DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 07/06/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claim(s) 1-17, 19-27, 29-38, 40-53 are rejected under 35 U.S.C. 103 as being unpatentable over de Palo et al (US 2020/0030467 A1).
De Palo taught a pharmaceutical aqueous solution comprising (a) a complex formed by (ai) a radionuclide, and (aii) a target cell receptor binding organic moiety linked to a chelating agent; and (b) at least one stabilizer against radiolytic degradation [0003, 0005, 0014, 0054 at embodiment 4, 0106]; wherein the stabilizer was ascorbic acid, and/or salts thereof (e.g., sodium ascorbate) [0052]. Gentisic acid was taught, but not required [see ¶ 0052].
Claim 1 is rendered prima facie obvious over the teachings of de Palo, because it is prima facie obvious to combine prior art elements according to known methods, in order to yield predictable results. In the instant case, all the claimed elements (e.g., radiolabeled complex comprising radionuclide and targeting molecule linked to chelating agent; stabilizer) were known in the prior art (e.g., de Palo) and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would yield nothing more than predictable results (e.g., a radiolabeled complex) to one of ordinary skill in the art. MPEP 2143.A.
De Palo reads on claims 1, 6-7, 9-12, 27, 34-35 and 52-53.
Further regarding claims 9 and 27, the instant claims recite the transitional phrase “consisting essentially of”. Absent a clear indication in the specification or claims of what the basic and novel characteristics of the claimed composition actually are, the term "consisting essentially of" is construed as being equivalent in meaning to the term "comprising". See MPEP 2111.03 and 2163 II.A.1. No such clear indication is seen here.
Claims 2-5, 29, 36 and 38 are rendered prima facie obvious because de Palo taught 177Lu and a somatostatin receptor binding peptide linked to the chelating agent [0330-0331]; de Palo taught DOTA, DOTATOC and DOTATATE [0054, embodiments 16 and 17]. 177LuCl3 was taught at [0378].
Claim 8 is rendered prima facie obvious because additional buffers, including acetate buffer, were taught, though not required [0372, 0382].
Claims 13-15 are rendered prima facie obvious because de Palo taught stabilizer(s) is (are) present in a total concentration of from 0.2 to 20.0 mg/mL, preferably from 0.5 to 10.0 mg/mL, more preferably from 1.0 to 5.0 mg/mL, even more preferably from 2.7 to 4.1 mg/mL [0054, embodiment 4].
The instant claim 13 recites a weight ratio of sodium ascorbate to ascorbic acid between 30:1 and 70:1.
The instant claim 14 recites the concentration of ascorbic acid in the range from 0.5 to 5.0 mg/mL.
The instant claim 15 recites the concentration of the salt of ascorbic acid in the range from 10 to 100 mg/mL.
The instant claims 24, 43 recites a weight ratio of sodium ascorbate to ascorbic acid between 2:1 and 6:1.
The instant claims 25 and 44 recite the concentration of ascorbic acid in the range from 1-50 mg/mL.
The instant claims 26, 45 and 51 recite the concentration of the salt of ascorbic acid in the range from 10 to 100 mg/mL.
de Palo taught stabilizer(s) is (are) present in a total concentration of from 0.2 to 20.0 mg/mL, preferably from 0.5 to 10.0 mg/mL, more preferably from 1.0 to 5.0 mg/mL, even more preferably from 2.7 to 4.1 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A.
Claim 16 is rendered prima facie obvious because de Palo taught a composition which does not contain ethanol [0011, 0043].
Claims 17-18 are rendered prima facie obvious because de Palo taught a shelf life of from 24 h to 120 h [0054, embodiment 20]; radiochemical purity was ≥ 95 % [0235].
The instant claim 17 recites a shelf life of at least 96 h.
The instant claim 18 recites radiochemical purity for at least ≥ 97 % for at least 96 h.
De Palo taught a shelf life of from 24 h to 120 h; radiochemical purity of ≥ 95 %. A prima facie case of obviousness exists because of overlap, as discussed above.
Claims 19-20 are rendered prima facie obvious because de Palo taught administering a high dose within a short time frame. E.g. in the case of 177Lu-DOTA-TATE, the high dose of 7.4 GBq was provided in a small volume of 20.5 to 25.0 mL which allowed the IV infusion administration to be completed within about 20 to 30 minutes [0037].
Claim 19 recites 7.5 GBq ± 10 % of radioactivity.
Claim 20 recites a volume of 15 to 20 mL.
Palo taught administering a high dose within a short time frame. E.g. in the case of 177Lu-DOTA-TATE, the high dose of 7.4 GBq was provided in a small volume of 20.5 to 25.0 mL. A prima facie case of obviousness exists because of overlap, as discussed above.
Claims 21-23, 40-42 and 49-50 are rendered prima facie obvious because de Palo taught the presence of a stabilizer during complex formation and a stabilizer added after the complex formation [0040].
Claims 30 and 37 are rendered prima facie obvious because de Palo taught a volumetric radioactivity of up to 20 GBq/mL [0218].
The instant claim 30 recites a volumetric radioactivity of 0.42 GBq/mL ± 0.04 GBq/mL.
The instant claim 37 recites a volumetric radioactivity of 6.0 to 9.5 GBq/mL.
de Palo taught a volumetric radioactivity of up to 20 GBq/mL. A prima facie case of obviousness exists because of overlap, as discussed above.
Claims 31-33 are rendered prima facie obvious because de Palo taught treating cancer [0268].
Claim 47 is rendered prima facie obvious because de Palo taught a pH from 4.5 to 6.0 [0372].
The instant claim 46 recites a pH of about 4.0-5.5.
De Palo taught a pH from 4.5 to 6.0. A prima facie case of obviousness exists because of overlap, as discussed above.
Claims 47-48 are rendered prima facie obvious because de Palo taught forming the complex (solution of aqueous radionuclide mixed with aqueous solution of chelating agent linked to targeting moiety and stabilizer) at a temperature of from 70 to 99 °C for from 2 to 59 min [0108-0110 and 0116].
The instant claims 47-48 recite a temperature of 87 ± 4 °C performed for 25 ± 3 min. de Palo taught forming the complex at a temperature of from 70 to 99 °C for from 2 to 59 min. A prima facie case of obviousness exists because of overlap, as discussed above.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Applicant argued that de Palo includes gentisic acid. Applicant argued that de Palo’s abstract taught that two stabilizers is of particular advantage. Applicant additionally cited to ¶s [0040] and [0042] to argue the advantage of de Palo’s two different stabilizers. Applicant cited de Palo’s ¶s [0073-0074, 0181-0184], and at the claims and Example 1. Applicant argued that de Palo’s inventive concept, preferred embodiment and exemplified product uses gentisic acid and ascorbic acid, and claims a particular advantage. Applicant argued that de Palo teaches away from the claimed invention.
The Examiner disagrees. De Palo taught at least one stabilizer, as stated in the body of the rejection. De Palo did not teach that the at least one stabilizer had to be gentisic acid; and, de Palo does not require gentisic acid, contrary to what the Applicant has alleged.
At ¶ [0052], de Palo taught that, “in general, the stabilizers used were selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine.” Later, in the same paragraph, de Palo taught that “the preferred stabilizers were selected from gentisic acid and ascorbic acid.” However, the MPEP, at sections I and II, states that the (I) prior art is relevant for all that it contains; and that (II) nonpreferred and alternative embodiments also constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.
As such, de Palo’s gentisic acid is not required. De Palo only requires one stabilizer, and gives no mention as to what stabilizer is required. De Palo gives a list from which to choose the stabilizers. Two stabilizers are preferred from de Palo’s teachings; but, de Palo’s preferences are not a teaching away from that which is claimed.
The Applicant appears to allege that the Examiner is participating in impermissible hindsight analysis.
The Examiner disagrees. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See MPEP 2145. In the instant case, the rejection of the claims was based on a motivation to combine elements as claimed (radiolabeled complex comprising radionuclide and targeting molecule linked to chelating agent; stabilizer), by known methods, with no change in their respective functions, where the combination would yield nothing more than predictable results (e.g., a radiolabeled complex) [see the body of the rejection].
Applicant cited to Examples 1-3 and to Tables 1-2 and 5, to argued unexpected results over de Palo, relative to greater purity (99.2 % (instant) versus 96.1 % (de Palo); storage stability and radiochemical purity (98.83 % (instant) versus 94.23 % (de Palo)).
The Examiner disagrees that the Applicant has shown unexpected results. The Applicant has not provided data points with measurements of standard deviation, so it is not clear at this time as to whether or not the Applicant’s data is truly unexpected over de Palo, or is actually expected, in view of what was taught by de Palo. Furthermore, the claims are not so limited as to purity, storage stability and/or radiochemical purity, and at present, the claims do not appear patentably distinct from de Palo.
Claim(s) 28 is rejected under 35 U.S.C. 103 as being unpatentable over de Palo et al (US 2020/0030467 A1), in view of Liu et al (Bioconjugate Chem, 2003, 1052-1056).
The 35 U.S.C. 103 rejection over de Palo was previously discussed. As discussed, de Palo taught that the stabilizer(s) is (are) present in a total concentration of from 0.2 to 20.0 mg/mL, where sodium ascorbate and ascorbic acid were taught as the stabilizers.
De Palo did not teach a stabilizer concentration of 51 mg/mL ± 5.1 mg/mL, as recited in claim 28.
Liu taught stabilizers as a buffer agent and a radiolytic stabilizer, for the preparation and stabilization of radiolabeled DOTA-biomolecule conjugates [abstract], where the concentration of the stabilizer was between 20 and 100 mg/mL [page 1053, last paragraph at Radiolabeling Experiment].
Regarding the concentration of the stabilizer, the differences in the claimed subject matter and the prior art are 51.1 ± 5 mg/mL, as recited in claim 28, versus between 20 and 100 mg/mL, as taught by Liu.
De Palo was not silent as the amount of the stabilizer. For example, de Palo taught stabilizer(s) is (are) present in a total concentration of from 0.2 to 20.0 mg/mL. However, de Palo was not specific the claimed 51.1 ± 5 mg/mL concentration. Nevertheless, Liu taught that this ingredient was useful in concentrations between 20 and 100 mg/mL, an amount that overlaps the amount instantly recited. This ingredient, and its amount, is recognized to have different effects (radiolytic stabilization, as taught by Liu at the abstract) with changing amounts used. Thus, the general condition (the concentration) is known, and the amount of this ingredient is recognized to be result effective. As such, result effective variables can be optimized by routine experimentation, and it would have been prima facie obvious to optimize the amount of the stabilizer in the composition taught by de Palo et al, as taught by Liu. See MPEP 2144.05.
With the combination of de Palo and Liu, the ordinarily skilled artisan would have had a reasonable expectation of success in arriving at the claimed stabilizer concentration.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Applicant argued nonobviousness based upon dependency.
The Examiner disagrees. The claim rejection is maintained, in view of obviousness over the cited prior art.
Claim(s) 39 is rejected under 35 U.S.C. 103 as being unpatentable over de Palo et al (US 2020/0030467 A1), as evidenced by Basu et al (Semin Nucl Med, 50:447-464, 2020).
The 35 U.S.C. 103 rejection over de Palo was previously discussed.
Additionally, de Palo taught 177Lu-DOTA-TATE, at 7.4 GBq [¶s 0037 and 0379], in a single dose per mL [claims 17 and 21-22].
Although de Palo taught 177Lu-DOTA-TATE at 7.4 GBq, de Palo was not specific 100 ± 10 µg/mL, as recited in claim 39.
Nevertheless, Basu evidenced that the radiopharmaceutical product 177Lu-DOTA-TATE, as a finished product, is available in ready-to-use single dosages containing 7.4 GBq ± 10% activity of 177Lu and 100 µg of DOTA-TATE (e.g., targeting molecule linked to chelating agent) [page 451, last paragraph, bridging to the top of page 452].
It is prima facie obvious to one of ordinary skill in the art that de Palo’s 177Lu-DOTA-TATE at 7.4 GBq contains 100 µg/mL, in a single dose, as evidenced by Basu.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Applicant argued nonobviousness based upon dependency.
The Examiner disagrees. The claim rejection is maintained, in view of obviousness over the cited prior art.
Nonstatutory Double Patenting
A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 9, 11, 13, 18-26 and 28-29 of copending Application No. 19/028,880.
Although the claims at issue are not identical, they are not patentably distinct from each other because the species recited in the copending claims (radiolabeled complexes) falls within the genus (stable formulations for radionuclide complexes) recited in the claims of the instant application, and thus read on the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Applicant will take appropriate action upon indication of allowability.
The Examiner responds that allowable subject matter has not been identified in the present application. A Terminal Disclaimer is required to obviate the NSDP rejection.
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.
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/CELESTE A RONEY/Primary Examiner, Art Unit 1612
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