DETAILED ACTION
This Office action details a 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 .
Status of Claims
Claims 1-15 are cancelled. Claims 16-34 are new.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 24 Oct. 2025 and 13 Nov. 2025 have been considered by the examiner.
Response to Amendment
The amendments filed on 5 Dec. 2025 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claims 1, 6, 8-9, and 11-13 because of minor informalities is withdrawn.
In view of Applicants amendments, the rejection of claims 1-15 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 5-7 under 35 USC 102(a)(2) as being anticipated by Blower et al. (US 11,826,436 B2; filed 10 Mar. 2015) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-15 under 35 USC 103 as being unpatentable over Blower et al. (US 11.826,436 B2; filed 10 Mar. 2025) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-15 under 35 USC 103 as being unpatentable over Ebenhan 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 Radiopharm.; published 5 Feb. 2019) is withdrawn.
New Grounds of Rejection
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) 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. (Bioconjugate Chem.; published 2012; see attached 892).
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 in dry form 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 vial comprising the PSMA binding ligand of formula (I), sodium acetate and gentisic acid as a stabilizer against radiolytic degradation wherein the vial does not contain ascorbic acid or ethanol; (ii) adding a solution of the 68Ga into the vial; (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). Chloride salts have been found to give rise to fast radiolabeling (< 5 min) at room temperature (col. 17) 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 disclose the claimed powder or method using a powder comprising sodium chloride optionally in an amount between 10 mg and 100 mg, 30 mg and 50 mg or 40 mg, or an amount of PSMA ligand of formula (I) between 5 mg and 60 m, 10 mg and 40 mg or 10 mg or 15, or an amount of sodium acetate between 20 mg and 80 mg, 42 mg and 52 mg or 47 mg, or an amount of gentisic acid that is between 0.5 mg and 2 mg, 0.8 mg and 1.2 mg or about 1 mg. Blower et al. do not further expressly disclose a kit having the claimed powder in dried form.
Eder et al. teach a 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging (see title). Eder et al. teach the compound Glu-NH-CO-NH-Lys(Ahx)-HBED-CC
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(scheme 1). HBED-CC is an efficient 68Ga chelator with fast complexing kinetics and high in vitro as well as in vivo stability (see pg. 688). Eder et al. teach 68Ga and 67Ga-labeling using GaCl3 (pg. 690).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify powder and method of Blower et al. (powder comprising DFKZ-PSMA-11 (instant formula I), (sodium) acetate, and gentisic acid, and method of 68Ga-labeling using the dried powder) so that the acetate buffer is a sodium acetate buffer and so that the dried powder further comprises sodium chloride and so that the method adds an aqueous solution of 68Ga into a single vial containing the obvious dried powder further comprising sodium chloride but does not contain ascorbic acid or a bulking agent such as mannitol and mixes and incubates that solution for a period of time to obtain the 68Ga-labelled DFKZ-PSMA-11 and so that the sodium acetate is sufficient to maintain a pH of about 4 at the incubation step) as taught by Blower et al. and Eder et al. because the addition of sodium chloride would have been expected to advantageously enable a suitable buffer/tonifying agent that optionally aids the formation of GaCl3 and because a pH of about 4 would have been expected to provide an optimal 68Ga-labeling pH. Generally, differences in amounts will not support patentability of the subject matter. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). A person of ordinary skill in the art would have arrived at an amount of the DKFZ-PSMA-11 that is 5 mg and 60 mg or 10 mg and 40 mg or 15 mg through routine experimentation in order to arrive at an effective amount of DKFZ-PSMA-11 that provides optimal radiochemical yield and optimal radiopharmaceutical dose. 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 mg and 50 mg, or 40 mg through routine experimentation in order to provide optimal tonicity and/or labeling rate enhancement. 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 47 mg through routine experimentation in order to gentisic acid that is between 0.2 mg and 2 mg, 0.8 mg and 1.2 mg or 1 mg through routine experimentation in order to arrive at an amount of radiostabilizer that inhibits radiolysis. 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 kit having a single vial comprises that obvious dried powder having the compound of instant formula (I) wherein the single vial does not contain ascorbic acid or ethanol and optionally bulking agents such as mannitol as taught by Blower et al. and Eder et al. because that kit would have been expected to advantageously enable a simplified kit production of the 68Ga-DFKZ-PSMA-11 from a stabilized dried powder having a tonifying agent or rate enhancing reaction incorporated therein.
Claim(s) 16-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ebenhan et al. (Molecules; published 2015; see IDS filed on 27 Oct. 2022), in view of Blower et al. (WO 2016/142702 A1; published 15 Sep. 2016; see attached 892) and Garcia-Arguello et al. (J. Label. Compd Radiopharm.; published 5 Feb. 2019; see IDS filed on 27 Oct. 2022).
Ebenhan et al. teach development of a single vial kit solution for radiolabeling of 68Ga-DKFZ-PSMA-11 (68Ga-HBED-CC-(Ahx)Lys-NH-CO-NH-Glu; DKFZ-PSMA-11=instant formula (I)) and its performance in prostate cancer (see title). Ebenhan et al. teach that DKFZ-PSMA-11 has superior imaging properties and allows for highly-specific complexation of the generator-based radioisotope 68Ga. The study is intended to develop a single vial kit solution to radiolabeled buffered DKFZ-PSMA-11 with 68Ga. The final product was injected into patients. The kits containing 5 nmol DKFZ-PSMA-11 showed rapid, quantitative 68Ga-complexation and all quality measures met the release criteria to human application (see abstract). Ebenhan et al. teach a freeze-dried kit containing DKFZ-PSMA-11 and sodium acetate (pg. 14862). A minimum of 5 nmol DKFZ-PSMA-11 was required in combination with 10 min incubation time at rt to warrant a 95%-100% complexation of 68Ga. Using an ethanolic solution (radiostabilizer) allowed recover of 84%-95% 68Ga-DKFZ-PSMA-11 with C18 purification. Ambient temperature labeling was a prerequisite; all crude radiolabeling solutions met the pH rang of 4-4.5 (see pg. 14863). The kit pellet was presented in a homogeneous-solid powder form, thus, no pellet bulking agents were added to the kit. The pellet dissolved rapidly to yield a clear particle free solution (pg. 14864). If the DKFZ-PSMA-11 labeling formulation can be supplied in GMP compliant kit form, it can be made available to all the PET/CT facilities in South Africa and beyond. The kit derived 68Ga-DKFZ-PSMA-11 demonstrated expected bio-distribution (pg. 14870). The performance of the DKFZ-PSMA-11 kit appears similar to published findings with DKFZ-PSMA-11, which were produced in module or cassette like procedure (pg. 18470). The kit is safe and useful, ready to use diagnostic agent in PCT with diagnostic performance (pg. 14871). Ebenhan et al. teach an in-house kit vial formulation of DKFZ-PSMA-11 where DKFZ-PSMA-11 and sodium acetate trihydrate were mixed. The kit vials were lyophilized. Stage 2 involves a true one-vial-one-step-radiolabeling approach followed by supplementing the kit vial with 1.5 mL of 2.5 M sodium acetate trihydrate and 3 mL of saline (connotes NaCl) to yield a physiological pH (pg. 14872). Ebenhan et al. teach that stage 2 voids the purification step (pg. 14864).
Ebenhan et al. do not teach the instant powder in dried form further comprising sodium chloride and gentisic acid as a stabilizer against radiolytic degradation or the instant method for labeling DKFZ-PSMA-11 with 68Ga or 67Ga radioisotope wherein the method adds an aqueous solution of the 68Ga or 67Ga radioisotope into the single vail containing the instant powder and mixes and incubates the solution for a period of time for obtaining the 68Ga-labeled DKFZ-PSMA-11. Ebenhan et al. do not further teach a kit for carrying out that radiolabeling method wherein the kit comprises the instant powder in a single vial. Ebenhan et al. do not further teach the claimed amounts for DKFZ-PMSA-11, sodium chloride, sodium acetate and gentisic acid.
Blower et al. teach methods and kits for preparing radionuclide complexes (see title). Blower et al. teach DKF-PSMA-11 (pg. 12). The chelator in the composition comprises a pharmaceutically acceptable buffer and pharmaceutically acceptable base reagent as a ‘pre-mix’ (pg. 5). Pharmaceutically acceptable buffers include sodium chloride (pg. 9). Tonicifying agents may be selected from sodium chloride (pg. 19). The buffer is present in an amount ranging from 5 to 95 mol percent (pg. 9). The reagents used are in solid form, in particular in lyophilized for freeze dried form. This allow them to form stable mixture that may be stored for transported (pg. 7). Suitable free radical scavengers are those that protect against autoradiolysis such as ascorbic acid or gentisic acid. The kit may contain 1-4% w/w free radical scavenger. The invention provides for kits, the kit comprising a pharmaceutically acceptable buffer and optionally a pharmaceutically acceptable basic reagent and a chelator able to chelate within a pH range of from 3 to 8 and at a moderate temperature. The chelator is in an admixture with the buffer composition in the kit. The kits are suitably in solid form in particular in lyophilized or freeze-dried form. Each kit comprises reagents to carry out one or more molecular imaging procedures held within a container (pg. 19). Blower et al. teach a vial comprising a lyophilized reagent mixture described in previous example but also containing 1-2 mg of ascorbic acid (pg. 26).
Garcia-Arguello et al. teach automated production of [68Ga]Ga-DOTANOC and [68Ga]Ga-PSMA-11 using a TRACERlab FXFN synthesis module (see title). Garcia-Arguello et al. teach that Meuller described the use of acidified 5 M NaCl solution to generate [68Ga]GaCl4. Sodium chloride solutions with a pH lower than 3 should be sufficient to keep Ga3+ solution in water to avoid the formation of insoluble Ga(OH)3 (see pg. 147). Garcia-Arguello et al. teach the radiosynthesis of [68Ga]Ga-PSMA-11. At mixture of L-ascorbic acid and sodium acetate was added to the reactor. Then a solution of NaCl was passed through the cation exchange cartridge resulting in an anionic complex [68Ga]GaCl4-. A solution of 10 µg of PSMA-11 in 0.5 mL of was added to the reactor (see pg. 148).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Ebenhan et al. (method for 68Ga labeling DKFZ-PSMA-11, a solution comprising 68Ga-DKFZ-PSMA-11 obtained by that method, a powder comprising DKFZ-PSMA-11 and sodium acetate and kit comprising a single vial with DKFZ-PSMA-11 and sodium acetate) so that the method, solution, powder and kit further contain in the single vial sodium chloride and a radiostabilizer such as gentisic acid and so that the 68Ga labeling method voids a C18 purification step as taught by Ebenhan et al., Blower et al., and Garcia-Arguello et al. because the sodium chloride would been expected to advantageously provide a buffer/tonifying agent that aids in the formation of 68GaCl3 and because the radiostabilizer such as gentisic acid would have been expected advantageously protect the 68Ga-DFKZ-PSMA-11 from radiolytic degradation and because voiding a C18 purification step would have been expected to advantageously enable a true one-vial-one step labeling approach . Differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). A person of ordinary skill in the art would have arrived at an amount of DKFZ-PSMA-11 that is between 5 µg and 60 µg through routine experimentation in order to arrive at an effective amount of DKFZ-PSMA-11 that provides optimal radiochemical yield and radiopharmaceutical dose. A person of ordinary skill in the art would have arrived at amount of sodium chloride that is at least 10 mg through routine experimentation in order to provide optimal reactivity/buffering/tonicity to the 68Ga-DKFZ-PSMA-11 reaction and formulation. A person of ordinary skill in the art would at arrived at an amount of sodium acetate that is at least 20 mg through routine experimentation in order to provide an optimal buffering capacity. A person of ordinary skill in the art would have arrived at an amount of gentisic acid that is at least 0.2 mg through routine experimentation in order to provide an amount of radiostabilizer that inhibits radiolysis. Regarding claims 3, 10 and 15, the method, solution, dry composition, and kit of Ebenhan et al. do not contain any bulking agent such as carbohydrate and polymeric agent.
Applicants Arguments
Applicants assert that Blower shows that HBED is the chelator that was found to some of the worst results and to be the only chelator never reaching a 95% labeling irrespective of the concentration used. Blower teaches away from using their method to radiolabel HBED. The labeling method disclosed by Ebenhan comprises a purification step on a C18 column in the presence of ethanol. The present method does not contain a purification step of the radiolabeled PSMA ligand let alone a purification step using a C18 SPE method. Regarding Garcia-Arguello the presently claimed invention excludes the use of ascorbic acid.
Applicant's arguments filed 5 Dec. 2025 have been fully considered but they are not persuasive. Blower claims a method for preparing 68Ga-labeled DKFZ-PSMA-11, which is the compound of instant formula (I) comprising the HBED-CC chelator (see Eder cited above), the method comprising eluting 68Ga from a 68Ga radionuclide generator into a single vial containing a dried powder composition comprising an admixture of the DKFZ-PSMA-11, gentisic acid, and (sodium) acetate buffer thereby forming 68Ga-labeled DKFZ-PSMA-11. Blower’s claims are of the utmost importance. Accordingly, a person of ordinary skill in the art would not have understood Blower as teaching away from the 68Ga-labeling the DKFZ-PSMA-11 comprising the HBED chelator. At pg. 692, the Eder reference cited by Blower reports a radiochemical yield of 99% in less than 1 at room temperature. In addition, the Eder reference cited by Blower reports a chemical structure of DKFZ-PSMA-11 that is identical to instant formula. The claims of Blower mainly differ from the instant claims because the claims of Blower are silent about sodium chloride being in the dried powder composition. However, Blower teaches sodium chloride as an advantageous pharmaceutical buffer and tonifying agent. A recognized advantage is the strongest reason to combine. Since the 68Ga-labeled DKFZ-PSMA-11 prepared by Blower is meant to be suitable for administering to subjects for PET imaging, it would have been obvious to a person ordinary skill in the art before the effective filing date to modify the dried powder of Blower so that the powder further contains an amount of sodium chloride that provides optimal tonicity to the composition without further manipulation by medical staff. Ebenhan teaches and motivates voiding the C18 purification step to arrive at a true one-vial-one-step labeling approach. The claimed invention relates to a powder and kit that do not exclude a purification step. Garcia-Arguello teaches sodium chloride as advantageous for keeping 68Ga3+ solution in water to avoid the formation of insoluble Ga(OH)3. Like Blower, Garcia-Arguello teaches and motivates the addition of radiolysis inhibitor to a radiopharmaceutical composition formed from 68Ga. Blower teaches gentisic acid as alternative to ascorbic acid. Accordingly, it would have been obvious to a person of ordinary skill in the art before the effective filing date to form the powder and kit using gentisic acid as the radiolysis inhibitor rather than ascorbic acid because that powder and kit would have been expected enable the production of a radiopharmaceutical composition exhibiting reduced oxidative degradation relative to the composition without the antioxidant.
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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618