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 .
DETAILED ACTION
Claims 1-14 of A. Toutov et al., US 17/998,785 (June 1, 2021) are pending. Claims 1-11 and 13 are rejected. Claim 12 and 14 are objectionable.
Claim Interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See, MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art and dictionaries. MPEP § 2111.01 (III).
The Claims
The claims are directed to method for electrospray ionization-assisted fluoridation. Independent claim 1 is reproduced below:
1. A method for electrospray ionization-assisted fluoridation, comprising
providing a target molecule for a fluorine isotope to be installed on and
optionally dissolving the target molecule in a first solvent to obtain a target molecule solution;
providing a fluorine anion and dissolving the fluorine anion in a second solvent to obtain a fluoride solution;
mixing the target molecule solution with the fluoride solution to obtain a reaction mixture;
optionally adding one or more reagents for activation of either the fluorine anion, or the target molecule, or both to the reaction mixture;
applying an ionization potential and mode to the reaction mixture, and
nebulizing the reaction mixture under the ionization potential and mode to create a plurality of microdroplets comprising the reaction mixture;
allowing the target molecule and the fluorine anion to chemically interact within the plurality of microdroplets to produce a reaction product,
wherein the plurality of microdroplets continuously desolvates until collection;
collecting the plurality of microdroplets comprising the reaction product in a collection vessel;
to obtain a fluoridation product of the chemical reaction between the target molecule and the fluorine anion in clinical-quality yield and purity.
Working Concept of the Claimed Invention
The specification teaches fluoridation of target molecules by application of electrospray ionization (ESI), by turning solution reaction media into accelerated, desolvated microdroplets, which undergo continuous and rapid solvent evaporation (desolvation) as they move towards collection, which, in turn, increases reagents concentrations and, thus, greatly enhances reactions' efficiencies. Specification at page 15, [0053].
Electrospray ionization (ESI) is a technique in which high voltage is applied to a liquid to produce aerosol ions. Specification at page 12, [0048]; P. Kebarle et al., 20 Mass Spectrometry Reviews, 898-917 (2009) (“Kebarle”); L. Konermann et al., 85 Analytical Chemistry, 2-9 (2013) (“Konermann”). Typically, during an ESI process, a solution comprising molecules of interest is ionized by application of high electrical current and vaporized (for example assisted by a coaxial gas flow) to produce a fine mist of charged droplets, wherein the resulting charged droplets may be next forwarded (for example, by a gas flow) to a MS system for mass spectroscopy, or otherwise collected and analyzed. Id. The initial ESI droplets have radii in the micrometer range. See Konermann at page 3, col. 1. The droplets emitted undergo rapid solvent evaporation ultimately yield the final generation of ESI droplets with radii of a few nanometers. Konermann at page 3, col. 1 (See Konermann Fig. 1). Gaseous analyte ions that are detected by mass spectrometer are produced from these highly charged nanodroplets. Konermann at page 3, col. 1 (See Konermann Fig. 1).
The working principle of the claimed invention is that rather than electrospray ionization (ESI) of a single analyte, claim 1 requires “mixing the target molecule solution with the fluoride solution to obtain a reaction mixture” and “nebulizing the reaction mixture under the ionization potential and mode to create a plurality of microdroplets comprising the reaction mixture”, whereby (per claim 1) the target molecule is fluorinated within the microdroplet as the microdroplet concentrates, to give the fluorinated reaction product.
Interpretation of “applying an ionization potential and mode to the reaction mixture”
The specification teaches that “In some embodiments, the ESI ionization mode of the instant methods is positive, while in other embodiments, it is negative”. Specification at page 17, [0058]. The specification does not define the meaning of “mode”.
In the art of electrospray ionization (ESI), "negative mode" and "positive mode" refer to the polarity of the ions generated from an analyte to be detected by a mass spectrometer. J. Gaumet et al., 11 Journal of the American Society for Mass Spectrometry, 338-344 (2000); P. Liigand et al., 89 Analytical Chemistry, 5665-5668 (2017). That is, the analyte either forms negative ions (negative mode) or cations (positive mode).
Claim Objections
Improper Markush Group
Claims 2, 7, 12, 14 are objected to because they are not drafted in proper Markush format. Applicant may overcome this rejection by using the following standard language in defining a Markush grouping.
“wherein the alternative is selected from the group consisting of A, B, C and D”; or
“wherein the alternative is A, B, C or D”. See MPEP § 2173.05(h).
For example, claim 2 can be amended to recite:
2. The method of claim 1, wherein the fluorine anion is selected from the group consisting of. 19F-[[;]] and 18F-.
Such amendment improves claim clarity, that the claims are interpreted as directed to a closed Markush group.
Claim Rejections - 35 USC § 112(a) (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-11 and 13 are rejected under 35 U.S.C. 112(a) because the specification, while enabling one of skill in the art to make and use the following subject matter (where proposed amendments to claim 1 is indicated by underlined text):
1. A method for electrospray ionization-assisted fluoridation, comprising
providing a target molecule for a fluorine isotope to be installed on, selected from the group consisting of compounds 8, 9, 16, 23, 24, and 25 of specification Example 3 (see specification Fig. 11 for structures) and
optionally dissolving the target molecule in a first solvent to obtain a target molecule solution;
providing a fluorine anion and dissolving the fluorine anion in a second solvent to obtain a fluoride solution;
mixing the target molecule solution with the fluoride solution to obtain a reaction mixture;
optionally adding one or more reagents for activation of either the fluorine anion, or the target molecule, or both to the reaction mixture;
applying an ionization potential and mode to the reaction mixture, and
nebulizing the reaction mixture under the ionization potential and mode to create a plurality of microdroplets comprising the reaction mixture;
allowing the target molecule and the fluorine anion to chemically interact within the plurality of microdroplets to produce a reaction product,
wherein the plurality of microdroplets continuously desolvates until collection;
collecting the plurality of microdroplets comprising the reaction product in a collection vessel;
to obtain a fluoridation product of the chemical reaction between the target molecule and the fluorine anion in clinical-quality yield and purity.
does not reasonably enable one of skill in the art to make and use the full claim scope of the claimed method with any target molecule
Factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993). The burden is on the examiner to show that the specification as filed and what was well known to one of skill in the art at the time of filing does not reasonably enable the full scope of the claimed invention. MPEP § 2164.05 (citing Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021); In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991).
Guidance and State of the Prior Art/Level of Predictability
Liu reports acceleration of reaction rates in microdroplets formed in the course of spray-based ionization. C. Liu et al., 10 Chemical Science, 9367-9373 (2019) (“Liu”). Liu teaches that Microdroplets show a strikingly different reactive environment from that of the corresponding bulk phase. Liu at page 9367, col. 1. Liu teaches that However, the flow rate (ca. 10 mL min-1) for the microdroplet reaction in ESI-MS is not high enough for preparative organic synthesis; although multiplexed ESI sprayer tips have even been used in the preparative method, the scale-up of microdroplet reactions in air is still challenging. Liu at page 9367, col. 2.
Wei teaches reactions occurring in confined individual microdroplets within an aerosol and that besides its use as an analytical tool, one can also take advantage of the dilute gas phase of mass spectrometry to perform chemical reactions. Z. Wei et al., 71 Annual Review of Physical Chemistry, 31-51 (April 2020) (“Wei”). Wei states that a key challenge is how the high reactivity and chemical specificity inherent in molecular ions generated by MS can be used to perform synthesis, ideally on a large scale and under ambient conditions. Wei at page 32, 2nd paragraph. Wei teaches that in most microdroplet reaction experiments, variables such as droplet size, temperature, and concentration are not easy to hold constant. Wei at page 34, last paragraph. Wei teaches that one important point is that droplet size and lifetime affect the reaction rate, so one can observe quite different extents of reaction when varying the distance from the sprayer to the MS inlet. Wei at page 34, 1st paragraph. Wei teaches that many factors cause the accelerated reactions in microdroplets, such as temperature, concentration, pressure, reagent orientation, and an increase in the intrinsic rate constant. Wei at page 42, last paragraph. Wei further teaches that due to both the larger surface-to-volume ratio and the more effective diffusion within small volumes, reaction acceleration in microdroplets is much greater than that in larger droplets or in bulk. Wei at page 43, 1st paragraph. Besides these factors, the special interface physical and electrochemical properties such as extreme pH, abnormal dielectric constant, and surface potential also contribute to making microdroplet chemistry different from bulk chemistry, and they need to be investigated more in the future. Wei at page 43, 1st paragraph.
X. Yan et al., Angewandte Chemie, International Edition, 12960-12972 (2016) (“Yan”) provides similar teachings to Wei with respect to unpredictability. Yan teaches that:
However, some fundamentals involved in this process are not yet fully understood, and a major challenge is the characterization of droplets with sizes below the diffraction limit, which have ultrashort lifetimes owing to rapid evaporation. Each of these factors hinders investigation in this regime and makes the problem hard to solve by conventional characterization methods. The fact that such droplets can support unusual chemical reactivity suggests that it might be possible to acquire information about the nature of the droplets by following their chemical reactions.
Yan at page 12969, col. 2 (emphasis added). Yan discusses that effect of microdroplet evaporation rate is an unpredictable variable with respect to product distribution. Yan at page 12967, col. 2. In this regard, Yan teaches that increasing the distance between the electrospray Ionization (ESI) emitter and the mass spectrometry (MS) inlet provides the droplets with more time to evaporate (increasing reagent concentrations) before they reach the MS inlet and dramatically changes the product distribution. Yan at page 12967, col. 2.
Gao teaches that chemical reactions in microdroplets exhibit specific properties that are not observed in bulk solutions, especially dramatic acceleration of reaction rates, which are often thousands to millions of times greater than that in the bulk. D. Gao et al., 25 Chemistry a European Journal, 1466-1471 (2019) (see page 1466 at col. 2). Gao teaches that instead of showing remarkable reaction-rate acceleration, some reactions in microdroplets show completely different reaction routes, possibly owing to the significantly different microenvironment in microdroplets. Id. For example, Gao teaches that the Diels–Alder reaction of 3,5-hexadienyl acrylate ester in microdroplets could not provide the desired Diels–Alder product in all cases even in the presence of catalyst, but just generated instead the hydrolyzed product, hexa-3,5-dien-1-ol. Id. In contrast, the desired Diels–Alder product can be easily obtained in aqueous media at high temperature using indium(III) triflate as a catalyst in bulk-phase. Id.
No art discusses or supplements the instant specification with respect to the claimed invention of fluoridation of target molecules by application of electrospray ionization (ESI), by turning solution reaction media into accelerated, desolvated microdroplets, which undergo continuous and rapid solvent evaporation (desolvation).
The art clearly indicates that chemical reactions within microdroplets is complex and unpredictable. Further, the claims are directed a nascent technology. MPEP § 2164.03 (citing Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) “[n]ascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction”).
Guidance in the Specification
The specification teaches that the capability of ESI technique to promote and or accelerate various chemical reaction is being extensively investigated. Specification at page 13, [0050]. The specification further teaches that
However, although there exist multiple reports investigating ESI effect on accelerating and or promoting various chemical reactions, such reports, typically, only track and analyze the reaction progression/kinetics via, for example, MS, and none suggests using ESI to deliberately drive a given reaction towards a specific desired product, or further adjusting conditions of such ESI-assisted reactions in order to maximize the yield of the desired product, and, most importantly, none reports collecting such product in meaningful amounts for further applications. In other words, no report to date has suggested using an ESI setup as a purely synthetic/standalone module
Specification at page 14, [0050].
Up though page 21, the specification provides general guidance only. In specification Example 1, only general guidance appears to be presented. Specification at pages 22-24, Example 1. For instance, the specification provides the following disclosure as part of Example 1:
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However, these ranges appear broad and the specification does not teach particular parameters for particular target compounds. For example, when (what target compounds) are used with a positive mode? A negative mode? Specification Example 1 cites Fig. 11 as providing provides a number of specific fluoridation examples illustrating many embodiments of the instant fluoridation methods, including ESI-assisted fluoridation of SiFA (reaction 25) and HetSiFA (reactions 22-24) moieties. However, Fig. 11 provides only reaction equations with no specific ESI conditions disclosed. Further, Fig. 11 appears to be prophetic.
Specification Example 2 also appears general in nature, and appears to be prophetic. Specification at page 25, [0007]. Specification Example 2 is directed to general conditions for mixing a target molecule in specific solvents at specific concentrations, without any ESI parameters or discussion of which target molecules these solvent/concentration guidelines are applicable. Specification at page 25, [0007].
Specification Example 3, by way of Table 2, states that it “provides examples of reaction conditions optimized for the ESI-assisted radiofluoridation” for six of the target molecules (substrates) shown in FIG. 11 (i.e., Fig. 11 substrates, 8, 9, 16, 23, 24 and 25), where %conversion is calculated based on relative peak areas. Specification at pages 24-25, [0078]. Table 2 specifies, fluoride salt (i.e., Kf or CsF), solvent, ESI mode, ESI potential (V), nebulizing gas temperature (NGB) and spray flow rate and provides a conversion rate. Specification Example 3 states that “values for this table were calculated based on the mass spectrometry analysis of the reaction mixture products using the equation provided below, wherein RPA represents relative peak area”. Specification at page 25, lines 1-2. Specification Example 3 (drafted in the past tense) is therefore not a prophetic example.1 Specification Example 3, however, does not state the amounts (for example in micrograms) of product prepared.
In sum, the bulk of the specification is general guidance. Specification Example 3 provides some specific electrospray ionization parameter guidance for six target compounds with the fluoride salt as KF or CsF. Specification at pages 24-25, [0078]. Specification Example 3, however, does not state the amounts (for example, in nano or picomoles) of product prepared.
Claim Breadth
Claim 1 is extremely broad with respect to the “target molecule” as it includes any target molecule. Further claim 1 is broad in that it includes (does not specify) the conditions required for the following claim 1 steps:
Claim 1 . . . applying an ionization potential and mode to the reaction mixture, and
nebulizing the reaction mixture under the ionization potential and mode to create a plurality of microdroplets comprising the reaction mixture;
allowing the target molecule and the fluorine anion to chemically interact within the plurality of microdroplets to produce a reaction product,
wherein the plurality of microdroplets continuously desolvates until collection . . .
Further, as discussed above, neither the art of record nor the specification teaches a target molecule, structure-function correlation allowing one of skill in the art to predict such conditions. Dependent claims 2-11 and 13 do not narrow claim 1 in these respects. Claims 1-11 and 13 are thus very broad and general in nature.
The Quantity of Experimentation Needed Is Undue
In the current case, claims 1-11 and 13 are rejected under 35 U.S.C. § 112(a), for lack of enablement because upon balancing the above-discussed factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full claim scope without undue experimentation. The primary Wands factor considered is the claim breadth in view of the unpredictability and lack of guidance in the specification and art of record.
The guidance in the specification does not balance the vast claim breadth versus the unpredictability. As discussed above, the specification (save for Example 3) provides general guidance. Specification Example 3 provides some specific electrospray ionization parameter guidance for six target compounds with the fluoride salt as KF or CsF. Specification at pages 24-25, [0078]. However, in view of the unpredictability, specification Example 3 cannot be viewed as sufficient guidance for the practice of the full scope of the claim 1 steps of:
Claim 1 . . . applying an ionization potential and mode to the reaction mixture, and
nebulizing the reaction mixture under the ionization potential and mode to create a plurality of microdroplets comprising the reaction mixture;
allowing the target molecule and the fluorine anion to chemically interact within the plurality of microdroplets to produce a reaction product,
wherein the plurality of microdroplets continuously desolvates until collection . . .
because Wei teaches that one important point is that droplet size and lifetime affect the reaction rate, so one can observe quite different extents of reaction when varying the distance from the sprayer to the MS inlet. Wei at page 34, 1st paragraph. Wei teaches that many factors cause the accelerated reactions in microdroplets, such as temperature, concentration, pressure, reagent orientation, and an increase in the intrinsic rate constant. Wei at page 42, last paragraph. In another example, Gao teaches that chemical reactions in microdroplets exhibit specific properties that are not observed in bulk solutions, especially dramatic acceleration of reaction rates, which are often thousands to millions of times greater than that in the bulk. D. Gao et al., 25 Chemistry a European Journal, 1466-1471 (see page 1466 at col. 2). Gao teaches that instead of showing remarkable reaction-rate acceleration, some reactions in microdroplets show completely different reaction routes, possibly owing to the significantly different microenvironment in microdroplets. Id.
In view of the lack of guidance in the art and specification, the parameters needed for each of the above cited claim 1 steps must be adjusted and determined individually for each target molecule. And even then, the desired fluoridation might not be effected. For example, Gao teaches that the Diels–Alder reaction of 3,5-hexadienyl acrylate ester in microdroplets could not provide the desired Diels–Alder product in all cases even in the presence of catalyst, but just generated instead the hydrolyzed product, hexa-3,5-dien-1-ol. Id. In contrast, the desired Diels–Alder product can be easily obtained in aqueous media at high temperature using indium(III) triflate as a catalyst in bulk-phase. Id.
The art of record does not supplement the instant specification with respect to the claimed invention of fluoridation of target molecules by application of electrospray ionization (ESI), by turning solution reaction media into accelerated, desolvated microdroplets, which undergo continuous and rapid solvent evaporation (desolvation). No art teaches or provides guidance with respect to the claim 1 microdroplet fluoridation. In this resepct, the claims are directed a nascent technology. MPEP § 2164.03 (citing Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) “[n]ascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction”).
Rejections 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b) and (f):
(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.
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
Pursuant to 35 U.S.C. 112(b), the claim must apprise one of ordinary skill in the art of its scope so as to provide clear warning to others as to what constitutes infringement. MPEP 2173.02(II); Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f):
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f). MPEP § 2181(I). The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function. MPEP § 2181(I).
Unclear Claim Steps/Limitations
Claims 8 is rejected under 35 U.S.C. 112(b)/(f) as indefinite because the meaning of “additional means” is unclear. Claim 8 recites as follows:
8. The method of claim 1, wherein additional means are provided to assist with desolvation of the plurality of microdroplets, and or to guide a flow of the plurality of microdroplets towards the collection vessel, and or to otherwise accelerate the chemical reaction within the plurality of microdroplets.
Use of the word “means” in claim 8 with the functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f). MPEP § 2181(I). The proper test for meeting the definiteness requirement is that the corresponding structure (or material or acts) of a means- (or step-) plus-function limitation must be disclosed in the specification itself in a way that one skilled in the art will understand what structure (or material or acts) will perform the recited function. MPEP 2181(II)(A). The most relevant portions of the specification are as follows:
[0058] . . . In many embodiments, the reaction conditions, including the extent of the microdroplet desolvation, are further optimized by determining and using the solubility parameters (i.e., the free-energy relationship of the solvents, gases, and reagents) to optimize the microdroplets' pathway to the collection vessel . . .
Specification at page 17, [0058].
[0074] In many embodiments, as the reaction mixture is nebulized by the ESI sprayer and the solvents are evaporated from the microdroplets, the desired reaction is accelerated. Accordingly, in many embodiments, the parameters affecting the production of the microdroplets are adjusted as described herein to promote continuous desolvation process that further favors acceleration of the desired reaction. For example, in many embodiments, the solvent evaporation is promoted by the injection of an inert or otherwise non-reactive gas into the ESI sprayer. In many embodiments, the inert or otherwise non-reactive gas is used both to promote the desolvation of the reagents and, thus, accelerate the desired reaction, and, also, to guide the microdroplets to the collection vessel.
Specification at page 23, [0074]
[0075] In many embodiments, next, the reactants-loaded microdroplets/effluent travel from the ESI sprayer to a collection vessel. In such embodiments, the length and trajectory of the microdroplets are adjusted to allow for the most efficient desolvation process to occur in order to maximally accelerate the desired reaction.
Specification at page 23, [0075]. However, these specifications portions recite no physical structures nor guidance as to what physical method steps or analysis is performed to (per claim 8) to “to assist with desolvation of the plurality of microdroplets, and or to guide a flow of the plurality of microdroplets towards the collection vessel, and or to otherwise accelerate the chemical reaction within the plurality of microdroplets”. The above specification portions do not sufficient describe the corresponding structure (or material or acts) of the claim 8 means-plus-function limitation in a way that one skilled in the art will understand what structure (or material or acts) will perform the recited claim 8 function. MPEP 2181(II)(A). Claim 8 is therefore indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim 1 upon which it depends, or for failing to include all the limitations of the claim upon which it depends for the following reasons. Claim 7 recites as follows:
7. The method of claim 1, wherein the ionization mode is selected from the group consisting of: positive, negative.
However, the “mode” as recited in claim 1 can only be “positive” or “negative” in the first place. Specification at page 17, [0058]; see also Claim Interpretation above. As such, claim 7 fails to recite a limitation that further limits claim 1.
Subject Matter Free of the Art of Record
Claims 1-14 are free of the art of record. The closest art of record is Z. Wei et al., 71 Annual Review of Physical Chemistry, 31-51 (April 2020) (“Wei”) in view of either Y. Joyard et al., 21 Bioorganic & Medicinal Chemistry, 3680-3688 (2013) or C. Waldmann et al., WO 2016/191424 (2016) (“Waldmann”).
Wei teaches that various organic reactions, including important synthetic reactions involving C–C, C–N, and C–O bond formation as well as reactions of biomolecules, are accelerated when the reagents are present in sprayed or levitated microdroplets or in thin films. Wei at Abstract. Wei teaches that the reaction rates increase by orders of magnitude with decreasing droplet size or film thickness and the effect is associated with reactions at the solution–air interface. Wei at Abstract. Wei teaches that with respect to reactions occurring in confined individual microdroplets within an aerosol, one can also take advantage of the dilute gas phase of mass spectrometry to perform chemical reactions. Wei at page 33. However, Wei teaches that accelerated reactions in microdroplets is unpredictable. In this regard, Wei states that a key challenge is how the high reactivity and chemical specificity inherent in molecular ions generated by MS can be used to perform synthesis, ideally on a large scale and under ambient conditions. Wei at page 32, 2nd paragraph. Wei teaches that in most microdroplet reaction experiments, variables such as droplet size, temperature, and concentration are not easy to hold constant. Wei at page 34, last paragraph. Wei teaches that one important point is that droplet size and lifetime affect the reaction rate, so one can observe quite different extents of reaction when varying the distance from the sprayer to the MS inlet. Wei at page 34, 1st paragraph. Wei teaches that many factors cause the accelerated reactions in microdroplets, such as temperature, concentration, pressure, reagent orientation, and an increase in the intrinsic rate constant. Wei at page 42, last paragraph. Wei further teaches that due to both the larger surface-to-volume ratio and the more effective diffusion within small volumes, reaction acceleration in microdroplets is much greater than that in larger droplets or in bulk. Wei at page 43, 1st paragraph. Besides these factors, the special interface physical and electrochemical properties such as extreme pH, abnormal dielectric constant, and surface potential also contribute to making microdroplet chemistry different from bulk chemistry, and they need to be investigated more in the future. Wei at page 43, 1st paragraph. Wei does not teach fluoridation as instantly claimed.
Joyard teaches the syntheses of new nitroimidazole compounds using silicon–[18F]fluorine chemistry for the potential detection of tumor hypoxia are described. Y. Joyard et al., 21 Bioorganic & Medicinal Chemistry, 3680-3688 (2013). Joyard teaches that the traditional 18F-labeling requires azeotropically dried [18F]fluoride under basic reaction conditions at high temperature with the use of a cation-complexing agent, generally Kryptofix [2.2.2], in order to increase the reactivity of fluoride. Joyard at page 3680, col. 1. Joyard teaches the 18F radiolabeling SiFA compound 17a and 17b to give radiolabeled [18F]18 as follows:
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Joyard at pages 3687-3688 (“5.3.3. 18F radiolabeling SiFA compound 17a and 17b”). Joyard employs Kryptofix 2.2.2. One of ordinary skill is not motivated to adopt the electrospray ionization technique of Wei to the Joyard process in view of the unpredictability taught by Wei and additional art of record (see § 112(a) discussion above), so as to arrive at the claimed process.
Waldmann teaches heteroaromatic Silicon-Fluoride- Acceptors, which are useful for PET scanning. Waldmann at Abstract. Waldmann teaches the following exemplary synthesis of a radiolabeled silicon precursor for use in PET scanning.
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Waldmann at page 32. The claimed method is not obvious in view of Waldmann because one of ordinary skill does not have a reasonable expectation that performing this reaction according to the instantly claimed electrospray ionization-assisted fluoridation within a microdroplet would result in the desired product. As discussed in detail above, the art teaches that that chemical reactions within microdroplets is complex and unpredictable. One of ordinary skill does not have a reasonable expectation that upon ionization of the starting 19F product (to give either an anion, negative mode or cation, positive mode), such anion or cation would react, similar to the neutral 19F material, to give the desired 18F isotopically labeled product. MPEP § 2143.02 (a reasonable expectation of success is required to support a § 103 rejection).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER R PAGANO whose telephone number is (571)270-3764. The examiner can normally be reached 8:00 AM through 5:00 PM.
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 Prophetic examples may be written in future or present tense (not past tense), which is a drafting technique assists readers in differentiating between actual working examples and prophetic examples. MPEP § (II) (citing Properly Presenting Prophetic and Working Examples in a Patent Application, 86 FR 35074 (July 1, 2021)).