DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 16-34 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 Apr. 2026 has been entered.
Status of Claims
Claims 1-15 are cancelled. Claims 16, 19-26, and 29-32 are amended.
Response to Amendment
The amendments filed on 17 Apr. 2026 have been entered.
Response to Arguments
The rejection of claims 16-34 under 35 USC 103 as being unpatentable over Blower et al. (US 11,826,436 B2; filed 10 Mar. 2015), in view of Eder et al. (Bioconjugate Chem.; published 2012) is withdrawn.
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.
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.
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) 16-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ebenhann et al. (Molecules; published 2015), in view of Blower et al. (WO 2016/142702 A1; published 15 Sep. 2016) and Garcia-Arguello et al. (J. Label. Compd Radiopharm.; published 5 Feb. 2019) for the reasons cited in the Office action filed on 18 Dec. 2025.
Applicants Arguments
Applicants assert that the labeling method disclosed by Ebenhan comprises a purification step on a C18 column in the present of ethanol. The presently claimed method does not contain a purification step of the radiolabeled PSMA binding ligand let alone a purification step using a C18 solid phase extraction method. The presently claimed invention excludes the use of ethanol. Blower does not remedy the defects of Ebenhan. Blower do not teach a radiolabeling method using a powder comprising sodium chloride wherein sodium chloride is present to allow freeze drying the components of the powder under extreme conditions without affecting their properties. In the presently claimed method, the radiolabeling of the PSMA binding ligand of formula (I) is carried out in the presence of gentisic acid as stabilizer against radiolytic degradation. The presently claimed invention excludes ascorbic acid. Garcia-Arguello discusses the Mueller method and teaches that sodium chloride a pH lower than 3 should be sufficient to keep Ga3+ soluble in water and to avoid the formation of insoluble Ga(OH)3, so our aim was to study the efficiencies of mixtures of 5 M NaCl and diluted HCl with different pH for the elution of gallium-68 from the cation-exchange cartridge. Garcia-Arguello does not teach anything about the use of sodium chloride in the powder comprising the PSMA binding ligand of formula (I) to which the aqueous solution of the radioactive isotope in HCl is intended to be added to carry out the radiolabeling.
Applicant's arguments filed 17 Apr. 2026 have been fully considered but they are not persuasive. At pg. 14872, Ebenhan provides for a kit vial and power for solution for injection wherein the powder is obtained by freeze-drying and comprises a PSMA ligand of formula (I) and sodium acetate as a buffering agent. Ebenhan teaches a true one-step labeling approach followed by supplementing the kit vial with 1.5 mL of 2.5 M sodium acetate trihydrate and 3 mL of saline to yield a physiological pH. At pg. 14864, Ebenhan teaches voiding a purification step. At pg. 14864, Ebenhan teaches that 5 nmol DKFZ-PSMA-11 was buffered with sodium acetate. After supplementing 1.0 ml 68Ga (0.6 N HCl) to the kit vial, the pellet dissolved rapidly. Ebenhan differs from base claims 16, 23 and 29 as amended only because Ebenhan does not teach a kit vial further containing sodium chloride and gentisic acid as a stabilizer against radiolytic degradation. Regarding the sodium chloride, at pgs. 9 and 19, Blower teaches sodium chloride as suitable pharmaceutical buffer and tonify agent. Since Ebenhan teaches voiding the purification step, a person of ordinary skill in the art would have had reason and motivation to supplement the kit vials of Ebenhan with sodium chloride without adversely affecting the pH of the radiolabeling reaction. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method, kit and powder of Ebenhan to include sodium chloride because sodium chloride would have been expected to provide a suitable pharmaceutically acceptable buffer and tonifying agent capable of maintaining tonicity when using a method that voids a purification step. Although Garcia-Arguello teaches the use of NaCl in the context of keeping Ga3+ soluble in water of an eluent, a person of ordinary skill in the art would have nonetheless understood Garcia-Arguello to teach that NaCl aids in solubilizing Ga3+ and avoiding the formation of Ga(OH)3. It would have been further obvious to a person of ordinary skill in the art before the effective filing date to modify Ebenhan to include sodium chloride as pharmaceutically acceptable buffer in the reaction vial because the sodium chloride would have been expected aid in solubilizing 68Ga under reaction conditions. Regarding gentisic acid, Blower teaches gentisic acid as one of two stabilizing agents for stabilizing against radiolytic degradation. Although Garcia-Arguello uses ascorbic acid, a person of ordinary skill in the art would have understood from Blower that gentisic acid is just as good for stabilizing against radiolytic degradation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Ebenhan by further including gentisic acid in the kit formulation as taught by Blower et al. because the gentisic acid would have been expected to advantageously enable stabilization against radiolytic degradation.
Regarding the amended amounts of the PSMA binding ligand of formula (I), sodium chloride, sodium acetate, and gentisic acid, the amended amounts are result effective variables that a person of ordinary skill in the art would have arrived at through routine experimentation. MPEP 2144.05.II.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 16-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Blower et al. (US 11,826,436 B2; filed 10 Mar. 2015), in view of Eder et al. (Pharmaceuticals; published 2014).
Blower et al. claim a method for preparing a complex comprising a radioisotope of gallium, the method comprising adding HCl gallium radioisotope eluate from a 68Ga radionuclide generator without additional preparation purification or concentration steps to a chelator composition wherein the chelator composition comprises an acetate buffer sufficient to increase the pH to a level in the range of 3 to 8, DKFZ-PSMA-11 being a chelator able to chelate radioactive gallium in the pH range and at a temperature of 10-30oC, and gentisic acid wherein the composition is in freeze-dried (dry) form, the gallium radioisotope solution is added directly to the dry chelator composition (claim 1).
(reads on a powder for a solution for injection the powder obtained by freeze drying comprising i) a PSMA ligand do instant formula (I), ii) sodium acetate as buffering agent; and iii) gentisic acid as a stabilizer against radiolytic degradation wherein the powder does not contain ascorbic acid or ethanol; wherein the powder does not contain bulking agents such as mannitol.
In addition this reads on a method of for labeling a PSMA ligand of instant formula (I) with 68Ga, the method comprising (i) providing a single vial comprising a powder in dried form obtained by freeze drying and comprising the PSMA binding ligand of formula (I), acetate and gentisic acid as a stabilizer against radiolytic degradation wherein the vial does not contain ascorbic acid or ethanol; (ii) adding a 0.1 M HCl solution of the 68Ga into the vial, thereby obtaining a solution of said PSMA ligand of formula (I) with the 68Ga; (iii) mixing the solution obtained in (ii) and incubating it for a sufficient period of time for obtaining the 68Ga-labeled compound of formula (I) and wherein the vial does not contain a bulking agent such as mannitol and the sodium acetate is suitable for maintaining a pH from 3 to 6 at the incubating step.)
Blower et al. teach the DKFZ-PSMA-11 taught by Eder et a. (Bioconjugate Chem.; 2012, 688). Suitable buffers and/or tonifying agents include sodium chloride and sodium acetate (cols. 6, 18). By combining a chelator of this type with alkaline salt and buffer, the composition may be used directly with gallium solutions having a range of pHs (col. 5). The invention provides a kit, the kit comprising a pharmaceutically acceptable buffer and a chelator that is able to chelated radiogallium in the range of 3-8 and at moderate temperature. The components of the kit are in freeze dried form (col. 18). The invention provides for cold kits for use in a range of clinical situations where 68Ga us utilized. Physiologically acceptable products may be generated rapidly and easily (col. 20). The amount of chelator is from 0.1-10 µmol or 10-100 µM (col. 6). The buffer is present in the dry composition from 5 to 95 mol percent (col. 6).
Blower et al. do not claim the claimed powder or kit thereof comprising sodium chloride optionally in an amount between 10 mg and 100 mg, 30 and 5 mg, or 40 mg or claim sodium acetate optionally in an amount between 20 mg and 80 mg, 42 mg and 52 mg, or 57 mg. Blower et al. do not claim an amount of PSMA ligand of formula (I) between 5 µg and 60 µg, 10 µg and 40 µg, or 15 µg or claim an amount of gentisic acid between 0.5 mg and 2 mg, 0.8 mg and 1.2 mg and 1 mg. Blower et al. do not claim the claimed method for labeling wherein the single vial contains the claimed powders comprising sodium acetate as the buffering agent and sodium chloride.
Eder et al. teach a novel preclinical and radiopharmaceutical aspect of [68Ga]Ga-PSMA-HBED-CC (see title). Eder et al. teach that by combining HBED-CC with the PSMA inhibitor Glu-urea-Lys, a favorable aromatic part is introduced into the radiotracer which was found to be necessary requirement for a sustainable interaction with PSMA receptor. HBED-CC represents a high effective chelator. Extraordinary high thermodynamic stability constants of >1039 were determined for the complexation of Ga with HBED which allows for fast labeling at ambient temperature (pg. 780). Disposable cassette kits and chemicals including the precursor PSMA-HBED-CC (DKFZ-PSMA-11) in GMP-compliant grade was used for the radiosynthesis (pg. 783). 1.9 µg of PSMA-HBED-CC was dissolved in a mixture of 1.5 M acetate buffer and 1 M ascorbic acid as the mixture was transferred to a reaction vessel. The 68Ga-generator was eluted with 10 µL of 0.6 M HCl and the mixture was transferred to a cation exchange cartridge and eluted with 5 M NaCl solution into the reaction vessel. The reaction was heated for 10 min (pg. 784). HBED-CC complexes [68Ga]Ga3+ more efficiently at low concentrations and low temperatures. Labeling of HBEB-CC was effective at pH values between 3.5 and 5 (pg. 785). Eder et al. teach 67Ga (pg. 785). Eder et al. used different sodium acetate solutions (pH 3.2-5.5) in concentrations ranging from 20 mM to 1.5 M. The optimal reaction conditions with average radiochemical yield of 80% were found using 1 mL or 1.5 M sodium acetate buffer solution with a pH of the reaction mixture ranging from 3.6 to 4.2. Although the 68Ga-eluat was purified and concentrated using 5 M NaCl solution, sodium acetate buffer solution with volumes smaller than 1 mL were not able to stabilize the pH of reaction mixture sufficiently (pgs. 790-791).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Blower et al. (powder composition comprising DFKZ-PSMA-11 (instant formula I), acetate buffer, and gentisic acid as a stabilizer against radiolytic degradation wherein the powder does not contain ascorbic acid or ethanol or any bulking agent such as mannitol) by forming a kit comprising the powder in single vial and so that the powder further comprises sodium chloride as taught by Blower et al. because that kit would have been expected to enable facile radiolabeling and because the sodium chloride would have been expected to provide a suitable buffer or tonifying agent expected to assist in solubilizing 68Ga under labeling conditions. It would have been obvious to further modify the compositions of Blower et al. so that the acetate buffer is a sodium acetate buffer as taught by Blower et al. and Eder et al. because the sodium acetate buffer would have been expected to advantageously enable a suitable pH range for 68Ga labeling in high radiochemical yield.
The amounts of the PSMA binding ligand of formula (I), sodium chloride, sodium acetate, and gentisic acid are result effective variables that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at an amount of PSMA binding ligand of formula I that is between 5 µg and 60 µg, 10 µg and 40 µg, 15 µg and 30 µg or is 15 µg through routine experimentation in order to arrive at an optimal amount of precursor ligand that provides an optimal RCY and specific activity under labeling conditions. A person of ordinary skill in the art would have arrived at an amount of sodium chloride that is between 10 mg and 100 mg, 30 and 50 mg or about 40 mg through routine experimentation in order to arrive at an optimal amount of buffer and solubilizing agent capable of providing an optimal RCY and/or enable optimal tonicity in the case where elaborate separation is not required owing the high RCY. A person of ordinary skill in the art would have arrived at an amount of sodium acetate that is between 20 mg and 80 mg, 42 mg and 52 mg, or is about 47 mg through routine experimentation in order to arrive at an optimal amount of buffering agent suitable for maintaining an optimal pH value. A person of ordinary skill in the art would have arrived at an amount of gentisic acid that is between about 0.5 mg and 2 mg, 0.8 mg and 1.2 mg, or is about 1 mg through routine experimentation in order to arrive at optimal amount of stabilizing agent.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Blower et al. so that the method for labeling provides the powder obtained by freeze-drying made obvious by Blower et al. and Eder et al. in a single vial and adds an aqueous solution of radioisotope such as 68Ga or 67Ga in HCl into the vial thereby obtaining a solution of the PSMA ligand of formula (I) with radioisotope, and mixes the solution for a period of time to obtain the PSMA ligand radiolabeled with the radioactive isotope as taught by Blower et al. and Eder et al. because that labeling method would have been expected to enable an advantageous simple and convenient kit preparation of the advantageously labeled DFKZ-PSMA-11 under optimized conditions.
Applicants Arguments
Applicants assert that claim 16 recites in part a method for labeling PSMA binding ligand of formula (I) with 68Ga or 67Ga wherein an aqueous solution of HCl is added to a single vial containing a powder in dried form obtained by freeze drying. Eder was published about 5 yrs before the Blower document and can therefore be considered as the first one known to those skilled in the art. The results in Eder show that under to conditions of the Eder radiolabeling method, HBED-CC is a more efficient chelator of gallium radioisotope than DOTA. Nothing in Eder allows one of ordinary skill in the art to generalize the conclusion deduced from the experimental results obtained under specific labeling reaction conditions to different labeling reaction conditions. Blower reports experimental results obtained by applying their radiolabeling method to a range of different chelators. Blower concludes that acceptable labeling efficiencies in excess of 95% were only found with THP and DFO. Figure 1 clearly shows that HBED is the chelator that was found to exhibit some of worst chelation efficiency and to be the only chelator never reaching 95% labeling irrespective of the concentration used. The Blower document teaches away from using their method radiolabel HBED. One of ordinary skill in the art could only conclude that only the radiolabeling method in Eder is worth considering. The Examiners statement according to which Blower at col. 17 teach that chloride salts have been found to give rise to fast radiolabeling at room temperature cannot be considered as reflecting the teaching of Blower. It is not clear why one of ordinary skill in the art would have singled out a mixture of sodium acetate and sodium chloride as buffering agents for the radiolabeling of PSMA ligands of formula (I) with 68Ga or 67Ga when in a particular embodiment Blower excludes acetate buffers and in particular sodium acetate from preferred buffers. It is not clear why one skilled in the art would have sodium chloride to the powder comprising the PSMA binding ligand of formula (I). GaCl3 is not formed during the radiolabeling reaction but is already present in the aqueous solution of the radioactive isotope in HCl that is added to the single vial. Blower does not teach or suggest a radiolabeling method using a powder comprising sodium chloride wherein the sodium chloride is present to allow freeze drying of the components of the powder under extreme conditions without affecting their properties.
Applicant's arguments filed 17 Apr. 2026 have been fully considered but they are not persuasive. In a single claim, Blower claims a method for labeling DKFZ-PSMA-11 using 68Ga. Accordingly a person of ordinary skill in the art would have understood the 68Ga-labeling of DKFZ-PSMA-11 claimed by Blower to be enable and a preferred embodiment. In addition, Eder 2014 teaches as DKFZ-PSMA-11 as an advantageous and suitable PSMA PET imaging agent wherein the HBED-CC chelator provides a favorable interaction with the PSMA binding site. Eder describes an optimized 68Ga-labeling including kit labeling of the DKFZ-PSMA-11 where the optimized labeling uses the sodium acetate buffer to obtain average RCY of 80%. Accordingly, a person ordinary skill in the art would have reason and motivation to select Blowers’ claimed 68Ga labeling method and freeze dried powder comprising the DKFZ-PSMA-11 having the HBED-CC chelator and then optimize the method and powder with a reasonable expectation of success. Blowers claimed method and powder require a buffer that is an acetate buffer and at col. 6, Blower teaches sodium acetate and sodium chloride as pharmaceutical buffers. Reading a list and selecting known compound to meet known requirements is no more ingenuous selecting the last piece to put in the last opening of a jig saw puzzle. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Although Eder 2014 teaches an NaCl solution for elution of 68Ga, a person of ordinary skill in the art would have understood that NaCl can be added to the reaction vial without adversely affecting reaction condition since NaCl is present as part of the eluate. In addition, a person of ordinary skill would have understood that NaCl provides solubilizing properties since it enables an eluate comprising 68Ga in reactive form. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the claim 1 of Blower et al. so that method and powder comprising DKFZ-PSMA-11 include the sodium acetate buffer and sodium chloride because sodium acetate and sodium chloride would have been expected to provide suitable pharmaceutically acceptable buffers capable of maintaining optimal pH range and because the sodium chloride would have been expected aid in solubilizing 68Ga in the reaction mixture.
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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