obvious because:
1a) ‘688 taught the antibody as an immune-conjugate comprising a monoclonal antibody linked to a cytotoxic agent, wherein the agent is a radioactive isotope
1b) ‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with a single dose of 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA.
2) ‘931 taught administering a dose of about 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg and Quesenberry taught adult mice weight about 28 g. Thus, the effective dose of about 0.3 µg/mouse is about 0.1 mg/kg and the effective dose of 200 nCi is about 7 µCi/kg which is about 5 µCi/kg;
3a) ‘688 taught: i) the antibody could be humanized wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins; ii) treatment of a human subject with cancer; and iii) the 7C6 antibody effectively bound MICA in vivo and prevented MICA shedding;
3b) ‘931 taught 225Ac-DOTA conjugates are effective in vivo;
4) ‘688 taught: i) diagnostic assays and methods for accurately classifying whether a biological sample expresses cell-restricted MICA or whether the levels of cell-restricted MICA are modulated thereby indicative of cancer; ii) subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection ; and iii) a method of detecting MICA in a biological sample in vitro or in vivo, wherein in vivo techniques for detection of a MICA polypeptide include introducing into a subject a labeled anti-MICA antibody, wherein the antibody is labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques;
5a) ‘688 and ‘931 taught the antibody or immunoconjugate may be administered once every 4 weeks.
5b) ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate. Thus, dosing every 28 days would be expected to be safe.
There is a reasonable expectation of success because:
1a) Li taught administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an α-particle emitting-labeled antibody targeting MICA/B which is an NKG2DL targeting agent was effective in method of treating a mammalian subject with colorectal cancer, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC.
1b)‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA.
2) Quesenberry taught adult mice weight about 28 g. Thus, the effective dose of about 0.3 µg/mouse is about 0.1 mg/kg and the effective dose of 200 nCi is about 7 µCi/kg which is about 5 µCi/kg;
3a) ‘688 taught: i) the antibody could be humanized wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins; ii) treatment of a human subject with cancer; and iii) the 7C6 antibody effectively bound MICA in vivo and prevented MICA shedding;
3b) ‘931 taught 225Ac-DOTA conjugates are effective in vivo;
4) diagnosis of a human subject with MICA positive cancer before treatment would allow the MICA radioconjugate to be more effective because the cancer cells would be known to express the radioconjugate target;
5a) ‘688 and ‘931 taught the antibody or immunoconjugate may be administered once every 4 weeks.
5b) ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate. Thus, dosing every 28 days would be expected to be safe.
This would produce a method of treating a human subject (instant claims 26) with a solid melanoma skin cancer (instant claim 2) comprising administering a therapeutic pharmaceutical composition (instant claim 27) comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a single dose (instant claim 11) or a dose every 28 days (instant claim 12) of a humanized NKG2DL targeting agent of an anti-MICA antibody (instant claims 6 and 30) of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA (instant claims 7 and 31), wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA (instant claims 23-24 and 33-35 ), wherein the humanized 7C6 antibody comprises a VH with an identical CDR-H1-H3 to instant SEQ ID NO:4-6 and a VL with an identical CDR-L1-L3 of instant SEQ ID NO:1-3 (instant claim 25 and 38 ), wherein the therapeutically effective dose is between 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg (instant claims 9-10 and 28-29), wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC (instant claim 1), wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least IO-fold lower than an unconjugated NKG2DL targeting agent (instant claim 4), wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer (instant claim 5), wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent (instant claim 19).
Claims 1-2, 4-7, 9-15, 19, 23-29, 30-31, 33-35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.), Li HK et al. (Biochem Biophys Res Comm 2018 506(4) 1078-1084), and Quesenberry KE et al. (https://web.archive.org/web/20171213183832/https://www.merckvetmanual.com/all-other-pets/mice/description-and-physical-characteristics-of-mice 2017) as applied to claims 1-2, 4-7, 9-12, 19, 23-29, 30-31, 33-35, and 38 above, and further in view of Lian S et al. (Scientific Reports 2019 9 4532).
‘688, ‘931, Li and Quesenberry are described above.
‘688 did not teach further including an additional therapy of immune checkpoint therapy and CD47 blockade, but this is obvious in view of Lian.
Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone (abstract). Lian taught melanoma cells expressed PD-L1 and CD47 (Fig. 1). Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone (Fig. 3).
Regarding instant claims 13-15, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘688, ‘931, Li, and Quesenberry above – by:
further including an additional therapy of administering a therapeutically effective amount of an immune checkpoint therapy of a PD-L1 antibody inhibitor, and a therapeutically effective amount of CD47 blockade of a CD47 antibody inhibitor in view of Lian.
This is obvious because:
1a) Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone.
1b) Lian taught melanoma cells expressed PD-L1 and CD47;
1c) Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone.
There is a reasonable expectation of success because:
1a) Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone.
1b) Lian taught melanoma cells expressed PD-L1 and CD47;
1c) Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone.
This would produce a method of treating a human subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a single dose or a dose every 28 days of a humanized NKG2DL targeting agent of an anti-MICA antibody of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA, wherein DOTA is the a radiochelating agent p-SCN-Bn-DOTA, wherein the therapeutically effective dose is between 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least I0-fold lower than an unconjugated NKG2DL targeting agent, wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer, wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent, wherein the method further includes an additional therapy of administering a therapeutically effective amount of an immune checkpoint therapy of a PD-L1 antibody inhibitor, and a therapeutically effective amount of CD47 blockade of a CD47 antibody inhibitor (instant claims 13-15).
Claims 1-2, 4-7, 9-12, 19-20, 23-29, 30-31, 33-35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.), Li HK et al. (Biochem Biophys Res Comm 2018 506(4) 1078-1084), and Quesenberry KE et al. (https://web.archive.org/web/20171213183832/https://www.merckvetmanual.com/all-other-pets/mice/description-and-physical-characteristics-of-mice 2017) as applied to claims 1-2, 4-7, 9-12, 19, 23-29, 30-31, 33-35, and 38 above, and further in view of Yoon JK et al. (Int J Mol Sci 2020 21(12):4309. doi: 10.3390/ijms21124309).
‘688, ‘931, Li and Quesenberry are described above.
‘688 did not teach diagnosing MISA positive cancer with a radioconjugate comprising administering a MISA antibody with an 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging but this is obvious in view of Yoon.
Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr (t1/2 = 3.3 days) is favorable for evaluating the in vivo distribution of monoclonal antibodies (abstract). Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days (page 4, paragraph 3). Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors (page 4, paragraph 3).
Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans (page 4, paragraph 3).
Regarding instant claim 20, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘688, ‘931, Li, and Quesenberry above – by:
exchanging the 89Zr-trastuzumab with 89Zr-humanized 7C6 to detect MISA in view of Yoon; and
further including diagnosing MISA positive cancer with a radioconjugate comprising administering a MISA antibody with an 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging in view of Yoon.
This is obvious because:
1) 89Zr-humanized 7C6 would allow detection of MISA in tumors to ensure therapeutic success;
2a) Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr is favorable for evaluating the in vivo distribution of monoclonal antibodies.
2b) Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days
2c) Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors.
2d) Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans
There is a reasonable expectation of success because:
1) 89Zr-humanized 7C6 would allow detection of MISA in tumors to ensure therapeutic success;
2a) Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr is favorable for evaluating the in vivo distribution of monoclonal antibodies.
2b) Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days
2c) Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors.
2d) Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans
This would produce a method of treating a human subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a single dose or a dose every 28 days of a humanized NKG2DL targeting agent of an anti-MICA antibody of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA, wherein DOTA is the a radiochelating agent p-SCN-Bn-DOTA, wherein the therapeutically effective dose is between 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least IO-fold lower than an unconjugated NKG2DL targeting agent, wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer, wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent, wherein diagnosing MISA positive cancer further comprises administering the humanized 7C6 MISA antibody with a 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging (instant claim 20).
Claims 1-2, 4-8, 9-12, 19, 23-29, 30-31, 33-35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.), Li HK et al. (Biochem Biophys Res Comm 2018 506(4) 1078-1084), and Quesenberry KE et al. (https://web.archive.org/web/20171213183832/https://www.merckvetmanual.com/all-other-pets/mice/description-and-physical-characteristics-of-mice 2017) as applied to claims 1-2, 4-7, 9-12, 19, 23-29, 30-31, 33-35, and 38 above, and further in view of Godbersen C et al. (Mol Cancer Ther 2017 16(7):1335–1346).
‘688, ‘931, Li and Quesenberry are described above.
‘688 did not teach a soluble NKG2DL receptor as the targeting agent, but this is obvious in view of Godbersen.
Godbersen taught compositions of: 1) huNKG2D-OKT3 comprising the extracellular portion of the human NKG2D receptor fused to a CD3ε binding scFv, known as OKT3; and 2) B2-OKT3 comprising a scFv that targets MICA on tumor cells and CD3ε on human T cells (abstract), wherein huNKG2D-OKT3 and B2-OKT3 increase targeting to melanoma cancer cells compared to a non-targeted OKT3 control (Fig. 1F), and wherein the huNKG2D-OKT3 and B2-OKT3 are effective at activating T cells against human melanoma tumor cell samples (Fig. 5).
Regarding instant claim 8, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘688, ‘931, Li, and Quesenberry above – by:
exchanging the humanized anti-MICA antibody of 225Ac-DOTA-7C6 for a soluble recombinant human NKG2D receptor comprising the extracellular portion of the human NKG2D receptor in view of Godbersen.
This is obvious with a reasonable expectation of success because:
Godbersen taught compositions of a: 1) huNKG2D-OKT3 fusion comprising the extracellular portion of the human NKG2D receptor; and 2) B2-OKT3 comprising a scFv that targets MICA on tumor cells were both effective at targeting cancer cells with either a human NKG2D receptor or an antibody to MICA for cancer cell death. Thus, a soluble human recombinant NKG2D receptor fusion conjugate would be obvious with a reasonable expectation of success to effectively target NKG2G ligand expressing cancer cells with other cancer killing agents such as 225Ac.
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.
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Claims 1-2, 4-7, 9-13, 15, 19, 23-29, 30-31, 33-35, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 21-34 of copending Application No. 17/725,544 in view of WO 2018/217688 (FERRARI DE ANDRADE L et al.), and WO 2019/094931 (SANDESH S et al.).
‘554 taught a methods for treating cancer in a mammalian subject comprising administering a therapeutically radiolabeled cancer targeting agent and an effective amount of a CD47 blockade of a CD47 antibody in copending claims 2-17 and 21-34. ‘554 taught a method for treating cancer in a mammalian subject comprising administering a therapeutically radiolabeled cancer targeting agent and an effective amount of a CD47 blockade of a CD47 antibody, wherein the radiolabeled cancer targeting agent is labeled with an alpha particle emitting radionucleotide in copending claim 2, wherein the cancer targeting agent is an antibody against 5T4 in copending claim 4, wherein the one or more radiolabeled cancer targeting agents comprise a composition of 225Ac- labeled antibody and non-radiolabeled antibody, the composition comprising a radiation dose of 0.1-2.0 pCi/kg body weight of the subject and a protein dose of 0.1-5.0 mg/kg body weight of the subject, and/or the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject in copending claim 5, wherein the cancer is colorectal cancer or gastric cancer, ovarian cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, pancreatic cancer, renal cancer in copending claim 7, wherein the wherein the cancer targeting agent is an antibody against MICA in copending claim 17,
‘544 did not teach: 1) conjugating the antibody to the radiochelating agent p-SCN-Bn-DOTA for chelating the 225Ac in therapeutic pharmaceutical composition further comprising a pharmaceutically acceptable carrier, 2) treating a human subject with a humanized 7C6 antibody MICA antibody, 3) before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent in view of ‘688; and 4) administering the radioconjugated MICA antibody every 28 days, which would include at least two doses, but this is obvious in view of ‘688 and ‘931;
‘688 taught a NKG2DL targeting agent of an anti-MICA antibody 7C6 that binds the α3 domain of MICA (Fig. 1A), wherein the anti-MICA antibody 7C6 inhibits MICA release from cancer cells and increases cancer cell MICA surface expression in vitro (page 11, [0044] and Fig. 1B-D) and in vivo (Fig. 2C), wherein the sequence of 7C6 is taught in Fig. 21 which comprises a VH comprising ‘688 SEQ ID NO:7 and a VL comprising ‘688 SEQ ID NO:8, wherein the dose of antibody in vivo was 200 μg/mouse (pages 93-94, [00298]). ‘688 taught a method of effectively treating a subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an NKG2DL targeting agent of an anti-MICA antibody of 7C6 (Fig. 2). ‘688 taught the antibody as an immune-conjugate comprising a monoclonal antibody linked to a cytotoxic agent, wherein the agent is a radioactive isotope (page 6, [0029]). ‘688 taught the monoclonal antibody which bind to MICA comprise heavy and light chain variable regions, the heavy chain CDR1, CDR2, and CDR3 sequences comprising ‘688 SEQ ID NOs: 1-3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences comprising ‘688 SEQ ID NOs: 4-6 (page 2, [008]). ‘688 taught combination the method described herein, further comprising administering to the subject an additional therapy of immunotherapy and checkpoint blockade (pages 9-10, [0041]). ‘688 taught a NKG2DL targeting agent of an anti-MICA antibody 7C6-hIgGl-DANA mutant lacked Fc receptor binding and had reduced NK killing capabilities (pages 12-13, [0046] and Fig 3), but still decreased MICA shedding (pages 19-20, [0059] and Fig. 16). ‘688 taught a method of treating a subject with a solid melanoma skin cancer comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an NKG2DL targeting agent of an anti-MICA antibody of 7C6-DANA with reduced NK cell killing capabilities decreased MICA shedding but had limited capacity to kill a solid melanoma skin cancer (Fig. 17). ‘688 taught the antibody could be humanized (pages 4-5, [0020]) wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins (page 32, [0094]), and treatment of a human subject with cancer (pages 9-10, [0041]). ‘688 taught diagnostic assays and methods for accurately classifying whether a biological sample expresses cell-restricted MICA or whether the levels of cell-restricted MICA are modulated thereby indicative of cancer, (page 69. [00224]). ‘688 taught In some instances, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection (page 79, [00248]). ‘688 taught a method of detecting MICA in a biological sample in vitro or in vivo, wherein in vivo techniques for detection of a MICA polypeptide include introducing into a subject a labeled anti-MICA antibody, wherein the antibody is labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques (pages 71-72, [00229]). ‘688 taught administration of the anti-MICA antibody every 4 weeks (page 82. [00259]).
‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with a single dose of 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA (page 5, [0026] and Fig. 9; page 4, [0020] and Fig. 3). ‘931 taught administering a dose of about 0.01 mg/kg to 1 mg/kg patient weight of antibody labeled with a radioisotope (pages 10-11, [0047]). ‘931 taught an effective amount of 225Ac-CD38 as 1 or 5 µCi/kg (page 10, [0046]). ‘931 taught the anti-CD38 antibody may be administered once every 4 weeks (page 23, [0098]). ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate (Fig. 10A).
Regarding instant claims 1-2, 4-7, 9-13, 15, 19, 23-29, 30-31, 33-35, 38, it would have been obvious for a person having ordinary skill in the art to take the methods of copending claims 2, 4-5, 7, and 17 for a method for treating cancer in a mammalian subject comprising administering a therapeutically radiolabeled cancer targeting agent and an effective amount of a CD47 blockade of a CD47 antibody, wherein the radiolabeled cancer targeting agent is labeled with an alpha particle emitting radionuclide, wherein the cancer targeting agent is an antibody against MICA, wherein the radiolabeled cancer targeting agents comprise a composition of 225Ac- labeled antibody and non-radiolabeled antibody, the composition comprising a radiation dose of 0.1-2.0 pCi/kg body weight of the subject and a protein dose of 0.1-5.0 mg/kg body weight of the subject, wherein the cancer is colorectal cancer or skin cancer – and modifying it to:
conjugating the antibody to the radiochelating agent p-SCN-Bn-DOTA for chelating the 225Ac in therapeutic pharmaceutical composition further comprising a pharmaceutically acceptable carrier view of ‘931;
treating a human subject with a humanized 7C6 antibody MICA antibody comprising heavy and light chain variable regions, the heavy chain CDR1, CDR2, and CDR3 sequences comprising ‘688 SEQ ID NOs: 1-3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences comprising ‘688 SEQ ID NOs: 4-6 in view of ‘688;
before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent in view of ‘688;
administering the radioconjugated MICA antibody every 28 days, which would include at least two doses in view of ‘688 and ‘931;
This is obvious because:
1a) ‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with a single dose of 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA.
2a) ‘688 taught: i) the effective 7C6 antibody could be humanized wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins; ii) treatment of a human subject with cancer; iii) the 7C6 antibody effectively bound MICA in vivo and prevented MICA shedding;
2b) ‘931 taught 225Ac-DOTA conjugates are effective in vivo;
3) ‘688 taught: i) diagnostic assays and methods for accurately classifying whether a biological sample expresses cell-restricted MICA or whether the levels of cell-restricted MICA are modulated thereby indicative of cancer; ii) subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection ; and iii) a method of detecting MICA in a biological sample in vitro or in vivo, wherein in vivo techniques for detection of a MICA polypeptide include introducing into a subject a labeled anti-MICA antibody, wherein the antibody is labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques;
4a) ‘688 and ‘931 taught the antibody or immunoconjugate may be administered once every 4 weeks.
4b) ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate. Thus, dosing every 28 days would be expected to be safe.
There is a reasonable expectation of success because:
1a) ‘931 taught a method of effectively treating a subject with a solid cancer expressing CD38 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab, wherein the immunoconjugate was dose responsive with a single dose of 200 and 400 nCi, wherein an equivalent dose of 0.3 μg naked unconjugated daratumumab was ineffective, and wherein a 30-fold higher dose of naked unconjugated daratumumab about as effective as 0.3 µg of 200 nCi 225Ac-DOTA-daratumumab, wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA.
2a) ‘688 taught: i) the effective 7C6 antibody could be humanized wherein amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins; ii) treatment of a human subject with cancer; iii) the 7C6 antibody effectively bound MICA in vivo and prevented MICA shedding;
2b) ‘931 taught 225Ac-DOTA conjugates are effective in vivo;
3) ‘688 taught: i) diagnostic assays and methods for accurately classifying whether a biological sample expresses cell-restricted MICA or whether the levels of cell-restricted MICA are modulated thereby indicative of cancer; ii) subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection ; and iii) a method of detecting MICA in a biological sample in vitro or in vivo, wherein in vivo techniques for detection of a MICA polypeptide include introducing into a subject a labeled anti-MICA antibody, wherein the antibody is labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques;
4a) ‘688 and ‘931 taught the antibody or immunoconjugate may be administered once every 4 weeks.
4b) ‘931 taught mammalian subjects administered 0.3 µg of CD38 targeting immunoconjugate 225Ac-DOTA-daratumumab with a single dose of 200 nCi were gaining weight 28 days after administration of the immunoconjugate. Thus, dosing every 28 days would be expected to be safe.
This would produce a method of treating a human subject (instant claims 26) with a solid skin cancer (instant claim 2) comprising administering a therapeutic pharmaceutical composition (instant claim 27) comprising a pharmaceutically acceptable carrier, an effective amount of a CD47 blockade of a CD47 antibody (instant claims 13 and 15), and a therapeutically effective amount of a single dose (instant claim 11) or a dose every 28 days (instant claim 12) of a humanized NKG2DL targeting agent of an anti-MICA antibody (instant claims 6 and 30) of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA (instant claims 7 and 31), wherein the DOTA conjugate is the product of conjugating the radiochelating agent p-SCN-Bn-DOTA (instant claims 23-24 and 33-35 ), wherein the humanized 7C6 antibody comprises a VH with an identical CDR-H1-H3 to instant SEQ ID NO:4-6 and a VL with an identical CDR-L1-L3 of instant SEQ ID NO:1-3 (instant claim 25 and 38 ), wherein, the composition comprising a radiation dose of 0.1-2.0 pCi/kg body weight of the subject and a protein dose of 0.1-5.0 mg/kg body weight of the subject (instant claims 9-10 and 28-29), wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC (instant claim 1), wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least I0-fold lower than an unconjugated NKG2DL targeting agent (instant claim 4), wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer (instant claim 5), wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent (instant claim 19).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-7, 9-15, 19, 23-29, 30-31, 33-35, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 21-34 of copending Application No. 17/725,544 in view of WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.) and Lian S et al. (Scientific Reports 2019 9 4532).
The claims of copending ‘544 patent in view of ‘688 and ‘931 teach the limitations of claims 1-2, 4-7, 9-13, 15, 19, 23-29, 30-31, 33-35, and 38 for the reasons set forth above.
‘544, ‘688 and ‘931 are described above.
‘544 does not teach further including an additional therapy of immune checkpoint therapy and CD47 blockade, but this is obvious in view of Lian.
Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone (abstract). Lian taught melanoma cells expressed PD-L1 and CD47 (Fig. 1). Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone (Fig. 3).
Regarding instant claims 13-15, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘544, ‘688, ‘931, Li, and Quesenberry above – by:
further including an additional therapy of administering a therapeutically effective amount of an immune checkpoint therapy of a PD-L1 antibody inhibitor, and a therapeutically effective amount of CD47 blockade of a CD47 antibody inhibitor in view of Lian.
This is obvious because:
1a) Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone.
1b) Lian taught melanoma cells expressed PD-L1 and CD47;
1c) Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone.
There is a reasonable expectation of success because:
1a) Lian taught simultaneously blocking CD274 (PD-L1) and CD47 checkpoints which were respectively signals of “don’t find me” and “don’t eat me” on circulating tumor cells by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone.
1b) Lian taught melanoma cells expressed PD-L1 and CD47;
1c) Lian taught an effective method of treating a subject with a cancer that expressed PD-L1 and CD47 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an anti-PD-L1 blocking antibody, and an anti-CD47 blocking antibody which was more effective than only an anti-PD-L1 blocking antibody or an anti-CD47 blocking antibody alone.
This would produce a method of treating a human subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a single dose or a dose every 28 days of a humanized NKG2DL targeting agent of an anti-MICA antibody of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA, wherein DOTA is the a radiochelating agent p-SCN-Bn-DOTA, wherein the therapeutically effective dose is between 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least I0-fold lower than an unconjugated NKG2DL targeting agent, wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer, wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent, wherein the method further includes an additional therapy of administering a therapeutically effective amount of an immune checkpoint therapy of a PD-L1 antibody inhibitor, and a therapeutically effective amount of CD47 blockade of a CD47 antibody inhibitor (instant claims 13-15).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-7, 9-13, 15, 19-20, 23-29, 30-31, 33-35, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 21-34 of copending Application No. 17/725,544 in view of WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.) and Yoon JK et al. (Int J Mol Sci 2020 21(12):4309. doi: 10.3390/ijms21124309).
The claims of copending ‘544 patent in view of ‘688 and ‘931 teach the limitations of claims 1-2, 4-7, 9-13, 15, 19, 23-29, 30-31, 33-35, and 38 for the reasons set forth above.
‘544, ‘688 and ‘931 are described above.
‘544 does not teach diagnosing MISA positive cancer with a radioconjugate comprising administering a MISA antibody with an 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging but this is obvious in view of Yoon.
Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr (t1/2 = 3.3 days) is favorable for evaluating the in vivo distribution of monoclonal antibodies (abstract). Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days (page 4, paragraph 3). Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors (page 4, paragraph 3). Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans (page 4, paragraph 3).
Regarding instant claim 20, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘544, ‘688, ‘931, Li, and Quesenberry above – by:
1) exchanging the 89Zr-trastuzumab with 89Zr-humanized 7C6 to detect MISA in view of Yoon; and
2) further including diagnosing MISA positive cancer with a radioconjugate comprising administering a MISA antibody with an 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging in view of Yoon.
This is obvious because:
1) 89Zr-humanized 7C6 would allow detection of MISA in tumors to ensure therapeutic success;
2a) Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr (t1/2 = 3.3 days) is favorable for evaluating the in vivo distribution of monoclonal antibodies.
2b) Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days
2c) Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors.
2d) Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans
There is a reasonable expectation of success because:
1) 89Zr-humanized 7C6 would allow detection of MISA in tumors to ensure therapeutic success;
2a) Yoon taught 89Zr is an emerging radionuclide that plays an essential role in immuno-positron emission tomography (PET) imaging, wherein the long half-life of 89Zr (t1/2 = 3.3 days) is favorable for evaluating the in vivo distribution of monoclonal antibodies.
2b) Yoon taught the optimal time interval between the intravenous injection of 89Zr-trastuzumab and PET imaging for a high tumor to background contrast is 4–8 days
2c) Yoon taught 89Zr-trastuzumab can detect most metastatic sites (liver and bone) in patients with HER2-positive breast cancer as well as unsuspected HER2-positive metastatic sites even in patients with HER2-negative primary breast cancer, indicating the heterogeneity of the tumors.
2d) Yoon taught evaluating the HER2 status of tumors is crucial for clinical decision making for patients planning anti-HER2 therapy, wherein a whole body evaluation of HER2 expression with 89Zr-trastuzumab PET is helpful, particularly when a tumor biopsy is unfeasible, and wherein the imaging results for HER2 expression may support or change the treatment plans
This would produce a method of treating a human subject with a solid melanoma skin cancer comprising administering a therapeutic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a single dose or a dose every 28 days of a humanized NKG2DL targeting agent of an anti-MICA antibody of 225Ac-DOTA-7C6, wherein 7C6 binds the α3 domain of MICA, wherein DOTA is the a radiochelating agent p-SCN-Bn-DOTA, wherein the therapeutically effective dose is between 0.01 mg/kg to 1 mg/kg of antibody and about 1 or 5 µCi/kg, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is an amount effective to deplete or ablate NKG2DL-positive solid cancer independent of depletion or ablation mediated by ADCC, wherein the therapeutically effective amount of the radioconjugated NKG2DL targeting agent is naturally an amount at least IO-fold lower than an unconjugated NKG2DL targeting agent, wherein the cancer comprises a solid tumor and the therapeutically effective amount of the radioisotope labeled NKG2DL targeting agent above is naturally an amount effective to increase expression of NKG2DL on solid cancer, wherein before administering the therapeutically effective amount of the radioconjugated MICA antibody diagnosing the subject with MICA-positive cells; and if the subject has MICA-positive cells, proceeding with administering to the subject the therapeutically effective amount of a MICA targeting agent, wherein diagnosing MISA positive cancer further comprises administering the humanized 7C6 MISA antibody with a 89Zr radiolabel, waiting a period of time for the tumor tissue to accumulate the antibody with the radiolabel, and detect the MISA positive cancer cells with PET imaging (instant claim 20).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-13, 15, 19-20, 23-29, 30-31, 33-35, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 21-34 of copending Application No. 17/725,544 in view of WO 2018/217688 (FERRARI DE ANDRADE L et al.), WO 2019/094931 (SANDESH S et al.) and Godbersen C et al. (Mol Cancer Ther 2017 16(7):1335–1346).
The claims of copending ‘544 patent in view of ‘688 and ‘931 teach the limitations of claims 1-2, 4-7, 9-13, 15, 19, 23-29, 30-31, 33-35, and 38 for the reasons set forth above.
‘544, ‘688 and ‘931 are described above.
‘544 does not teach a soluble NKG2DL receptor as the targeting agent, but this is obvious in view of Godbersen
Godbersen taught compositions of: 1) huNKG2D-OKT3 comprising the extracellular portion of the human NKG2D receptor fused to a CD3ε binding scFv, known as OKT3; and 2) B2-OKT3 comprising a scFv that targets MICA on tumor cells and CD3ε on human T cells (abstract), wherein huNKG2D-OKT3 and B2-OKT3 increase targeting to melanoma cancer cells compared to a non-targeted OKT3 control (Fig. 1F), and wherein the huNKG2D-OKT3 and B2-OKT3 are effective at activating T cells against human melanoma tumor cell samples (Fig. 5).
Regarding instant claim 8, it would have been obvious for a person having ordinary skill in the art to modify the effective method of ‘544, ‘688, ‘931, Li, and Quesenberry above – by:
1) exchanging the humanized anti-MICA antibody of 225Ac-DOTA-7C6 for a soluble recombinant human NKG2D receptor comprising the extracellular portion of the human NKG2D receptor in view of Godbersen.
This is obvious with a reasonable expectation of success because:
1) Godbersen taught compositions of a: 1) huNKG2D-OKT3 fusion comprising the extracellular portion of the human NKG2D receptor; and 2) B2-OKT3 comprising a scFv that targets MICA on tumor cells were both effective at targeting cancer cells with either a human NKG2D receptor or an antibody to MICA for cancer cell death. Thus, a soluble human recombinant NKG2D receptor fusion conjugate would be obvious with a reasonable expectation of success to effectively target NKG2G ligand expressing cancer cells with other cancer killing agents such as 225Ac.
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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