DETAILED ACTION
This Office action details a first action on the merits for the above referenced application No. Claims 1-2, 5, 8-14, 16, 18-19, 22, 24-26, 30, and 32-33 are pending in this application.
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 .
Priority
This application is a 35 USC 371 National Stage filing of international application No. PCT/US2022/042257 filed on 31 Aug. 2022, and clams benefit to US provisional application Nos. 63/279,355 and 63/239,463 filed on 15 Nov. 2021 and 1 Sep. 2021, respectively.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 28 Feb. 2024 has been considered by the examiner.
Claim Objections
Claims 1, 5, 18, 24, and 32 are objected to because of the following informalities: in claim 1, a “(I)” should be placed under the first formula of the claim; in claims 5 and 32, the “and/or R2” should be “and R2”; in claim 18 each instance of “protein/peptide” should be “protein or peptide”; and in claim 24, just before the period, “the peptide” should be “the protein or the peptide”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19 and 25 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 19, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 25, the recitation of “the compound” is indefinite because it is not clear what compound is being referred to. The Examiner suggests replacing “the compound” with “the compound (II)”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-2, 5, 8-10, 12-14, 16, 18-19, 22, 24-26, 30, and 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zeglis et al. (WO 2018/213537 A1; published 22 Nov. 2018; see attached 892), in view of Zalutsky et al. (WO 2018/178936 A1; published 4 Oct. 2018; see attached 892).
Zeglis et al. teach reagent for site-selective bioconjugation of proteins or antibodies (see title). Zeglis et a. teach a method comprising steps of: exposing a label to a substrate that comprises a cysteine residue wherein the label comprises
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wherein R is a chelator or click chemistry synthon ([0014]). Zeglis et al. teach a composition of matter comprising PODS
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([0015]).
(PODS reads in part on structure (I)
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wherein R1=Me; a=c=2; b=3; and L1=H.)
Zeglis et al. teach a scheme depicting the reaction of PODS with model thiol
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(Fig. 2). Zeglis et al. teach Zr-DFO-mal
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and Lu-CHX-A’’-DTPA-mal (pg. 13). Zeglis et al. teach Michael addition of a thiol bearing biomolecule on a radionuclide bearing maleimide (Fig 1). PODS can be appended by numerous cargos through its terminal primary amine, allowing conjugation of the cargo to the biomolecule ([0032]). Radioimmunoconjugates created using these novel bifunctional chelators displayed higher in vitro stability than their maleimide-derived cousins ([0031]). Zeglis et al. teach conjugation to a model antibody trastuzumab (tumor targeting antibody for HER2 positive breast cancer) ([0037]). PODS displayed rapid and selective reactivity with thiols and was successfully used to site specifically modify a model antibody with a fluorophore. PODS-DFO and PODS-CHX-A’’-DTPA were successfully used for site specific modification and radiolabeling of trastuzumab. 89Zr-DFO-PODS-huA33 was revealed to be superior especially for imaging and long delay (>48 h p.i.). The use of PODS could make a significant difference in human patient imaging. ([0055]). The PODS based reagent holds equal promise for the site-specific modification of cysteine-bearing antibody fragments, peptides and proteins as well ([0056]).
Zeglis et al. do not teach a compound of the claimed structures (I), (II), (III) or a radiolabeled protein or peptide such as a tumor targeting antibody of formulas (V), and (VI) comprising the fragments
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,
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, and
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wherein X is SnR3, B(OH)2, or a radiohalogen such as 211At or a method of performing imaging or treating cancer in a subject comprising administering the protein or peptide of claim 9. Zeglis et al. do not teach a method of labeling a protein or peptide with a radiohalogen comprising reacting the compound (II) with a protein or the peptide such as an antibody. Zeglis et al. do not further teach a compound of the formula (III) comprising a CGG tail or a method of labeling further comprising removing the carbamate protecting groups from the compound prior to reacting the compound with the protein/peptide and modifying the protein/peptide by adding C-terminal CGG tail to the protein/peptide wherein the compound reacts to form a thioether bond between the compound (II) and the protein
Zalutsky et al. teach radiolabeled biomolecules and their use (see title). Zalutsky et a. teach prosthetic compounds that are effective for radiolabeling. Biomolecules include antibodies, peptides, and other proteins (pg. 2). Zalutsky et al. teach a scheme for synthesis of four radiohalogenated 5F7 VHH conjugate
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. Labeling 5F7 was accomplished by reaction with iso-[211At]SAGMB which were obtained by treatment with Boc2-iso-[211At]SAGMB with TFA. (pg. 41). Significantly higher binding affinity was observed for iso-[211At]SAGMB-5F7. Changing the nature of the prosthetic agent did not affect residualization of radioactivity in HER2-positive cancer cells (pg. 2). Tumor accumulation of iso-[211At]SAGMB-5f7 was almost 50% higher. Normal tissue uptake was low, particularly for iso-[211At]SAGMB-5F7 and iso-[131I]SGMIB-5f7 (pgs. 42-43). The excellent results obtained with anti-HER2 VHH SGMIB conjugate provided motivation for evaluating the potential utility of guanidinomethyl substituted prosthetic groups for labeling 5F7 VHH with 211At (pg. 44). Zalutsky et al. teach a GGC tail and 5F7-GGC (pgs. 38, 44-45, 47). It was demonstrated that the anti-HER2 5F7 VNN can be labeled with 211At in reasonable yields with excellent retention of affinity and immunoreactivity after labeling (pg. 48). Zalutsky et al. teach diagnostic imaging methods including PET using radionuclides such as 75Br, 76Br, 124I and the like and SPECT using radiohalogens such as 123I, 131I, and 76Br and the like (pg. 18).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Zeglis et al. (PODS and peptide or protein conjugated PODS such as trastuzumab conjugated PODS and other proteins comprising cysteine) by attaching iso-[211At]SAGMB/iso-[125/131I]SGMIB or a Me3Sn precursor thereof to the amine of PODS’s amino-PEG moiety to arrive at a compounds having instant structures (I) and (V) wherein L1=C(O),; Y=CH; X=SnMe3, 124/125/131I, 211At, L2=-(CH2)1-; and G=guanidine (protected carbamate) as taught by Zeglis et al. and Zalutsky et al. because the those prosthetic group modified PODS derivatives including antibody/peptide conjugated derivatives would have been expected to advantageously enable radiohalogen alpha/beta therapy or diagnostic PET/SPECT imaging using conjugates expected to have high stability and high tumor to non-target tissue ratios. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compounds of Zeglis et al. so the that the proteins further comprise a CGG tail that reacts with PODS derivative to form a compound of formula (VIII) as taught by Zeglis et al. and Zalutsky et al. because the CGG tail would have been expected to advantageously enable site selective conjugation of the protein to the PODS derivative owing to the cysteine group.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zeglis et al. by further performing molecular imaging in a subject comprising administering to the subject an effective amount of the obvious radiohalogenated peptide/protein/antibody to detect cancer cells such as breast cancer cells as taught by Zeglis et al. and Zalutsky et al. the imaging would have been expected to advantageously enable non-invasive in vivo PET/SPECT imaging and optional detection of cancer cells.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Zeglis et al. by further treating cancer in a subject comprising administering to the subject an effective amount of the obvious radiolabeled protein or peptide as taught by Zeglis et al. and Zalutsky et al. because it would have been expected to advantageously enable in vivo alpha-/beta- therapy of cancer cells using conjugates expected to have high in vivo stability and high tumor to non-target ratios.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zeglis et al. by further labeling a protein/antibody with a radiohalogen comprising (i) obtaining the obvious prosthetic group modified PODS having structure (II) and when R3 is H, reacting the obvious compound (II) with the protein/antibody or when R3 is carbamate protecting group reacting the compound (II) with protein/antibody.
It would have been obvious to a person of ordinary skill in the art before the effective filing to further modify the labeling method of Zeglis et al. by further removing carbamate protecting groups from the compound prior to reacting the obvious compound (II) with the protein or peptide and modifying the protein or peptide by adding a C-terminal GGC tail to the protein or peptide wherein the compound reacts with the cysteine of the GGC tail to form a thioether bond between the compound (II) and the protein or peptide as taught by Zeglis et al. and Zalutsky et al. because Zeglis et al. teach as PODS thiol selective labeling and because adding a C-terminal GGC tail and reacting the obvious compound with the C of the GGC tail to for a thioether bond would have been expected to advantageously enable site selective conjugation of the protein to the PODS derivative owing to the cysteine group.
Claim(s) 1-2, 5, 8-14, 16, 18-19, 22, 24-26, 30, and 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zeglis et al. (WO 2018/213537 A1; published 22 Nov. 2018; see attached 892), in view of Zalutsky et al. (WO 2018/178936 A1; published 4 Oct. 2018; see attached 892), in further view of Wu et al. (CN 1733721 A- English translation; published 2006; see attached 892).
Zeglis et al. teach as discussed above.
Zeglis et al. do not further teach a radiolabeled protein or peptide of formula (VII) and comprising further comprising the Mal linking group.
Zalutsky et al. teach as discussed above.
Wu et al. teach maleimide derivatives and its preparation method and uses (see title). Wu et al. teach biotechnology field and field of medicaments (pg. 2). Wu et al. claim maleimide derivatives of formula I
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wherein X=NH or S and M is an alkylene between 2-18 carbons (claim 1) and its preparation method (pg. 3). The PEG amine or PEG sulfur alcohol are heated to 40oC-80oC in chloroform or methylene chloride and the reaction products are obtained (pg. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zeglis et al. so that the amino ethyl maleimide linker connects to the amino PEG of the PODS and the obvious prosthetic group to arrive at the compound of instant formula (VIII) as taught by Zeglis et al. and Wu et al. because the Mal linker would have been expected to enable easy connection to an amino PEG by heat in solvent and because the Mal linker would have been to provide an equivalent linker enabling attachment to the obvious prosthetic group by amide conjugation.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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