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 .
Election/Restrictions
Applicant’s election without traverse of [18F]flurpiridaz as species of fluorinated compound in the reply filed on 7/1/2026 is acknowledged. Claims 1-19 are pending, of which claim 19 is withdrawn from consideration as being directed to a non-elected species. Claims 1-18 are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding claim 1, in line 5, the phrase in parentheses following a further drying step “(fluoride activation step),” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention, as the step is referred to as a drying step followed by a fluoride activation step in parentheses. See MPEP § 2173.05(d). The recitation of “drying step (b) (the fluoride activation step)” also occurs in claims 4 and 5. Clarification is requested.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The following reference was found during a search for the elected species, it should not be interpreted that a comprehensive search was performed for all non-elected species.
Claim(s) 1, 4, 5, 8, 10-13, 17 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wickstrom et al. (US 2013/0324715).
Wickstrom discloses a synthesis of [18F]FDG: Vial A contained K222 (43.7 mg, 117 µmol), K.sub.2CO.sub.3 (7.8 mg, 56.7 µmol) in 79.5% (v/v) MeCN(aq) (825 µl). Vial B contained the precursor (39 mg, 81.2 µmol) in 2.0 ml of MeCN with 1700 ppm water. Vial C contained of MeCN (4.1 ml). Vial D contained 2 M NaOH (4.1 ml). Vial E contained 2.3 M phosphoric acid (4.1 ml). Aqueous [18F]fluoride (1 ml, 100-200 Mbq) was passed through the QMA and into the 18O-H2O recovery vial. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (450 µl) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 µl, vial C). Approximately 1.6 ml of precursor solution (corresponds to 31.2 mg; 65 µmol precursor) from vial B was added to the reactor and heated at 125 C. for 2 min. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was first washed with water, then incubated with 2M NaOH (2.0 ml) for 2 min. The crude mixture was mixed with water (1.5 ml) and 2.3 M phosphoric acid (1.5 ml) and passed through the HLB and Alumina cartridges into the product vial made of glass (30 ml). Water (9 ml) was then sent through the HLB and Alumina cartridges and into the product vial. The purified formulation of [18F]FDG contained a Final volume of 15 ml. Radiochemical purity was tested by radio-TLC using a mixture of MeCN:H2O (95:5) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FDG fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 22 min (paragraph 0075).
Accordingly, Wickstrom discloses evaporating water and acetonitrile from a solution comprising [¹⁸F]fluoride; further drying comprising azeotropic distillation of water from said solution comprising [¹⁸F]fluoride with acetonitrile; and labelling a precursor compound with [¹⁸F]fluoride from the solution comprising [¹⁸F]fluoride. With regard to the limitation directed to the water content after the drying step and precursor, while water content is not explicitly recited, see MPEP 2112. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty."). In the instant case, it is considered that since the same steps are performed by Wickstrom (evaporation and azeotropic distillation) using the same solvent system as claimed, the claimed features would necessarily be present. Further regarding claim 17, HPLC is performed and impurity B is not disclosed. Regarding claim 18, an automated radiosynthesis apparatus is taught (paragraph 0010).
Claim(s) 1, 2, 4-11 and 15-17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Yan (WO 22/023439), as evidenced by Otaru et al. (Molecules, 2020, 25, 1208).
Yan discloses radiolabelled compounds, precursor compounds and reference compounds, as well as pharmaceutical compositions comprising the radiolabelled compounds, which are for use in a diagnostic method practised on the human or animal body using positron emission tomography (PET).
Radiolabelling procedures are taught on pages 30-31. Precursor compounds were radiolabelled to form 18F-labelled compounds. These 18F-labelled compounds were then oxidised to obtain their oxidised analogues.
Radiofluorination was performed by the nucleophilic substitution of the alkyl iodine in the precursor compounds, FM069 and FM083. [18F]Fluoride (~200-1200 MBq) in water was trapped in a carbonated QMA cartridge (Waters Sep-Pak light) pre-treated with water (10 mL), and released with 1.0 mL of Kryptofix 222 and potassium carbonate mixture (30:15 mM) dissolved in acetonitrile/water (85:15). After removing the solvents by heating at 110 °C under a stream of nitrogen for 15 min, azeotropic distillation with anhydrous acetonitrile (400 µL) was repeated twice at 90 °C for another 15 min. A solution of precursor (16 µmol) in anhydrous acetonitrile (400 µL) was then added and heated at 80 °C for 15 min in a closed Wheaton vial. The reaction was cooled to room temperature and quenched by addition of water (100 µL) and purified by semi-preparative HPLC.
Accordingly, Yan discloses evaporating water and acetonitrile from a solution comprising [¹⁸F]fluoride; further drying comprising azeotropic distillation of water from said solution comprising [¹⁸F]fluoride with acetonitrile; and labelling a precursor compound with [¹⁸F]fluoride from the solution comprising [¹⁸F]fluoride.
With regard to the limitation directed to the water content after the drying step and precursor, while water content is not explicitly recited, see MPEP 2112. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty."). In the instant case, it is considered that since the same steps are performed by Yan (evaporation and azeotropic distillation) using the same solvent system as claimed, the claimed features would necessarily be present. Further regarding claim 17, HPLC is performed and impurity B is not disclosed.
Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: (A) Prove the primary reference contains an "enabled disclosure;" (B) Explain the meaning of a term used in the primary reference; or (C) Show that a characteristic not disclosed in the reference is inherent. For example, "to serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991). See MPEP 2131.01.
In the instant case, Otaru is included to show that anhydrous acetonitrile, employed by Yan, inherently has less than 10 ppm water (page 11).
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Cesati et al. (US 2015/0196672) in view of Yan (WO 22/023439) and Siebenneicher et al. (WO 13/173630), in further view of Otaru et al. (Molecules, 2020, 25, 1208).
Cesati teaches compounds with imaging moieties for imaging a subject. The present invention also relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, a composition or plurality of imaging agents is enriched in 18 F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs (abstract).
An exemplary compound is shown in Embodiment 259:
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Radiofluorination procedures are taught in paragraphs 0568-0603.
In some embodiments a column is washed (e.g., with aqueous K2CO3), and the resulting solution diluted (e.g., with MeCN) and/or concentrated (e.g., to dryness using elevated temperature and/or reduced pressure). Anhydrous [18F]KF and/or [18F]Et4NF may be obtained and reacted with a compound or a salt thereof (paragraph 0592).
In some embodiments, a solution comprising a 18F species is heated to a temperature ranging from room temperature to about 200 C. For example, a solution comprising a [18F]-fluoride may be heated to elevated temperatures to encourage evaporation of the solvent (e.g., to about 100 C.). In some embodiments, a solution is heated to a temperature ranging from about 90-120 C. or from about 100-150 C. In some embodiments, a solution is heated to about 75 C., about 85 C., about 95 C., about 105 C., etc. (paragraph 0595).
In some embodiments, a solution is placed under a reduced pressure of about 100 mm Hg, etc. Those of ordinary skill in the art would be able to select and/or determine conditions suitable for a particular process (paragraph 0596).
In certain embodiments, a fluoride species and/or a reagent, if present, is then contacted with an imaging agent precursor under conditions that result in conversion of the imaging agent precursor to the imaging agent product via nucleophilic fluorination. Those of ordinary skill in the art would be able to select conditions suitable for use in a particular reaction (paragraph 0597).
Preparation of imaging agents using a custom robotic device18[ F] Fluoride prepared according to Example 65A was applied to a previously activated MPl anion exchange resin (BioRad) contained within a small volume plastic housing. The loaded cartridge was then placed into an elution loop located within a custom designed robotic radiosynthesis system and introduced when needed using one of the following methods.
Method A: [ F]Fluoride 1 Ci) was transferred from the resin to a glass vessel using an aqueous solution of tetraethylammonium bicarbonate (1.1 - 1.3 molar equivalents). The resulting mixture was then concentrated to dryness at elevated temperature (120 0C) and reduced pressure. Anhydrous acetonitrile was then added to the concentrated solution and all volatiles removed once again using elevated temperature (70 0C) and reduced pressure.
Method B: [ F]Fluoride (1 Ci) was transferred from the resin to a glass vessel using an aqueous solution of potassium bicarbonate (3 molar equivalents). The resulting mixture was then concentrated to dryness at elevated temperature (120 0C) and reduced pressure. A solution of Kryptofix™ (4 molar equivalents) in anhydrous acetonitrile was then added to the concentrated solution and all volatiles removed once again using elevated temperature (70 0C) and reduced pressure. A solution of the desired precursor (5-10 pmol) in anhydrous acetonitrile was then18added to the glass reaction vessel in order to solvate both [ F]fluoride and the remaining reaction components. The resulting solution was then transferred to a new glass vessel, heated to 90 0C and maintained 10 min. After cooling to ambient temperature, the solution was diluted with water and directly purified by HPLC (paragraph 1696-7).
Cesati does not specifically recite an azeotropic distillation step by after initial drying (evaporation) of 18F, prior to performing a labeling step.
Yan teaches radiolabelled compounds, precursor compounds and reference compounds, as well as pharmaceutical compositions comprising the radiolabelled compounds, which are for use in a diagnostic method practised on the human or animal body using positron emission tomography (PET).
Radiolabelling procedures are taught on pages 30-31. Precursor compounds were radiolabelled to form 18F-labelled compounds. These 18F-labelled compounds were then oxidised to obtain their oxidised analogues.
Radiofluorination was performed by the nucleophilic substitution of the alkyl iodine in the precursor compounds, FM069 and FM083. [18F]Fluoride (~200-1200 MBq) in water was trapped in a carbonated QMA cartridge (Waters Sep-Pak light) pre-treated with water (10 mL), and released with 1.0 mL of Kryptofix 222 and potassium carbonate mixture (30:15 mM) dissolved in acetonitrile/water (85:15). After removing the solvents by heating at 110 °C under a stream of nitrogen for 15 min, azeotropic distillation with anhydrous acetonitrile (400 µL) was repeated twice at 90 °C for another 15 min. A solution of precursor (16 µmol) in anhydrous acetonitrile (400 µL) was then added and heated at 80 °C for 15 min in a closed Wheaton vial. The reaction was cooled to room temperature and quenched by addition of water (100 µL) and purified by semi-preparative HPLC.
Siebenneicher teaches surprisingly rapid and simple reformulation of very polar radiopharmaceuticals containing multiple acidic functional groups to solutions suitable for injecting into mammals (abstract).
Radiolabeling procedures are taught in Example 1+: Aqueous [18Fjfluoride solution was trapped in a small anion exchange Sep-Pak Plus Q A cartridge (Waters) {preconditioned with 5 mi 0.5 M K2CO3 solution and 10 mL water). The radioactivity was eluted with a solution mixture (1 .0 mg KCO3 in 0.5 ml water and 5.27 rng K222 in 1 .5 ml MeCN) from the QMA cartridge into a 5 mL conic Wheaton vial. The solvent was evaporated under a stream of nitrogen at 1 10°C. Azeotropic drying was repeated three times with 1.0 mL portions of acetonitrile ().
Otaru teaches that Fluorine-18 is the most widely used positron emission tomography (PET) radionuclide currently in clinical application, due to its optimal nuclear properties. The synthesis of 18F-labeled radiotracers often requires harsh reaction conditions, limiting the use of sensitive bio- and macromolecules as precursors for direct radiolabeling with fluorine-18. We aimed to develop a milder and efficient in vitro and in vivo labeling method for trans-cyclooctene (TCO) functionalized proteins, through the bioorthogonal inverse-electron demand Diels-Alder (IEDDA) reaction with fluorine-18 radiolabeled tetrazine (abstract).
DNA synthesis quality anhydrous acetonitrile (max. 10 ppm water) was purchased from Merck (page 11).
No-carrier-added 18F-Fluoride was produced in-house with Cyclone 10/5 cyclotron (IBA, Louvain-la-Neuve, Belgium) through a 18O(p,n)18F nuclear reaction, by bombarding H218O with 10 MeV protons. The radiosynthesis was carried out in a semiautomatic synthesis unit (DM Automation), with an integrated preparative HPLC system for the purification of the radiotracer. The nucleophilic 18F– was trapped on a Waters QMA Light ion-exchange cartridge, followed by elution with a basic K[18F]FK2.2.2-complex solution. Water residue was evaporated azeotropically by adding anhydrous ACN, followed by heating, under a 40-mL/min argon flow.
Radiosynthesis of [18F]6 In the one-step method, precursor 6, dissolved in 500 µL of anhydrous acetonitrile, was added into the dried K[18F]F/K2.2.2 and incubated for 2 min (25 ◦C). The reaction mixture was diluted with an additional 500 µL of anhydrous acetonitrile for the radio-TLC and radio-HPLC analysis (page 13).
It would have been obvious to one of ordinary skill in the art at the time of the invention to one of ordinary skill in the art at the time of the invention to perform azeotropic distillation steps after an initial drying step to remove water from an aqueous MeCN solution containing 18F, prior to reaction with a precursor in preparation of an 18F labeled imaging agent when the teaching of Cesati is taken in view of Yan, Siebenneicher and Otaru. One would have been motivated to do so, with a reasonable expectation of success, because each of Cesati, Yan, Siebenneicher and Otaru are directed to 18F radiolabeling, and are concerned with providing anhydrous 18F. Yan and Siebenneicher teach two or three azeotropic distillation steps subsequent to an evaporation are known in the art for drying 18F containing solution for use in reaction with an imaging agent precursor. Further, Cesati teaches that those of ordinary skill in the art will be able to select and/or determine an appropriate set of reaction conditions (e.g., concentration, temperature, pressure, reaction time, solvents) suitable for use in a particular application. In some embodiments, an imaging agent may be further processed using one or more purification techniques, and may optionally be combined with additional components, such as a stabilizing agent (paragraph 0590).
With regard to the limitations directed to the water content after the drying step and precursor, while water content is not explicitly recited, see MPEP 2112. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty."). In the instant case, it is considered that since the same steps are performed by Yan (evaporation and azeotropic distillation) using the same solvent system as claimed, the claimed features would necessarily be present. Further regarding claim 17, HPLC is performed and impurity B is not disclosed. Further, Otaru teaches use of anhydrous MeCN and azeotropic distillation and as precursor solvent, and that the anhydrous MeCN contains less than 10 ppm water. Regarding claims 15 and 16, Yan teaches use of ~200-1200 MBq [18F]Fluoride.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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