DETAILED ACTION
The amendment filed on 04/27/2026 has been entered and fully considered. Claim 6 is canceled. Claims 1-5 and 7-15 are pending, of which claim 1, 8 and 15 are amended.
Response to Amendment
In response to amendment, the examiner modifies rejection over the prior art established in the previous Office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Claim(s) 1-5, 7-8 and 10-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ciavardelli et al. (Rapid Communications in Mass Spectrometry, 2007) (Ciavardelli).
Regarding claim 1, Ciavardelli teaches a method for labeling an agent, wherein the agent is an antibody fragment (abstract). Ciavardelli teaches that monoclonal antibody radiopharmaceuticals can be constructed from antibodies and that smaller engineered mAb-based molecules/fragments can be labeled with the same chemical approach (abstract). Ciavardelli further discloses a stable isotope labeled Fab dimer as a model.
Ciavardelli teaches labeling antibody-based drugs with the stable isotope of yttrium, 89Y, for evaluating pharmacokinetic profiles by ICP-MS (page 2345, par 1).
Ciavardelli teaches using p-SCN-Bz-DOTA, i.e., a DOTA chelating agent having an isothiocyanate reactive group, and preparing a Bz-DOTA-conjugated Fab′2 antibody fragment by incubating Fab′2 with p-SCN-Bz-DOTA (page 2344, par 7). Ciavardelli further teaches reacting the Bz-DOTA-Fab′2 solution with 89YCl3 to obtain 89Y-Bz-DOTA-Fab′2 (page 2345, par 1). Thus, Ciavardelli teaches a chelating agent having a reactive group, a non-radioactive metal substance, and an antibody labeled with the metal-chelator complex for pharmacokinetic evaluation.
Ciavardelli does not expressly teach performing the steps in the claimed order, namely first chelating the non-radioactive substance with the chelating agent and then binding the chelated chelating agent to the antibody via the reactive group. However, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify Ciavardelli by first chelating 89Y with p-SCN-Bz-DOTA and then reacting the isothiocyanate reactive group with the antibody fragment, because Ciavardelli teaches that the same final labeled antibody complex, 89Y-Bz-DOTA-Fab′2, is useful for radioactive-free pharmacokinetic evaluation. The modification merely reverses the order of two known labeling operations—metal chelation by DOTA and antibody conjugation through the reactive isothiocyanate group—to obtain the same predictable labeled antibody product.
One of ordinary skill in the art would have had a reasonable expectation of success because Ciavardelli teaches that DOTA-bearing antibody fragments form stable yttrium-labeled antibody complexes and that the detected yttrium was effectively bound to Bz-DOTA-Fab′2. The motivation for the modification would have been to provide the same stable-isotope labeled antibody complex for evaluating pharmacokinetics while using the known reactivity of p-SCN-Bz-DOTA to bind the chelator to the antibody.
Regarding claim 2, Ciavardelli teaches that wherein the non-radioactive substance is a metal (page 2345, par 1).
Regarding claim 3, Ciavardelli teaches that wherein the non-radioactive substance is yttrium (page 2345, par 1).
Regarding claim 4, Ciavardelli teaches that wherein the chelating agent (DOTA) having a reactive group is a chelating agent having an amino group or a carboxyl group as a coordinating group (page 2345, par 1). Ciavardelli discloses that the chelating agent is p-SCN-Bz-DOTA. DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid and contains carboxyl groups as coordinating groups. Ciavardelli expressly identifies p-SCN-Bz-DOTA as “2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid tetrachloride salt.” (page 2344, par 3).
Regarding claim 5, Ciavardelli teaches that wherein the chelating agent having a reactive group is a chelating agent having a reactive group introduced into any compound selected from DOTA (page 2345, par 1).
Regarding claim 7, Ciavardelli teaches that wherein the reactive group is a group capable of forming a chemical bond by reacting with an amino group or a thiol group (page 2344, par 7). Ciavardelli teaches that the reactive group is an isothiocyanate group. Ciavardelli identifies the chelating agent as “2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid tetrachloride salt (p-SCN-Bz-DOTA)” (page 2344, par 3) and discloses incubating Fab′2 with p-SCN-Bz-DOTA to prepare Bz-DOTA-Fab′2 (page 2344, par 7). The isothiocyanate reactive group is capable of forming a chemical bond by reacting with an amino group of the antibody fragment.
Regarding claim 8, Ciavardelli teaches a method for measuring the
pharmacokinetics of an antibody-based agent labeled with a non-radioactive substance. Ciavardelli teaches labeling an antibody fragment with stable isotope 89Y to form 89Y-Bz-DOTA-Fab′2, administering the labeled antibody fragment to mice (page 2345, par 3), collecting urine samples after administration (page 2345, par 3), and measuring the yttrium content in the urine by ICP-MS (page 2346, par 1).
Specifically, Ciavardelli discloses that two groups of five female mice were injected via the tail vein with 89Y-Bz-DOTA-Fab′2 solution and that urine samples were collected during 0-24, 24-48, and 48-72 hour intervals after administration (page 2345, par 3). Ciavardelli further discloses measuring yttrium in urine by ICP-MS to evaluate urinary clearance (page 2349, par 1). Therefore, Ciavardelli teaches labeling the antibody agent with a non-radioactive substance, administering the labeled antibody to a non-human animal, collecting a biological sample after administration, and measuring the content of the non-radioactive substance in the biological sample.
Regarding claim 10, Ciavardelli teaches that wherein the content of the nonradioactive substance is measured by mass spectrometry (page 2346, par 1).
Regarding claim 11-12, Ciavardelli teaches that wherein the mass spectrometry is plasma ionization mass spectrometry (page 2344, par 1)
Regarding claim 13, Ciavardelli teaches that wherein the non-human animal is a monkey, miniature pig, rat, mouse, rabbit, dog, or guinea pig (page 2345, par 3).
Regarding claim 14, Ciavardelli teaches that wherein the administration of the agent in step (ii) is intravenous administration (i.v.) (page 2345, par 3).
Claim(s) 9 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ciavardelli et al. (Rapid Communications in Mass Spectrometry, 2007) (Ciavardelli) in view of Boros et al. (EJNMMI Radiopharmacy and Chemistry, 2018,IDS) (Boro).
Regarding claim 9, Ciavardelli teaches measuring pharmacokinetics of a stable-isotope labeled antibody fragment by administering 89Y-Bz-DOTA-Fab′2 to mice and collecting urine samples after administration. Ciavardelli teaches that the method avoids radioactivity and allows pharmacokinetic evaluation using ICP-MS detection of the non-radioactive metal label.
Ciavardelli does not expressly teach labeling two or more agents with different non-radioactive substances and administering the two or more labeled agents to a single non-human animal.
However, Boros teaches the use of HPLC-ICP-MS for simultaneous in vivo characterization of imaging probes labeled with different non-radioactive metals, such as stable Ga and stable In, so that multiple probes can be tracked in the same biological experiment (abstract). It would have been obvious to one of ordinary skill in the art to modify Ciavardelli’s stable-isotope ICP-MS pharmacokinetic method by labeling two or more antibody agents with different non-radioactive metals and administering them to a single non-human animal, as taught by Boros, because ICP-MS can distinguish different elemental labels and thereby allows multiplex pharmacokinetic comparison while reducing animal-to-animal variability and reducing the number of animals required.
Regarding claim 15, Ciavardelli teaches measuring pharmacokinetics of an antibody agent by administering a stable-isotope labeled antibody fragment, 89Y-Bz-DOTA-Fab′2, to mice, collecting urine samples (page 2345, par 3), and measuring 89Y content by ICP-MS (page 2346, par 1). Ciavardelli teaches that this method is useful for evaluating pharmacokinetic profiles and urinary clearance of antibody-based drugs (page 2349, par 1).
Ciavardelli does not expressly teach screening two or more candidate antibody agents by comparing their measured pharmacokinetics and selecting an antibody exhibiting desired pharmacokinetics.
However, it would have been obvious to one of ordinary skill in the art to apply Ciavardelli’s stable-isotope ICP-MS pharmacokinetic measurement method to two or more candidate antibody agents and compare their pharmacokinetic profiles to select an antibody having desired pharmacokinetics. Ciavardelli expressly teaches that the method is suitable for evaluating pharmacokinetic profiles of antibody-based drugs and avoids radiation hazards and radioactive waste disposal (abstract). One of ordinary skill in the art would have been motivated to use such a radioactive-free pharmacokinetic assay as a screening tool for antibody candidates because pharmacokinetic behavior, including urinary clearance, was a known selection criterion for antibody-based drugs, and comparing candidates would predictably identify the candidate having the desired pharmacokinetic profile.
To the extent further support is needed for comparing multiple labeled agents in a single pharmacokinetic experiment, Boros teaches using HPLC-ICP-MS with stable isotope labels to characterize imaging probes in vivo and to distinguish different elemental labels (abstract). It would have been obvious to combine Boros’s multiplex stable-isotope ICP-MS approach with Ciavardelli’s antibody-based pharmacokinetic method so that multiple candidate antibodies could be labeled with different non-radioactive metals, administered, measured, compared, and selected based on desired pharmacokinetics.
Response to Arguments
Applicant’s arguments with respect to claim(s) claim 1 have been considered but are moot in view of new ground of rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./Primary Examiner, Art Unit 1797
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