DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-20 and 24-33 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 .
Status of Claims
Claim 1 is amended. Claims 21-23 are cancelled. Claims 31-33 are new.
Response to Amendment
The amendments filed on 21 Sep. 2026 have been entered.
The declaration under 37 CFR 1.132 filed 21 Sep. 2026 is insufficient to overcome the rejection of as set forth in the last Office action because of the reasons set forth below.
Dr. Wirtz (née Weineisen) declares that the USPTO incorrectly asserts that the composition disclosed in the Weineisen JNM publication inherently satisfies the claimed stability of ≥95% RCP at 72 h post formulation. For human application, to reasonably provide patient safety, suppress radiolytic degradation, and maintain high radiochemical purity in therapeutic human doses, the molar ratio of ligand to 177Lu was intentionally increased to a high level that is clearly outside of the currently claimed invention (i.e. 9:1 or more) for clinical application. The calculation in the supplemental materials relies on an unformulated reaction mixture containing low amounts of radioactivity (24.5 MBq of 177LuCl3) and the dosages administered to humans did not have the currently claimed molar ratio. There is no indicia that the passage cited by the USPTO would provide a radiochemical purity of >95% for at least 72 h after production. It is opined that the claimed formulation invention is uniquely different from the formulations and methods described in the Weineisen publication as well as by McCann and Pipes. It is submitted that the Weineisen publication does not recite any specific radioactivity concentration for human application nor for in vitro animal experiments. The Weineisen publication did not discuss any formulation that is shelf stable for 72 h. It is opined that the 95% radiochemical purity at 72 h after production is an unexpected property of the claimed invention given the other claimed features. It is opined that the claimed formulation provides a superior performance as compared to previous formulations of the prior art.
The Dr. Wirtz (née Weineisen) declaration filed 21 Sep. 2026 has been fully considered but it is not persuasive. Opinion testimony is entitled to some consideration and some weight so long as the opinion is not on the ultimate legal conclusion at issue. See In re Chilowsky, 306 F.2d 908, 134 USPQ 515 (CCPA 1962).
The instant claims are directed to a composition comprising a solution for injection, the composition comprising 177Lu-PSMA I&T, the molar ratio of the PSMA I&T to 177Lu from 3:1 to 8:1. The recitation of “for injection to a human patient in need thereof” is an intended use and the claims do not require the administration of the composition to a human subject. See Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation".)
While claims 1, and 31-33 require 177Lu-PSMA I&T at a radiochemical purity of ≥95% for at least 72 h after production, there is nothing unexpected about the enhancing shelf-life of 177Lu-PSMA I&T by adding an anti-radiolytic stabilizer. See for example McCann et al. (of record; cited herein). The Dr. Wirtz declaration does not provide for any unexpected results regarding the addition of anti-radiolytic stabilizer such as ascorbic acid to arrive at the radiochemical purity of ≥95% for at least 72 h.
While the Dr. Wirtz declaration when discussing human application asserts that to provide patient safety, suppress radiolytic degradation and maintain high radiochemical purity in the human doses, the molar ratio of ligand to 177Lu was intentionally increased to a high level that is clearly outside the claimed invention (i.e. 9:1 or more) for clinical administration, the instant claims do not require human application, but instead, require a dose from 1 GBq to 9 GBq which a person of ordinary skill in the art could have arrived at for at least ensuring one or more doses for animal experiments optionally requiring distribution and transport. The Dr. Wirtz declaration does not provide for any unexpected results attributable to a dose from 1 GBq to 9 GBq.
There are at least two prior art compositions cited herein having a solution comprising radiopharmaceutical composition comprising 177Lu PSMA I&T, the molar ratio of PSMA I&T to 177Lu is within the range of 3:1 to 8:1 and having high radiochemical purity after production. The Weineisen publication contains one prior art composition and the Cankaya publication (cited herein) contains the second. Unexpected results require a comparison with the closest prior art. A declaration must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). The Dr. Wirtz declaration does not contain a comparison with either the cited Weineisen publication composition or the cited Cankaya publication composition to demonstrate an unexpected result over the prior art compositions. At the preparation for labeling of PSMA I&T with lutetium-177 on ML, the Cankaya publication teaches that an ascorbic acid buffer plus reactive precursor were added to the vial with the golden cap. The reaction mixture was cooled down by adding 10 mL of 0.9% NaCl to the reaction mixture. The crude reaction mixture was subsequently transferred through the CM cartridge and a sterile filter into the product vial. Accordingly, it is understood that the Cankaya publication compositions comprises an anti-radiolytic stabilizer in addition to comprising 177Lu-PSMA I&T, the molar ratio of PSMA I&T to 177Lu in the range of 3:1 to 8:1.
Response to Arguments
In view of Applicants amendments, the rejection of claims 1-30 under 35 USC 103 as being unpatentable over McCann et al. (US 2022/0080059 A1; published 17 Mar. 2022) and Weineisen et al. (J. Med. Chem.; published 2015) is withdrawn.
In view of Applicants amendments, the rejection of claims 1, 4-5, 12-14, and 26-28 under 35 USC 102(a)(1) as being anticipated by Weineisen et al. (J. Nucl. Med.; published 2015) is withdrawn.
In view of Applicants amendments the rejection of claims 1-30 under 35 USC 103 as being unpatentable over Weineisen et al. (J. Nucl. Med.; published 2015), in view of McCann et al. (WO 2022/013610 A2; published 20 Jan. 2022) 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) 1-20 and 24-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCann et al. (WO 2022/013610 A2; published 20 Jan. 2022; see IDS filed on 4 Jun. 2025), in view of Pipes et al. (US 2022/0080059 A1; published 17 Mar. 2022; see IDS filed on 4 Jun. 2025) and Weineisen et al. (J. Med. Chem.; published 2015; see IDS filed 4 Jun. 2025).
McCann et al. teach radiopharmaceutical and methods (see title). McCann et al. teach an aqueous composition including 1) a complex of lutetium-177 and EuK-Sub-kf-iodo-y-DOTAGA and 2) one or more ascorbate compounds. The radiochemical purity of the composition is at least 99% where the composition is maintained at 30oC or less for 3 or more days following preparation (pg. 35). The 177Lu-PSMA I&T is provided as a sterile solution for intravenous use. A single dose vial will contain 6.8 ± 10% GBq 177Lu-PSMA I&T in 10-14 mL formulated with one or more radioprotectants and may include a buffer. The pH is from 5.0 to 7.0 (pg. 39). McCann et al. teach example 2 where radiolabeling was performed using no-carrier added 177LuCl3. The racemic 177Lu-PSMA-I&T or 177Lu-PSMA-I&T having optical excess of structure 2A was diluted using a reaction buffer and was added to a reaction vial (pgs 48-49). Reaction compositions were evaluated at 125 to 250 µg (in a 15 mL formulation; about 8 µg/mL to 16 µg/ mL PSMA I&T.) The preparation of 177Lu-PSMA-I&T following conditions described in condition 4 and condition 5, demonstrates for the first time a product that is >99% pure post incorporation reaction and maintains >95% radiochemical purity over 6 d at room temperature in the formulation composition. Condition 5 places 65 mg in the reaction composition and an admixture of 26 mg ascorbic acid and 66 mg gentisic acid in the formulation composition with 177Lu-PSMA-I&T (table 2). (Composition comprising a solution for injection into a human patient in need thereof in a single use vial wherein the solution comprises a radio-pharmaceutical composition comprising 177Lu-PSMA I&T and 177Lu-PSMA-I&T at a radiochemical purity of >95% for at least 72 h post production.) McCann et al. teaches a preferred preparation process (example 3). 177Lu-PSMA I&T having an optical excess of structure 2A in sterile aqueous solution is administered by intravenous injection. The dosing regimen may include four infusions of 6.8 ± 10% each, administered 8 wk apart (see pg. 55). A dose of 0.1 GBq to about 30 GBq may be administered (pg. 39). The one or more stabilizer compounds may include ethanol (pg. 37). McCann et al. teach ascorbate amounts ranging from 5 mg/mL to 90 mg/mL (pg. 15).
McCann et al. is silent about a molar ratio of PSMA I&T to 177Lu that is from 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 4.0:1.0 to 4.5:1.0, 4.5:1.0 to 5.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, or 3.5:1.0 to 7.5:1.0, 4.0:1.0 to 7.0:1.0, 4.5:1.0 to 7.0:1.0, 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0. McCann et al. does not expressly teach that the composition comprises dose range of 1 GBq to 9 GBq or the doses 7.4 GBq±0.3 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.20 GBq. McCann et al. do not expressly teach PSMA I&T at a concentration of 2.5 to 6 µg/mL, 3 to 8 µg/mL, and 5 to 12 µg/mL. McCann et al. do not expressly teach the following concentrations of ethanol: 0.1% (v/v) to 10% (v/v). McCann et al. do not exemplify as solution comprising 15 to 20 mL.
Pipes et al. teach radiolabeling and formulation for scale up of 64Cu-dotatate (see title). Pipes et al. teach supplying commercial quantities of radioactive diagnostic agent indicated for use with PET (see abstract). Pipes et al. teach 177Lu-dotatate ([0008]) and in certain embodiments the radionuclide is lutetium-177 ([0052]). The molar ratio of ligand to radionuclide is 5:1, 4:1, 3:1 ([0080]). Pipes et al. teach 5% ethanol (95% water) ([0093]). Pipes et al. teach the formation of Cu-DOTATATE at lower temperatures (example 3). Reaction conditions included a DOTATATE:Cu molar ratio of 4:1. The data confirm that labeling of dotatate is largely complete after 5 min (table 7). Pipes et al. teach the preparation of 64Cu-DOTATATE prepared at reduced DOTATATE concentration (example 6) and the effects of gentisic acid and ethanol on 64Cu-DOTATATE stability (example 7). Pipes et al. teach sodium ascorbate and 2.8% or 3.5% EtOH (table 9). Pipes et al. teach an improved purification yield of Cu-DOTATATE (example 11).
Weineisen et al. teach 68Ga- and 177Lu labeled PSMA I&T: optimization of the a PSMA targeted theranostic concept and first proof of concept human studies (see title). Weineisen et al. teach that PSMA I&T was developed and evaluated in detail both in vitro and in vivo (pg. 1170). For quantitative 177Lu complexation, 24.5 MBq of 177LuIII was reacted with 4.5-fold molar excess of PSMA I&T yielding 177Lu-PSMA I&T in specific activities of 27 GBq/µmol or more. For 177Lu PSMA I&T the radiochemical purity was 99.0%±1.0% as determined by HPLC and specific activities were achieved (pg. 1171). Weineisen et al. teach endoradiotherapy of patients using 177Lu-PSMA I&T. Both patients received 5.7 and 8 GBq of 177Lu PSMA I&T (pg. 1171). 177Lu-PSMA I&T shows high, specific and rapid uptake in all previously identified tumor lesions of the mCRPC patients (pg. 1175). Weineisen et al. teach that 0.91 nmol PSMA I&T was added to 24.5 MBq 177Lu-LuCl3 (120 GBq/µmol) in 0.05 M HCl. The pH was adjusted to pH 5 by the addition of NH4Oac (0.1 M, 150 µL). Incubation of 150-200 µg of PSMA I&T (in a 15 mL formulation, 10 µg/mL-13 µg/mL) with 6-8 GBq of 177LuCl3 at 90oC for 30 min in NaOAc (0.4 M, 800 µL, pH 5.5). To this buffer, 5-10 mg of gentisic acid was added to prevent radiolysis. The reaction solutions were diluted with saline and after sterile filtration a sample was taken for quality control (supplemental information).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of McCann et al. (composition for injection into a human patient in need thereof in a single use vial, wherein the solution comprises a radiopharmaceutical composition comprising 177Lu-PSMA I&T and ascorbic acid, and the 177Lu-PSMA I&T is at a radiochemical purity of ≥ 95% for at least 6 d post production) so that the composition comprises a molar ratio of PSMA I&T to 177Lu ranging from 3:1 to 8:1 as taught by Pipes et al. because the molar ratios would have been expected to production of 177Lu-PMSA I&T using an optimized amount of PSMA I&T at reduced temperatures such as 18oC in high yield and in about 5 min. The molar ratio is a result effective variable 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 molar ratios of PSMA I&T and 177Lu within the following ranges in order to reduce PSMA I&T concentration and improve purification yield: 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 4.0:1.0 to 4.5:1.0, 4.5:1.0 to 5.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, or 3.5:1.0 to 7.5:1.0, 4.0:1.0 to 7.0:1.0, 4.5:1.0 to 7.0:1.0, 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0. The concentration of PSMA I&T is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at the following concentration ranges in order to arrive at an optimal precursor amount that provides quantitative complexation of 177Lu and stability: 2.5 to 6 µg/mL, 3 to 8 µg/mL and 5 to 12 µg/mL.It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify composition of McCann et al. so that the dose of the composition comprises the dose range of 1 GBq to 9 GBq or the doses 7.4 GBq±0.30 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.30 GBq as taught by McCann et al. because those doses would have been expected to enable an optimal therapeutically effective amount and because McCann et al. teaches doses in the range of 0.1 GBq to about 30 GBq are suitable doses for the radiotreatment of prostate cancer. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of McCann et al. so that the composition contains an ethanol amount such as 2.8% (v/v) or 3.5% (v/v) as taught by Pipes et al. because those ethanol amounts would have been expected to enable radioprotection against radiolysis and optimal solubility. The amount of ascorbic acid is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at an amount of ascorbic acid within the range of 15 mg/mL to 35 mg/mL through routine experimentation in order to optimize the amount of ascorbic acid that reduces radiolysis and optimizes shelf-life. The volume solution is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a solution that comprises 15 to 20 mL in order to arrive at a solution that comprises one or more doses of 177Lu-PSMA I&T.
Applicants’ Arguments
Applicants assert that the record now includes expert testimony from the lead author of the Weineisen publication. None of McCann, Pipes and Weineisen teach or suggest the claimed invention. The rejection therefor depends on an expectation that McCann’s stability would be retained after materially reducing ligand excess based on a ratio taken from a different, low activity preparation. Weineisen intentionally used a ratio above 9:1 or more for clinical administration. McCann used a ratio of 12:1. The prior art does not recognize that reducing ligand excess would predictably produce the claimed results. Dr. Wirtz explains that increasing a low activity preclinical preparation by approximately 40 fold is not a predictable result. Higher activity concentrations increase radiolysis and lower molar ratios at high activities reduce shelf life. Pipes does not cure these deficiencies.
Applicants’ arguments filed 21 Sep. 2026 have been fully considered but they are not persuasive. The Dr. Wirtz declaration was found to be ineffective for the reasons discussed above. The Weineisen publication does not teach or suggest that the molar ratio of ligand to 177Lu was intentionally increased to a high level that is clearly outside the scope of the claimed invention (i.e., 9:1 to more) for clinical administration. Instead, the Weineisen publication at pg. 1171 states that for quantitative 177Lu complexation, 24.5 MBq of 177LuIII was reacted with 4.5-fold molar excess of PSMA I&T. At supplemental information, the Weineisen publication provides one 177Lu labeling and composition where the mole ratio of PSMA I&T to 177Lu is 4.5:1. Weineisen is silent about the mole ratio of PSMA I&T to 177Lu at the second 177Lu labeling for human application. For the aqueous injectable composition at table 2, McCann teaches that conditions 4 and 5 result in products that are >99% pure post incorporation reaction and maintains >95% purity for 6 d at room temperature. Although McCann teaches using a range of precursor amounts, McCann does not provide for a mole ratio of PMSA I&T to 177Lu or provide any suggestion that the >95% purity for 6 d at room temperature is related mole ratio of PMSA I&T to 177Lu. McCann references Weineisen. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the aqueous injectable 177Lu-PSMA I&T compositions of McCann so that the mole ratio of PSMA I&T to 177Lu is 4.5:1 or further optimized because the optimized mole ratios would having been expected to at lease for provide for reduced precursor loads and cost reductions while enabling quantitative complexation.
Claim(s) 1-20 and 24-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weineisen et al. (J. Nucl. Med.; published 2015), in view McCann et al. (WO 2022/013610 A2; published 20 Jan. 2022).
Weineisen et al. teach as discussed above. Weineisen et al. teach 68Ga- and 177Lu labeled PSMA I&T: optimization of the a PSMA targeted theranostic concept and first proof of concept human studies (see title). Weineisen et al. teach that PSMA I&T was developed and evaluated in detail both in vitro and in vivo (pg. 1170). For quantitative 177Lu complexation, 24.5 MBq of 177LuIII was reacted with 4.5-fold molar excess of PSMA I&T yielding 177Lu-PSMA I&T in specific activities of 27 GBq/µmol or more. For 177Lu PSMA I&T the radiochemical purity was 99.0%±1.0% as determined by HPLC and specific activities were achieved (pg. 1171). Weineisen et al. teach endoradiotherapy of patients using 177Lu-PSMA I&T. Both patients received 5.7 and 8 GBq of 177Lu PSMA I&T (pg. 1171). 177Lu-PSMA I&T shows high, specific and rapid uptake in all previously identified tumor lesions of the mCRPC patients (pg. 1175). Weineisen et al. teach incubation of 150-200 µg of PSMA I&T with 6-8 GBq of 177LuCl3 at 90oC for 30 min in NaOAc (0.4 M, 800 µL, pH 5.5. To this buffer, 5-10 mg of gentisic acid was added to prevent radiolysis (5 mg/supplemental information).
For the first and second 177Lu-labelings, Weineisen et al. do not expressly teach that the 177Lu-PSMA I&T has a radiochemical purity of >95% for at least 72 h after production. For the second 177Lu-labeling. Weineisen et al. are silent about a molar ratio of PSMA I&T to 177Lu that is from 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0. For the first 177Lu-labeling, Weineisen et al. do not teach that the composition comprises a dose of from 1 GBq to 9 GBq. Weineisen et al. do not expressly teach PSMA I&T at a concentration of 2.5 to 6 µg/mL, 3 to 8 µg/mL, or 5 to 12 µg/mL. Weineisen et al. do not expressly teach the doses 7.4 GBq±0.3 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.20 GBq. Weineisen et al. do not expressly teach the following concentrations of ethanol: 0.1% (v/v) to 10% (v/v). Weineisen et al. do not expressly teach an antioxidant that is ascorbic acid or an antioxidant amount that is 10 mg/mL to 90 mg/mL or 15 mg/mL to 35 mg/ mL. Weineisen et al. do not exemplify as solution comprising 15 to 20 mL.
McCann et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Weineisen et al. (composition comprising 177Lu-PSMA I&T wherein the molar ratio of PSMA I&T to 177Lu is asserted to be 4.5:1.0) so that the composition has a radiochemical purity that is ≥95% for at least 72 h after production by adding anti-radiolytic stabilized such as ascorbic acid and/or gentisic acid as taught by McCann et al. because it would have been expected to advantageously enable a composition comprising 177Lu PSMA I&T suitable for human and remains stable for several days following formulation enabling extended storage and/or transport. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compositions of Weineisen et al. so that the composition comprises a dose of from 1 GBq to 9 GBq as taught by Weineisen et al. because those doses would have been expected to enable multiple doses for in vitro animal experiments optionally requiring transport and/or doses suitable for human application.
The molar ratio is a result effective variable 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 molar ratios of PSMA I&T and 177Lu within the following ranges in order to reduce PSMA I&T precursor load, improve purification yield and optimize specific activity: 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, or 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0.
It would have been obvious to a person of ordinary skill In the art before the effective filing date to further modify the compositions of Weineisen et al. so that the compositions have PSMA I&T at a concentration of 2.5 to 6 µg/mL, 3 to 8 µg/mL, or 5 to 12 µg/mL as taught by Weineiesen et al. and McCann et al. because those PSMA I&T concentrations would have been expected to enable an optimal precursor amount that provides quantitative complexation of 177Lu and stability.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify composition of Weineisen et al. so that the dose of the composition comprises 7.4 GBq±0.30 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.30 GBq as taught by Weineisen et al. and McCann et al. because those doses would have been expected to enable an optimal therapeutically effective amount and because McCann et al. teach doses in the range of 0.1 GBq to about 30 GBq are suitable doses for the radiotreatment of prostate cancer. MPEP 2144.05.II.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Weineisen et al. so that the composition contains an ethanol amount such as 0.01% v/v or 10% v/v as taught by McCann et al. because those ethanol amounts would have been expected to enable radioprotection against radiolysis and solubility enhancement. MPEP 2144.05.II.
It would have been obvious to a person of ordinary skill in the art to modify the compositions of Weineisen et al. so that the compositions contain ascorbic acid at an amount between 15 mg/mL to 35 mg/mL as taught by Weineisen et al. and McCann et al. because the ascorbic acid in that amount would have been expected to advantageously enable radiolysis inhibition and optimize shelf-life. The total volume solution is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a solution that comprises 15 to 20 mL in order to arrive at a solution that comprises one or more doses of 177Lu-PSMA I&T.
Applicants’ Arguments
Applicants assert that the Weineisen preparation is an unformulated reaction mixture; limited to 24.5 MBq; prepared for in vitro and animal studies; and devoid of anti-radiolytic stabilizers. Nothing in McCann suggests that its stability would be retained after reducing ligand excess into the claimed 3:1 to 8: 1 range. The Office cannot treat the claimed 72 h stability as an inevitable result of combining Weineisen and McCann.
Applicants assert unexpected results. The Dr. Denner declaration addresses the unexpected dosimetry and pharmacokinetic results. Dr. Wirtz reviewed the dosimetry comparison between the claimed invention, as evaluated in ECLIPSE and the McCann formulation as in SPLASH. Objective evidence of unexpected results must be considered as part of the obviousness analysis.
Applicants’ arguments filed 21 Sep. 2026 have been fully considered but they are not persuasive. The Weineisen declaration was found ineffective for the reasons discussed above. None of the submitted declarations contain a comparison with the closest prior art compositions in the Weineisen publication or Cankaya publication. In addition, the Cankaya publication provides for a composition comprising a solution for inject wherein the solution comprises a radiopharmaceutical composition comprising 177Lu-PSMA I&T, the mole ratio of the PSMA I&T in the range of 3:1 to 8:1 and the compositions comprise a dose from 1 GBq to 9 GBq. The Cankaya publication teaches the use of an ascorbate buffer. Regarding the Weineisen publication, the claims do not require administration to human subjects but instead require an intended use of for injection to human subjects.
For in vitro and animal experiments, a person of ordinary skill in the art would have had reason and motivation to arrive at a dose of 1 GBq to 9 GBq to account for potential mechanical losses and/or enable one or more animal experiments optionally requiring extended storage or transport. In addition, a person of ordinary skill in art would have had reason and motivation to arrive at a radiochemical purity of ≥95% for at least 72 h by addition of an anti-radiolytic stabilizer in order to prevent radiolysis prior to the experiment, and reduce production runs while ensuring the accuracy of the animal experiments. A person of ordinary skill in the art would not have had the benefit of the Dr. Wirtz declaration before the effective filing date. The Weineisen publication teaches that the mole ratio of PSMA I&T to 177Lu of 4.5:1 provides for quantitative 177Lu complexation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Weineisen so that the composition comprises a dose from about 1 GBq to 9 GBq and 177Lu-PSMA I&T is at a radiochemical purity of ≥95% for at least 72 h because those doses and radiochemical purities would have been expected to at least advantageously enable one or more high quality animal experiments optionally requiring transport.
Claim(s) 1-20 and 24-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cankaya et al. (EJNMMI Radiopharmacy Chem.; published 26 May 2023; see IDS filed on 13 Jul. 2026, in view of Weineisen et al. (J. Nucl. Med.; published 2015), and McCann et al. (WO 2022/013610 A2; published 20 Jan. 2022).
Cankaya et al. teach the optimization of 177Lu-labelling of DOTA-TOC, PSMA-I&T and FAPI-46 for clinical application (see title). Cankaya et al. teach that the purpose of this study is to optimize the precursor load of the three radiopharmaceuticals. For that, different precursor loads were evaluated and compared to previously reported findings. The precursor load was optimized for [177Lu]Lu-PSMA-I&T from 16.2 to 11.6 µg/GBq (see abstract).
(Molar ratio of PSMA I&T to 177Lu is computed to about 5.56:1 to 7.81:1.)
The synthesis of routinely used 177Lu-radiopharmaceuticals is usually performed with one patient dose of about 7.4 GBq lutetium-177. A method is presented for the preparation of [177Lu]Lu-PSMA-I&T using a total starting activity up to 26 Bq of [177Lu]LuCl3 for each batch, which is sufficient to obtain dose for up to 3 patients (pg. 2). At table 3, synthesis no. 3 has a starting activity of about 6.8 GBq and amount of PSMA-I&T of 14.8 µg/GBq (comprises a dose of from about 1 GBq to 9 GBq; in 10 mL, about 10 µg/mL; PSMA I&T to 177Lu ratio of about 7.6:1)
In clinical routine, we confirmed that with similar with similar staring activities of 22.4 (13.4 µg/GBq PSMA I&T) and 20.6 GBq (14.6 µg/GBq PMSA-I&T), >99% radiochemical purity was achieved (table 3; pg. 4). Cankaya et al. teach extensive efforts to further decrease the amount of precursor. Decreasing the precursor load has two advantages: firstly, increasing the molar activity for the benefit of quality of application and secondly, lowering the cost of synthesis (pg. 5). Cankaya et al. recommend to dilute product solution with sodium chloride 0.9% immediately after synthesis in order to decrease radiolysis (pg. 5). Cankaya et al. teach the preparation of PSMA I&T with 177Lu on ML easy. Ascorbic acid buffer was prepared according to the manufacturer’s protocol. An extra sterile vial with 10 mL of 0.9% NaCl was attached to the cassette. The reaction mixture was cooled down by adding 10 mL 0.9% NaCl to the reaction mixture. The crude reaction solution was subsequently transferred through the CM cartridge and a sterile filter into the product vial (pgs. 6-7). Cankaya et al. teach pH 5 (pg. 7).
Cankaya et al. do not teach expressly teach 177Lu-PSMA I&T at a radiochemical purity of ≥95% for at least 72 h after production. Cankaya et al. do not expressly teach the molar ratio of PSMA I&T to 177Lu that is from 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0. Cankaya et al. do not teach a composition comprising 0.01% v/v to 10% v/v ethanol or a composition comprising 15 mg/L to 35 mg/mL ascorbic acid or a solution comprising a pH of 4-5 or a total volume of 15 to 20 mL or PSMA I&T at a concentration of 2.5 to 6 µg/mL, 3 to 8 µg/mL, or 5 to 12 µg/mL.
McCann et al. teach as discussed above.
Weineisen et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Cankaya et al. (compositions comprising 177Lu-PSMA I&T wherein the molar ratio of PSMA I&T to 177Lu is computed to about 5.56:1 to 7.81:1 and wherein the compositions comprise a dose from about 1 GBq to 9 GBq and wherein the composition is suggested to comprise ascorbic acid) so that the composition has a radiochemical purity that is ≥95% for at least 72 h after production by addition of anti-radiolytic stabilizers such as ascorbic acid and/or gentisic acid as taught by McCann et al. because it would have been expected to advantageously enable a composition comprising 177Lu PSMA I&T suitable for human and remains stable for several days following formulation optionally allowing for extended storage and transport.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compositions of Cankaya et al. so that the composition comprises a dose of from 1 GBq to 9 GBq as taught by Cankaya et al., Weineisen et al., and McCann et al. because those doses would have been expected to enable multiple doses for in vitro animal experiments and/or doses suitable for human application.
The molar ratio is a result effective variable 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 molar ratios of PSMA I&T and 177Lu within the following ranges in order to reduce PSMA I&T load, lowing cost of synthesis and increasing the molar activity for quality application: 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 3.5:1.0, 3.5:1.0 to 4.0:1.0, 5.0:1.0 to 5.5:1.0 to 6.0:1.0, 6.0:1.0 to 6.5:1.0, 6.5:1.0 to 7.0:1.0, 7.0 :1.0 to 7.5:1.0, 7.5:1.0 to 8.0:1.0, or 5.0:1.0 to 7.0:1.0, or 5.5:1.0 to 7.0:1.0.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compositions of Cankaya et al. so that the compositions have PSMA I&T at a concentration of 2.5 to 6 µg/mL, 3 to 8 µg/mL, or 5 to 12 µg/mL as taught by Cankaya et al., Weineisen et al. and McCann et al. because those PSMA I&T concentrations would have been expected to enable at an optimal precursor amount that provides quantitative complexation of 177Lu and stability
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify composition of Cankaya et al. so that the dose of the composition comprises 7.4 GBq±0.30 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.30 GBq as taught by Cankaya et al. and McCann et al. because those doses would have been expected to enable an optimal therapeutically effective amount of 177Lu-PSMA I&T MPEP 2144.05.II.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Cankaya et al. so that the composition contains an ethanol amount such as 0.01% v/v or 10% v/v as taught by McCann et al. because those ethanol amounts would have been expected to enable radioprotection against radiolysis and solubility enhancement. MPEP 2144.05.II.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Cankaya et al. so that the composition has a pH in the range of 4 to 5 as taught by Cankaya et al. and McCann et al. because that pH range would have been expected to provide optimal 177Lu complexing and stability. MPEP 2144.05.II.
It would have been obvious to a person of ordinary skill in the art to modify the compositions of Cankaya et al. so that the compositions contain ascorbic acid at an amount between 15 mg/mL to 35 mg/mL as taught by Weineisen et al. and McCann et al. because the ascorbic acid in that amount would have been expected to advantageously enable radiolysis inhibition. The total volume solution is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a solution that comprises 15 to 20 mL in order to arrive at a solution that comprises one or more doses of 177Lu-PSMA I&T.
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.
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
