DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 21-42 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 1-20 are cancelled. Claims 21-40 are new.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 Oct. 2025 has been considered by the examiner.
Response to Amendment
The amendments filed on 21 Nov. 2025 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claims 1-2, 7, 9, 11-12, and 16-17 because of minor informalities is withdrawn.
In view of Applicants amendments, the rejection of claims 1-20 under 35 USC 112(b) for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 5-6 under 35 USC 102(a)(2) as being anticipated by Mariani et al. (WO 2021/001360 A1; filed 2 Jul. 2019) is withdrawn.
In view of Applicants amendments, the rejection of claims 1 and 5 under 35 USC 103 as being unpatentable over Blower et al. (WO 2016/142702 A1; published 15 Sep. 2016) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-20 under 35 USC 103 as being unpatentable over Blower et al. (WO 2016/142702 A1; published 15 Sep. 2016), in view of Asti et al. (Nucl. Med. Comm.; published 2012) and Ray et al. (WO 2017/165473 A1; published 28 Sep. 2017) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-20 under 35 USC 103 as being unpatentable over Blower et al. (WO 2016/142702 A1; published 15 Sep. 2016), in view of Asti et al. (Nucl. Med. Comm.; published 2012) and Mariani et al. (WO 2021/001360 A1; filed 2 Jul. 2019) and/or NCT03490032 (ClinicalTrials.goc; published 6 Apr. 2018) is withdrawn.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) 27-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mariani et al. (WO 2021/001360 A1; published 2021), in view of Luna-Gutiérrez et al. (J. Radioanal. Nucl. Chem.; published 2017; see attached 892).
Mariani et al. teach prostate specific membrane antigen (PSMA) ligands and uses thereof (see title). Mariani et al. teach PSMA-R2
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(pg. 9) and 68Ga-PSMA-R2 (pg. 11-). The results show that the after 1 h, the kidney uptake and the salivary gland uptake are lower for 68Ga-PSMA-R2. Moreover, the high tumor to kidney ratio after 1 h suggest a better visualization of the tumor in the case of 68Ga-PSMA-R2 (pg. 22). Mariani et al. teach 64Cu (pg. 9). Mariani et al. teach pharmaceutical compositions comprising a pharmaceutical carrier (pg. 13). The preferred methods of the invention are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution (pg. 13).
Mariani et al. do not teach a powder for a solution for injection consisting of the following: i) a PSMA-R2 in an amount between 10 and 100 mg, and ii) mannitol in an amount between 5 and 50 mg.
Luna-Gutiérrez et al. teach freeze-dried multi-dose kits for the fast preparation of 177Lu-Tyr3-octreotide and 177Lu-PSMA(inhibitor) under GMP conditions. From only lyophilized kit of DOTA-iPSMA it was possible to obtain from 5 to 10 doses suitable for patients. It is possible to obtain GMP-compliant 177Lu-peptides from sterile freeze-dried formulation without the need of using commercially available radiochemical synthesizers (abstract). It is possible to design freeze dried sterile formulations to obtain a lyophilized powder with the sterile solution of LuCl3 followed by heating in a vial for complete 177Lu-conjugate formation under sterile conditions (pg. 2182). Different amounts of 177Lu-iPSMA were used to evaluate the effect of the variations on the 177Lu-peptide radiochemical purity (pg. 2182). Luna-Gutiérrez et al. teach the manufacturing of freeze-dried kits. The peptide and mannitol/ascorbic acid solutions are mixed and then lyophilized for 19 h. After freeze-drying the formulation, the kit was stored at 2-8oC (pg. 2182). Luna-Gutiérrez et al. teach radiochemical synthesis. The total volume of 177LuCl3 and acetate buffer pH 5.0 was withdrawn using a sterile syringe and afterward employed for the reconstitution of the DOTA-iPSMA lyophilized kit. The reconstituted vial was heated in the dry bath at 95oC for 30 min (pg. 2183). The selected kit composition was: (1) one lyophilized vial containing 0.6 mg (DOTA-iPSMA) of the peptide, 100 mg of ascorbic acid and 50 mg of mannitol as a diluent, and (2) a second vial containing acetate buffer (pg. 2184). The lyophilized formulations were stable since the three validation batches consistently produced 177Lu-radiopharmaceuticals with radiochemical purities in agreement with established specifications (>97%) (pg. 2185).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Mariani et al. (compositions comprising PSMA-R2 optionally as a sterile powder prepared by freeze drying for the preparation of sterile injectable solutions) bv forming a powder consisting of PSMA-R2 (formula II) and mannitol (a well-known bulking agent) as taught by Mariani et al. and Luna-Gutiérrez et al. because the powder would have been expected to advantageously enable kit preparation of GMP compliant 68Ga-PSMA-R2 or 177Lu-PSMA-R2 optionally at multiple doses without the need for commercially available radiochemical synthesizers. 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). The amounts of PSMA ligand and mannitol in the powder are 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 PSMA-R2 that is between 10-100 mg, optionally 15 to 60 mg or 30 mg through routing experimentation in order to an optimal amount of PSMA-R2 suitable for one or more doses and capable of quantitative complexation and high radiochemical purity/stability. A person of ordinary skill in the art would have arrived at an amount of mannitol that is between 5 and 50 mg, optionally 10 and 30 mg or 20 mg in order to arrive at an optimal amount of bulking agent for the lyophilized powder based on the amount of PSMA-R2 used.
Claim(s) 21-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mariani et al. (WO 2021/001360 A1; published 2021), in view of Luna-Gutiérrez et al. (J. Radioanal. Nucl. Chem.; published 2017; see attached 892), in further view of Fugazza et al. (WO 2013/024013 A2; published 21 Feb. 2013; see attached 892).
Mariani et al. teach as discussed above.
Mariani et al. do not further teach a kit having a second vial comprising a buffering agent comprising formic acid and sodium hydroxide optionally for maintaining a pH between 2.5 and 4.0, 2.8 and 4.0, 3.0 and 4.0, 3.2 and 2.8, and optionally wherein the kit does not contain an antioxidant such as gentisic acid. Mariani et al. do not further teach a method of labeling the PSMA-R2 with 68Ga wherein the method comprises the steps of ii) adding a solution of the 68Ga to the first vial containing the obvious PSMA-R2 powder, iii) mixing the solution obtain in ii) with a buffering agent comprising formic acid and sodium hydroxide and incubating for a period of time and at a sufficiently elevated temperature for obtaining the PSMA-R2 labeled with 68Ga, and iv) adjusting the pH of the solution.
Luna-Gutiérrez et al. teach as discussed above.
Fugazza et al. teach a process for the preparation of complexes of 68Ga (see title). Fugazza et al. teach that the buffer should be non-toxic and able to buffer in the pH range of 3.5-5.0 (pg. 1). Depending on the selected chelator functionalized molecule heating at 75-90oC can be necessary. The formic acid/format buffer allows to establish the right pH and tolerate the eluate volume/acidity variation (pg. 3). Preferably the complexation reaction is carried out at a pH of 3 to 4.5 (pg. 6). The invention relates to a kit comprising ultrapure formic acid/formate buffer. The kit comprising: - a siliconized vial containing the chelator functionalized molecule and a siliconized vial containing a suitable ultrapure formic acid/formate mixture. The invention relates to a single vial containing the chelator functionalized molecule and suitable ultrapure formic acid/sodium formate (pg. 7). Fugazza et al. teach 68GaDOTApeptide labeling using ultrapure buffer formation and NaOH (carried out in the absence of gentisic acid; pg. 8) wherein formate and NaOH are added to vial containing the 68Ga and DOTA peptide.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify composition of Mariani et al. by further forming a kit further comprising ii) a second vial comprising a buffering agent comprising formic acid and sodium hydroxide in dry form as taught by Luna-Gutiérrez et al. and Fugazza et al. because that kit having a formic acid and NaOH in the second vial would have been expected to enable a kit comprising buffered solution capable of producing the best labeling conditions for 68Ga at a pH of about 3.8. The omission of an element is prima facie obvious if the element’s function is not desired. It would have been obvious to a person of ordinary skill in the art before the effective filing date to omit an antioxidant optionally wherein the antioxidant is gentisic acid when radiolysis is not issue or when gentisic acid is not desired.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Mariani et al. so that the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 is prepared by ii) adding a solution of 68Ga or 64Cu into the first vial thereby obtaining a solution of 68Ga or 64Cu and PSMA-R2, iii) mixing the solution in ii) with a buffering agent comprising sodium formate, formic acid and sodium hydroxide and incubating it for a sufficient period of time (~7 min) and at a sufficiently elevated temperature (75-95oC) for obtaining the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 and iv) adjusting the pH of the solution as taught by Luna-Gutiérrez et al., and Fugazza et al. because the adding and mixing would have been expected to advantageously enable GMP compliant production of the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 and because the adjusting the pH would have been expected to advantageously enable a pH suitable for use in diagnostic imaging. The temperature and/or period of time for the incubating step 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 temperature between 70oC and 100oC and/or incubating time of between 2 and 25 min through routine experimentation in order to arrive at optimal complexation temperature range and an optimal reaction time. When the radioisotope is 68Ga, a person of ordinary skill in the art would have arrived a temperature between 80oC and 95oC and period of time between 5 and 7 min through routine experimentation in order to arrive at optimal complexation temperature and reaction time. When the radioisotope is 64Cu a person of ordinary skill in the art would have arrived a temperature between 70oC and 95oC and period of time between 7 and 15 min through routine experimentation in order to arrive at optimal complexation temperature and reaction time.
Claim(s) 21-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ray et al. (WO 2017/165473 A1; published 2017), in view of Luna-Gutiérrez et al. (J. Radioanal. Nucl. Chem.; published 2017; see attached 892) and Fugazza et al. (WO 2013/024013 A2; published 21 Feb. 2013; see attached 892).
Ray et al. teach prostate-specific membrane antigen high affinity agents for endoradiotherapy of prostate cancer (see title). Ray et al. teach compound 2
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(see abstract; PSMA Ki=1.28 nM, example 3). Ray et al. teach radiometals selected as 68Ga, 67Ga and 64Cu (see pg. 6). Ray et al. teach kits and pharmaceutical compositions (see pg. 29-33).
Although Ray et al. disclose compound 2, a PSMA-R2 homologue, Ray et al. do not disclose PSMA-R2 or a powder for a solution for injection consisting or PSMA-R2 and mannitol. Ray et al. do not further teach a kit further comprising ii) a second vial comprising a buffering agent comprising formic acid and sodium hydroxide. Ray et al. do not further teach a method for labeling PSMA-R2 with 68Ga or 64Cu, the method comprising the steps of ii) adding a solution of the 68Ga to the first vial containing the obvious PSMA-R2 powder, iii) mixing the solution obtain in ii) with a buffering agent comprising formic acid and sodium hydroxide and incubating for a period of time and at a sufficiently elevated temperature for obtaining the PSMA-R2 labeled with 68Ga or 64Cu, and iv) adjusting the pH of the solution optionally in the absence of gentisic acid.
Luna-Gutiérrez et al. teach as discussed above.
Fugazza 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 Ray et al. by forming a 1 CH3 unit homologue of compound 2 to arrive PSMA-R2 and then form a powder for solution for injection consisting of the obvious PSMA-R2 and mannitol as taught by Ray et al. and Luna-Gutiérrez et al. because the obvious PSMA-R2 would have been expected to provide an equivalent homologue for imaging and therapy of PSMA associated disease and because the lyophilized powder would have been expected to advantageous enable GMP compliant kit production of radiotracers suitable for imaging and therapy of PSMA associated disease. Homologs are prima facie obvious due to a general expectation of similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
The amounts of PSMA ligand and mannitol in the powder are result effective variables 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 PSMA-R2 that is between 10-100 mg, optionally 15 to 60 mg or 30 mg through routing experimentation in order to an optimal amount of PSMA-R2 suitable for one or more doses and capable of quantitative complexation and high radiochemical purity/stability. A person of ordinary skill in the art would have arrived at an amount of mannitol that is between 5 and 50 mg, optionally 10 and 30 mg or 20 mg in order to arrive at an optimal amount of bulking agent for the lyophilized powder based on the amount of PSMA-R2 used.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Ray et al. by further forming a kit wherein the kit further comprises a second vial comprising a buffering agent comprising formic acid and sodium hydroxide as taught by Luna-Gutiérrez et al. and Fugazza et al. because that kit would have been expected to advantageously enable the best labeling conditions for 68Ga at an optimized pH of about 3.8. The omission of an element is prima facie obvious if the element’s function is not desired. It would have been obvious to a person of ordinary skill in the art before the effective filing date to omit an antioxidant optionally wherein the antioxidant is gentisic acid when radiolysis is not issue or when gentisic acid is not desired.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Ray et al. so that the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 is prepared by ii) adding a solution of 68Ga or 64Cu into the first vial thereby obtaining a solution containing 68Ga or 64Cu and PSMA-R2, iii) mixing the solution in ii) with a buffering agent comprising sodium formate, formic acid and sodium hydroxide and incubating it for a sufficient period of time (~7 min) and at a sufficiently elevated temperature (75-95oC) for obtaining the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 and iv) adjusting the pH of the solution as taught by Luna-Gutiérrez et al., Fugazza et al. because the adding and mixing would have been expected to advantageously enable GMP compliant production of the 68Ga-PSMA-R2 or 64Cu-PSMA-R2 and because the adjusting the pH would have been expected to advantageously enable an adjusted pH suitable for use in diagnostic imaging. The temperature and/or period of time for the incubating step 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 temperature between 70oC and 100oC and/or time of between 2 and 25 min through routine experimentation in order to arrive at optimal complexation temperature and reaction time. When the radioisotope is 68Ga, a person of ordinary skill in the art would have arrived a temperature between 80oC and 95oC and period of time between 5 and 7 min through routine experimentation in order to arrive at optimal complexation temperature and reaction time. When the radioisotope is 64Cu a person of ordinary skill in the art would have arrived a temperature between 70oC and 95oC and period of time between 7 and 15 min through routine experimentation in order to arrive at optimal complexation temperature and reaction time.
Applicants Arguments
Applicants assert that Blower teaches away from using their method to radiolabel DOTA. One of ordinary wanting to develop a method to efficiently radiolabel the PSMA binding ligand of formula (II) which comprises a DOTA chelating moiety would not consider the method of Blower as a suitable starting point. Blower does not teach or suggest a powder consisting of a PSMA ligand of formula (II) in an amount of 10-100 mg and mannitol in an amount of 5-50 mg. Neither Asti nor Mariani and/or NCT034900032 teach or suggest a powder consisting of the PSMA ligand of formula (II) in an amount of 10-100 mg and mannitol in an amount of 5-50 mg.
Applicant's arguments filed 21 Nov. 2025 have been fully considered but they are not persuasive. Mariani provides for the PSMA-R2 that reads on instant formula (II) capable of complexing a radioisotope such as 68Ga, 64Cu, or 177Lu for use in medical imaging. In addition, Mariani teaches and suggests a powder for a solution for injection obtain by freeze drying, the powder comprising PSMA-R2. At the abstract that summarizes of the claimed invention, Ray provides for compound 2 out three compounds. A person of ordinary skill in the art would have had adequate reason and motivation to select and then modify compound 2 in Ray to form PSMA-R2 as an equivalent PSMA binding homologue before the effective filing date. Luna-Gutiérrez teaches and motivates freeze dried kit formulations where one vial contains a powder consisting of DOTA-iPSMA, mannitol (bulking/tonifying agent), and ascorbic acid. It is prima facie to omit ascorbic acid when its function is not desired. For example, Mariani and Fugazza do not teach ascorbic acid as a requirement. According to Luna-Gutiérrez, the lyophilized kit and powder advantageously enables obtaining multiple GMP compliant doses of radiopharmaceutical from sterile freeze-dried formulations without the need of using commercially available radiochemical synthesizer. 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 Mariani by forming a powder for solution for injection consisting of PSMA-R2 and mannitol because that powder would have been expected to advantageously enable GMP compliant production of for example 68Ga-PSMA-R2 without the need of using a commercially available radiochemical synthesizer.
Conclusion
THIS ACTION IS MADE FINAL. 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