DETAILED ACTION
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 .
Response to Arguments
Applicant's arguments filed 01/02/2026 have been fully considered but they are not persuasive.
Applicant argues on Pg. 6-7 that Shirakami uses water in every working example and that Shirakami expressly teaches adjusting the solution to neutral or weakly alkaline pH to prevent volatilization of astatine. Applicant argues these teachings run directly counter to the claimed process which deliberately selects a volatile, chlorine-free solvent and then removes that solvent in a controlled manner to concentrate astaine-211.
However, this is not found persuasive because a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (see MPEP 2123 [R-5]). Although Shirakami does not explicitly list specific examples of using ethanol as volatile and polar solvent falling, the broader teachings that “in the present method, reduction to a solution containing 211At, for example aqueous solution, alcohol solution, for example ethanol, or an alcohol-aqueous solution, for example aqueous ethanol” (Pg. 2, par. 8; Pg. 3, par. 7-11) reasonably suggest ethanol as an operable solvent mixture and as such Shirakami presents a prima facie case of obviousness over the instantly claimed volatile polar solvent. Ethanol is listed as a suitable solvent in claim 5 of the instant invention.
Additionally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., chlorine-free) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Examiner notes chlorine appears to be mentioned once in the instant specification on Pg. 3, lines 11-19 describing a “by collecting astatine-211 with a chlorine free solvent such as alcohol…”. Accordingly, Shirakami teaching an alcohol solvent meets the limitation required by the claim.
Furthermore, as noted in the rejection, Shirakami teaching sodium bicarbonate meets the limitation “weak acid,” as outlined in the instant specification on Pg. 9 and in instant claims 2-4. Shirakami teaching ethanol as a solvent meets the limitation “volatile and polar solvent,” as outlined in the instant specification on Pg. 8 and in instant claim 5. Shirakami teaching the sodium bicarbonate alcoholic solution being added at room temperature requires cooling the evaporated astastine-211, meeting the limitation of step (3) and (4) as claimed. It is unclear how the process of Shirakami adding a weak acid salt teaches away from adding the weak acid salt.
Applicant argues on Pg. 7 that Wilbur discloses removal of acid following dissolution of bismuth metal in nitric acid in a so-called “wet method” while Wilbur does not teach removal of water or alcohol to concentrate asatine-211. Applicant argues Wilbur criticizes distillation methods and advocates for wet chemistry.
However, step (5) in claim 1 requires removing the solvent from the astaine-211 solution continuing the weak acid salt. In this regard, Wilbur teaches removing acid solution from an astaine-211 solution for the advantageous effect of providing an astaine-211 residue that can then be purified to provide larger quantities of astaine-211. In this regard, Wilbur teaches the deficiencies of Shirakami as required by the claims. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Additionally, it is unclear where Applicant is referring to in Wilbur regarding the criticism of distillation. Wilbur states in [0051] “Concentrating the eluted material can be performed by any applicable method known in the art. For example, in some embodiments, the eluted material is concentrated by distilling the eluting base from the eluted material,” while teaching in an example in [0064] that the acid was removed by distillation.
Applicant argues Shirakami does not teach or suggest vaporized astatine-211 is sent directly to a solvent immediately following thermal release. Applicant argues the present application introduces a solvent-based vapor trapping method. However, Shirakami teaches a method of preparing an astaine-211 solution that begins with alpha-particle irradiation of bismuth-209 in a cyclotron to provide astaine-211 prior to heating the substance to evaporate astatine-211, and dissolving the evaporated astatine-211 in a liquid in the presence of a pH modifier including sodium hydrogen carbonate (i.e. sodium bicarbonate (Pg. 3, par. 5-7; Pg. 3, Test Example 1, Examples 2-5). The process of irradiating bismuth with alpha-particle radiation to generate volatile astatine-211 that is then dissolved in a liquid in the presence of a pH modifier directly overlaps the process of claims 1-4. It is unclear how the process of Shirakami does not teach the claimed limitations.
Applicant argues Wilbur teaches a wet-chemistry method where bismuth is dissolved in acid while Shirakami teaches a distillation method. Applicant argues Wilbur expressly states distillation is problematic and not using dry distillation would be of significant value. Applicant argues the explicit criticism eliminates motivation to modify Shirakami with Wilbur.
However, step (5) in claim 1 requires removing the solvent from the astaine-211 solution containing the weak acid salt. In this regard, Wilbur teaches removing acid solution from an astaine-211 solution for the advantageous effect of providing an astaine-211 residue that can then be purified to provide larger quantities of astaine-211. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Additionally, it is unclear where Applicant is referring to in Wilbur regarding the criticism of distillation. Wilbur states in [0051] “Concentrating the eluted material can be performed by any applicable method known in the art. For example, in some embodiments, the eluted material is concentrated by distilling the eluting base from the eluted material,” while teaching in an example in [0064] that the acid was removed by distillation. Wilbur clearly teaches and suggests to skilled artisans that distillation to remove liquid is effective. Examiner notes that the concentration of solutions by distillation is extremely common in the art and is well within a skilled artisans ability to arrive at as a method of solvent removal.
Second, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Wilbur is not relied on to teach step 1-4 in claim 1 but rather Shirakami is. Wilbur is combined with Shirakami to teach the limitation of removing solvent.
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 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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1).
Regarding claim 1, Shirakami teaches a method of preparing an astaine-211 solution that begins with alpha-particle irradiation of bismuth-209 in a cyclotron to provide astaine-211 prior to heating the substance to evaporate astatine-211, and dissolving the evaporated astatine-211 in a liquid in the presence of a pH modifier including sodium hydrogen carbonate (i.e. sodium bicarbonate (Pg. 3, par. 5-7; Pg. 3, Test Example 1, Examples 2-5). Shirakami further teaches the liquid used to dissolve the astaine-211 can be an alcoholic solution comprised of ethanol (Pg. 3, par. 7-11). Shirakami teaches the astantine-211 dissolving step is conducted at room temperature, specifically at 0 to 40 °C (Pg. 3, par. 3).
Shirakami teaching sodium bicarbonate meets the limitation “weak acid,” as outlined in the instant specification on Pg. 9 and in instant claims 2-4. Shirakami teaching ethanol as a solvent meets the limitation “volatile and polar solvent,” as outlined in the instant specification on Pg. 8 and in instant claim 5. Shirakami teaching the sodium bicarbonate alcoholic solution being added at room temperature requires cooling the evaporated astastine-211, meeting the limitation of step (3).
The claim further requires “a step of removing the solvent from the astatine-211 solution containing weak acid salt obtained in step (4),” to which Shirakami does not explicitly discuss.
Wilbur teaches a process for isolation and purification of astatine-211 where following
irradiation of a bismuth sample to produce astatine-211 and dissolution in acid to prepare a solution comprising astatine-211, the acid solution is removed from the astatine-211 residue ([0017]; [0027]; [0042]).
Advantageously, removing the acid solution provides astatine -211 residues, which can be further processed to provide purified astatine-211 in larger quantities and greater yields than known methods ([0042]; [0054]; [0064]).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to remove the acid solution from the astatine-211 in the process of Shirakami in order to provide an astatine-211 residue that can be further purified in large quantities and with improved yield, as taught by Wilbur.
Regarding claim 2-4, Shirakami teaches sodium bicarbonate (NaHCO3) is added to the astatine-211 solution (Pg. 3, par. 4-6; Pg. 4, Example 1).
Regarding claim 5, Shirakami further teaches the liquid used to dissolve the astaine-211 can be an alcoholic solution comprised of ethanol (Pg. 3, par. 7-11). Shirakami teaching ethanol as a solvent meets the limitation “volatile and polar solvent,” as outlined in the instant specification on Pg. 8 and in instant claim 5.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1) and further in view of Goodman et al. (US20060292073A1).
Regarding claims 6-8, modified Shirakami teaches the method of preparing astaine-211 of claim 1 and the claims further require limitations to which Shirakami and Wilbur are silent.
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Goodman teaches a method of radiolabeling compounds (Abstract), where the radioactive labeling element is incorporated by exchange of trifluoromethanesulfonyloxy groups with alkali metal salts of halogen isotopes, including astaine-211 ([0014]; [0041]; Pg. 6, Scheme 2, step h; Scheme 5, step j).
It is noted Goodman depicts substitution of the trifluoromethanesulfonyloxy group with fluoride-18, however as noted above, Goodman describes the method as being effective with a variety of halogen isotopes, including astatine-211 ([0014]). The trifluoromethanesulfonyloxy meets the limitation “haloalkylsulfonyloxy” in claim 7 and “trifluoromethanesulfonyloxy” in claim 8. Further, the process of Goodman is understood to be a nucleophilic substitution reaction, where trifluoromethanesulfonyloxy is a leaving group being displaced by the incoming halogen isotope nucleophile. Further, this process is analogous to that disclosed in the instant invention in at least Pg. 10-14 of the instant specification, meeting the limitation “nucleophilic substitution reaction.”
Advantageously, the method disclosed by Goodman is reliable, efficient, and allows gram scale preparations of key precursors for radiolabeling ([0011]).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate a halogen isotope into a compound by nucleophilic substitution of a trifluoromethanesulfonyloxy in the process of Shirakami in order to incorporate halogen isotopes in a reliable and efficient manner that allows gram scale preparation of radiolabeled compounds, as taught by Goodman.
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1) and further in view of Ogawa et al. (Nuclear Medicine and Biology, 2015, 42, 875-879).
Regarding claims 9-12, modified Shirakami teaches the method of preparing astaine-211 of claim 1 and the claims further require limitations to which Shirakami and Wilbur are silent.
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Ogama teaches a process to prepare astatine-211 labeled compounds by standard electrophilic halogenation of aromatic rings substituted with tributylstannyl moieties with astatine-211 reagents (Abstract; Title; Fig. 1, Pg. 877, 3. Results).
The moiety Sn(nBu)3 taught by Ogawa meets the limitation “trialkylstannyl group” of claim 11, and “tributylstannyl group” of claim 12. Further, Ogawa describing the reaction as electrophilic halogenation of an aromatic ring substituted with tributylstannyl groups meets the limitation of “electrophilic substitution reaction” in claim 9 and “aromatic electrophilic substitution reaction” in claim 10.
Advantageously, electrophilic halogenation of corresponding tributylstannyl precursors with astatine-211 provides a very high radiochemical yield in the resulting products (Pg. 877, 3.1. Preparation of (+)-[211At]pAtV).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate astatine-211 into an aromatic ring by electrophilic halogenation of corresponding tributylstannyl precursors in the process of Shirakami in order provide compounds with a very high radiochemical yield, as taught by Ogawa.
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 Jordan Wayne Taylor whose telephone number is (571)272-9895. The examiner can normally be reached Monday - Friday, 7:30 AM - 5 PM EST; Second Fridays Off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sally A. Merkling can be reached on (571)272-6297. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.W.T./Examiner, Art Unit 1738
/SALLY A MERKLING/SPE, Art Unit 1738
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