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 .
Information Disclosure Statement
The information disclosure statement submitted November 20, 2024 is acknowledged and has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
On pg. 14 of the instant specification, the [18F]Fluoride on the first reaction arrow and the 18F atoms in the chemical structures in the reaction scheme are at poor resolution and difficult to read.
On pg. 14 of the instant specification, there appear to be typographical errors in the paragraph under Table 1 (the caption). In view of Table 2, it appears that there are “a” “b” and “c” letters that should be provided as superscripts. Otherwise, “aConditions” “bequiv” and “cRCY” are incorrectly spelled words.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see end of pg. 21). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 5 and 10 are objected to because of the following informalities:
The chemical structure provided in claim 5 is at poor resolution. It is difficult to discern the identities of the heteroatoms and numbers in the structure.
Claim 5 does not end in a period, as is required for each claim. See MPEP § 608.01(m).
In Claim 10, feature (b) of the oxidative addition reagent should have the same indentation as features (a) and (c).
Appropriate correction is required.
Claim Interpretation
Claims 1-15 require the presence or use of an “oxidative addition reagent” comprising Au(III), a ligand bound to Au(III), and an aryl or heterocycle ring coupled to an 18F or 11C moiety. Claim 10 requires the reaction between the oxidative addition reagent and a polypeptide and/or polysaccharide containing a sulfur atom to be an oxidative addition reaction. On pg. 3 of the instant specification, Applicant describes that when a biomolecule and the oxidative addition reagent are combined, the combination undergoes an oxidative addition reaction such that the 18F or 11C is coupled to a sulfur or selenium atom present in the polypeptide and/or polysaccharide. However, on pages 9 and 10 of the instant specification, Applicant describes the reaction of an aryl halide with the organometallic complex precursor (such as (Me-DalPhos)AuCl) to be an oxidative addition reaction. In the art of arylation of sulfur-containing biomolecules using gold organometallic complexes (see Messina, M. S.; et al., J. Am. Chem. Soc., 2018; herein after referred to as Messina), the examiner notes that the reaction labeled as an oxidative addition is the reaction between the aryl halide compound and the gold complex precursor, which converts Au(I) to Au(III) (Messina, pg. 7065, Introduction). Furthermore, in this art, the reaction in which the aryl group is transferred from the gold to the sulfur-containing biomolecule is termed a reductive elimination step (Messina, pg. 7065, Introduction). The examiner notes that the use of these terms in the art appears to partially contrast the phrasing in the instant application and particularly the claims. It appears Applicant has described in the specification that both the conjugation and removal of the aryl group from the gold are oxidative addition reactions.
As the claim language is consistent with the specification, the examiner will interpret that the specification provides support for calling both of these reactions oxidative addition reactions. However, as the examiner notes that this terminology seems to be partially contrary to the standard use in the art, for the purpose of examination of claim 10, art that teaches combining the oxidative addition reagent as claimed and a polypeptide or polysaccharide comprising a sulfur atom wherein the combination undergoes a reaction in which the 18F is coupled to a sulfur atom on the biomolecule will read on the claimed method regardless of whether or not the art explicitly describes the reaction as an oxidative addition. This is because the structural steps of the claimed methods will have been taught by the art and because of the use of terminology in the instant application inconsistent which typical use in the field of study.
Similarly, the examiner will interpret “oxidative addition reagent” as recited in the claims to be functional language or a statement of intended use. For the purpose of examination, given the instant specification and the use of the phrase “oxidative addition” in the art, the examiner will interpret compounds having the structure as claimed that are either formed by oxidative addition or taught to perform oxidative addition reactions to read on this reagent.
Claim Rejections - 35 USC § 112(a)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-5 and 10-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, this claim requires that the oxidative addition reagent is a reagent that reacts with a sulfur-containing biomolecule to couple an 18F or 11C moiety to the biomolecule. Claim 10 similarly requires the same coupling reaction to occur. The instant application provides support for reacting thiol functional groups in polypeptides and polysaccharides with the oxidative addition reagent to couple the 18F or 11C to the sulfur of the thiol in the biomolecule. However, the examiner considers this to not be a representative number of species of the target biomolecule for these reactions. In addition to thiol groups, sulfur containing biomolecules can contain thioethers, disulfides and sulfate groups. It is not apparent from the instant disclosure that the claimed invention is capable of performing the reactions as claimed to label thioether, disulfide, or sulfate sulfur atoms in biomolecules. No examples are provided teaching such reactions. Furthermore, Fig. 2 provides an explicit example ([18F]11) of an 18F radiolabeled peptide wherein the 18F-containing moiety is attached to a cysteine (thiol containing amino acid) and not a methionine (thioether containing amino acid) in the same molecule. As the sulfur atoms in thiols, thioethers, disulfides, and sulfates have different oxidation states and reactivities, it is not apparent in view of the provided examples that the compositions and reactions as claimed are supported for all sulfur-containing polypeptides and polysaccharides. Furthermore, claims 2-5 and 11-14 are rejected due to their dependence on claims 1 and 10 respectively.
Claim 13 recites that the oxidative addition reagent comprises an 18F labelled aryl iodide. However, the instant specification does not provide written support for an oxidative addition reagent comprising Au(III), a ligand bound to Au(III) comprising a phosphine, polydentate and/or monodentate ligand, and an aryl or heterocycle ring coupled to 18F wherein the aryl group is an 18F labelled aryl iodide. Nor is there support for any oxidative addition reagent comprising an 18F labelled aryl iodide. In view of pages 6, 7, 9, and 14 of the instant specification, it appears that Applicant describes that aryl iodides are used as a precursor reagent in the method of making the gold organometallic complex. It is taught that the aryl iodide is reacted with a gold complex to form the oxidative addition reagent and that due to this reaction, the fluoro-aryl iodide is no longer an aryl iodide due to the breaking of a bond between the iodine and a carbon of the aryl ring (page 14). Therefore, there is no written description of an oxidative addition reagent comprising an 18F labelled aryl iodide. For the purpose of examination, the examiner will consider art teaching the use of an 18F labelled aryl iodide in the making of the oxidative addition reagent to read on this claim.
Claim Rejections - 35 USC § 112(b)
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 1-5 and 11-13 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.
Claim 1 recites that the oxidative addition reagent comprises “an aryl or heterocycle ring coupled to a 18F or 11C moiety” and that the oxidative addition reagent reacts with a biomolecule when combined in solution to “couple the 18F or the 11C moiety to the biomolecule” (underlined emphasis added by examiner). In view of this language (particularly that of limitation (c) for the oxidative addition reagent), it is interpreted by the examiner that the 18F or 11C moiety is a functional group that is attached to the aryl or heterocycle ring that is part of the oxidative addition reagent. In view of this, the statement in the last clause of claim 1 that the 18F or 11C moiety is coupled to the biomolecule would be understood to mean that the 18F or 11C containing functional group (the moiety) that is attached to the aryl or heterocycle in the oxidative addition reagent is the structure that gets directly coupled to the biomolecule. However, in view of the disclosure on the whole, it appears what may be meant is that the whole aryl or heterocycle ring group modified with the 18F or 11C moiety is coupled to the biomolecule instead, thus indirectly coupling the 18F or 11C moiety to the biomolecule. This is in contradiction to the other interpretation provided above requiring that the coupling be direct and not involving the aryl or heterocycle ring being coupled. The scope of this limitation is different depending on which chemical group gets coupled to the biomolecule. As this limitation as written and in view of the disclosure as a whole can be interpreted multiple mutually exclusive ways, the scope of this limitation (and thus the claim on the whole) is rendered indefinite. Furthermore, as claims 2-5 depend upon claim 1 and fail to resolve this ambiguity of scope, these claims are rejected due to said dependence. For the purpose of examination, the examiner will interpret this limitation to mean that the aryl or heterocycle ring containing the 18F or 11C moiety is coupled to the biomolecule (indirect conjugation).
Claim 4 recites the optional limitation that “the polypeptide and/or the polysaccharide is coupled to an 18F moiety.” Claim 4 depends directly from claim 2 and indirectly from claim 1. Claim 1 requires an oxidation addition reagent comprising “an aryl or heterocycle ring coupled to a 18F or 11C moiety” and that the oxidative addition reagent reacts with a biomolecule when combined in solution to couple the 18F or 11C moiety to the biomolecule. In view of this, it is unclear whether the scope of the second limitation of claim 4 is a composition comprising a polypeptide and/or polysaccharide coupled to an 18F moiety and an oxidative addition reagent lacking an 18F moiety because a reaction between the oxidative addition reagent and biomolecule has occurred or if the scope is that both the polypeptide and/or polysaccharide and the oxidative addition reagent in the composition are coupled to 18F moieties. As it is unclear what the scope of claim 4 is, it is considered indefinite. For the purpose of examination, the examiner will interpret the scope of this limitation of claim 4 to be that both of the polypeptide and or polysaccharide and the oxidative addition reagent is attached to an 18F moiety.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation less than 60 minutes, and the claim also recites less than 30 minutes or less than 15 minutes which are narrower statements of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Furthermore, claims 12 and 13 are rejected due to their dependence on claim 11. For the purpose of examination, the examiner will interpret the scope of this limitation of claim 11 to be that of the broad range (less than 60 minutes).
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.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Stauber (Stauber, J. M.; et al., Inorg. Chem., 2021 – provided by applicant in IDS filed November 20, 2024) in view of Ma (Ma, G.; et al., Org. Lett., 2021 – provided by applicant in IDS filed November 20, 2024).
Stauber teaches Au(III) organometallic complexes and their use in cysteine S-arylation (pg. 5054, Abstract). More specifically, Stauber teaches multiple (P,N)Au(III) complexes with different (P,N) ligands and various aryl groups (pg. 5055, Figures 1 and 2; pg. 5056, Scheme 1 and Figure 3; pg. 5057, Figure 4; and pg. 5058, Figure 6). Stauber teaches using these organometallic complexes to conjugate aryl groups to cysteine residues in polypeptides (Figure 2; Figure 3; Scheme 1; Figure 5; and Figure 6). Stauber teaches that such reactions can occur in aqueous media comprising TRIS buffering agent and organic solvent additives (Scheme 1; and Figures 2, 3, 5, and 6). Stauber teaches that the reactions can be performed at 25°C and be completed in less than 5 minutes (Figure 2). Stauber teaches that the bioconjugation reactions proceed with nearly quantitative conversion efficiency (>99%) (pg. 5055, last paragraph through pg. 5056, first paragraph). Stauber teaches that the reagent used to generate the aryl-modified gold complex is an aryl iodide (Figures 2, 3, 4, and 6) and that this is an oxidative addition (pg. 5054, right column, first paragraph; and pg. 5058; right column, first paragraph). Stauber teaches that the aryl group may be modified with fluorine (Figure 2A).
Stauber does not teach the use of an aryl group comprising an 18F or 11C moiety.
Ma teaches the addition of 18F-modified aryl groups to cysteines in peptides using [18F]fluoro-4-(vinylsulfonyl)benzene ([18F]FVSB (pg. 530, Abstract). Ma teaches 18F radiolabeling of an aryl group to synthesize [18F]FVSB (pg. 531, Table 1). Ma teaches using [18F]FVSB to radiolabel a peptide (pg. 532, Table 2). Ma teaches optimization of reaction conditions for radiolabeling comprising varying the aqueous buffering reagent, pH, presence of an organic solvent additive, and amount of organic solvent additive to improve radiochemical yield (Table 2). Ma teaches that such reactions can be used to radiolabel a wide variety of peptide molecules specifically at cysteine residues (pg. 533, Figure 2). Ma teaches that the radiolabeling of the aryl group can be performed in 30 minutes and achieve over 90% RCY (Table 1) and that the peptide labeling can be done in 30 minutes and achieve RCY of about 90% (Table 2). Ma teaches that radiolabeled peptides are important PET imaging tools (pg. 530, left column, first paragraph). Ma teaches that [18F]FVSB can be used to prepare 18F-labeled peptides for PET molecular imaging(pg. 531, left column, paragraph 2).
A person of ordinary skill in the art would recognize that both Stauber and Ma teach methods of attaching aryl ring containing functional groups to peptides specifically at cysteine residues. Additionally, it would be recognized that both teach that these aryl groups can be modified by fluorine. It would further be recognized that Ma teaches that 18F-labeled peptides can be used for PET imaging applications.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the fluorine-containing aryl ring group of Stauber with the 18F atom label of Ma because Ma teaches that such a radionuclide label enables the use of reagents to site-specifically radiolabel peptides, allowing for the use of the peptide products for biomedical imaging applications (MPEP § 2143(I)(C)). This would predictably result in an 18F-labeled aryl group being attached to a gold organometallic complex and subsequently coupled to a cysteine in a polypeptide.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Stauber teaches that the aryl groups attached to the gold complex and then the polypeptides can contain fluorine and because Ma teaches that aryl groups can be modified with 18F moieties.
The skilled artisan would have been motivated to make this modification because Ma teaches that 18F-labeled products can be used for PET imaging in biomedical applications. Thus, using 18F-labeled aryl groups in the gold complex system of Stauber would enable fast and efficient radiolabeling of peptides for biomedical imaging use.
Regarding claim 1, Stauber teaches a reagent comprising Au(III), a bidentate ligand bound to Au(III) comprising a phosphine, and an aryl ring (Figure 2A; and pg. 5055, right column, first paragraph). Stauber teaches that this complex is synthesized via an oxidative addition reaction (pg. 5055, right column, first paragraph). Stauber teaches that the aryl group attached to Au(III) can have a fluorine group (Figure 2A, Structure 1c). Stauber teaches that combining the aryl-modified gold organometallic complex with a polypeptide comprising a sulfur atom in solution, the aryl group that may contain fluorine is coupled to the biomolecule (Figure 2C). Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the fluorine atom of Stauber with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety. As Stauber teaches that the fluorine atom on the aryl group is transferred to the biomolecule upon reaction, the examiner interprets this to mean that the 18F moiety put in place of the fluorine atom would similarly be coupled to the biomolecule. Therefore, the combined teachings of Stauber and Ma render claim 1 obvious.
Regarding claim 2, Stauber teaches combining the gold organometallic complex with a polypeptide comprising a sulfur atom (Figure 2C). Therefore, the combined teachings of Stauber and Ma render claim 2 obvious.
Regarding claim 3, Stauber teaches combining the gold organometallic complex and the polypeptide comprising a sulfur atom in the presence of water, which the examiner interprets to be an aqueous media, and TRIS buffering agent (Figure 2C). Therefore, the combined teachings of Stauber and Ma render claim 3 obvious.
Regarding claim 4, an exemplary polypeptide that Stauber teaches combining with the gold organometallic complex is glutathione (Figure 2C and 2D). Stauber teaches that the reagent used for this reaction is L-glutathione (pg. 5055, right column, last paragraph). The examiner interprets this to be the tripeptide molecule glutathione. The description of this structure does not include a protecting group nor is there a protecting group depicted in Figure 2D. Therefore, the examiner interprets the polypeptide to be an unprotected polypeptide. Additionally, Stauber teaches that similar organometallic systems have been used in cysteine S-arylation of unprotected peptides and proteins (pg. 5054, right column, paragraph 2). Furthermore, Stauber teaches that combining the gold organometallic complex and polypeptide in solution results in a fluoro-aryl-modified polypeptide (Figure 2C). The examiner notes that if the above described modification using the 18F moiety is made, the resulting polypeptide in the composition would be coupled to an 18F moiety. Therefore, the combined teachings of Stauber and Ma render claim 4 obvious.
Regarding claim 5, Stauber teaches a gold organometallic complex comprising Au(III) and the same phosphine-amine bidentate ligand and SbF6- counterion as the structure of claim 5 (Figure 1B and Scheme 1). Stauber teaches a chlorine halogen being attached to the Au(III) in the organometallic complex (Scheme 1), reading on the feature of the claimed structure wherein X is Cl. Stauber teaches that such organometallic complexes can include aryl groups attached to the gold (Scheme 1 and Figure 1B). Stauber teaches that fluoro-aryl groups are suitable in such complexes (Figure 2A). Additionally, Ma teaches 18F-labeled aryl groups for peptide radiolabeling (Figure 1). The above described modification (incorporation of 18F on the aryl ring in the gold complex) would result in a structure that reads on the full structure of claim 5. Therefore, the combined teachings of Stauber and Ma render claim 5 obvious.
Regarding claim 6, Stauber teaches a method in which a gold organometallic complex comprising Au(III), a bidentate ligand comprising a phosphine, and an aryl group with a fluorine moiety is combined together with a polypeptide comprising a sulfur atom (Figure 2C). Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the fluorine atom of Stauber with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety. Thus, the combined method would read on claim 6. Therefore, the combined teachings of Stauber and Ma render claim 6 obvious.
Regarding claim 7, Stauber teaches combining a gold organometallic complex comprising Au(III), a phosphine containing polydentate ligand, and an aryl ring containing a fluorine moiety with a polypeptide comprising a sulfur atom in an aqueous medium containing TRIS buffering agent (pg. 5055, Figure 2C). Therefore, the combined teachings of Stauber and Ma render claim 7 obvious.
Regarding claim 8, Stauber teaches performing the S-arylation reaction in a media containing TRIS buffering agent (Figure 2C). Therefore, the combined teachings of Stauber and Ma render claim 8 obvious.
Regarding claim 9, Stauber teaches that reactions combining the aryl-modified Au(III) organometallic complex used for S-arylation of cysteine in peptides can be performed using TRIS/MeCN solvent systems with various ratios of the TRIS aqueous component and the MeCN organic solvent component (Figures 2C, 3C, 5, and 6; and Scheme 1). Additionally, Ma teaches optimization of reaction conditions for radiolabeling comprising varying the aqueous buffering reagent, pH, presence of an organic solvent additive, and amount of organic solvent additive to improve radiochemical yield (Table 2). Ma specifically teaches that inclusion of methanol in the aqueous/organic solvent system at 25% or 50% improves radiochemical yield (Table 2).
It would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of making a composition by combining an Au(III) organometallic complex with a sulfur-containing polypeptide taught by Stauber with the substitution of MeCN for MeOH as the organic solvent additive as taught by Ma because Ma teaches that methanol is a suitable organic solvent additive for radiolabeling sulfur-containing polypeptides and because Ma teaches that the methanol inclusion improves radiochemical yields (MPEP § 2143(I)(B) and 2143(I)(C)). This would predictably result in a method using a TRIS buffer/methanol solvent system. The skilled artisan would have a reasonable expectation of success making this modification because both Ma and Stauber teach modification of peptides with aryl ring containing groups in aqueous/organic solvent systems. The skilled artisan would be motivated to make this modification because Ma teaches that methanol is suitable for this use and that it increased RCY.
The resulting method of this combination would use a TRIS buffer/methanol solvent system. Therefore, the combined teachings of Stauber and Ma render claim 9 obvious.
Regarding claim 10, Stauber teaches a method in which a gold organometallic complex comprising Au(III), a bidentate ligand comprising a phosphine, and an aryl group with a fluorine moiety is combined together with a polypeptide comprising a sulfur atom wherein the combination undergoes a reaction such that the aryl group containing the fluorine moiety is coupled to the sulfur atom present in the polypeptide (Figure 2C). Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the fluorine atom of Stauber with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety. As Stauber teaches that the fluorine atom on the aryl group is transferred to the biomolecule upon reaction, the examiner interprets this to mean that the 18F moiety put in place of the fluorine atom would similarly be coupled to the biomolecule. Though Stauber does not explicitly describe this reaction as an oxidative addition reaction, the examiner notes that the use of “oxidative addition reaction” in the context of the claim is contradictory to standard use in the art (see Claim Interpretation section). Furthermore, as the method taught by the combination of Stauber and Ma reads on all the structural steps required in claim 10, the taught method is understood to read on the limitations of the claimed method (see Claim Interpretation). Therefore, the combined teachings of Stauber and Ma render claim 10 obvious.
Regarding claim 11, Stauber teaches coupling an aryl group to a sulfur atom in a polypeptide at a temperature of 25°C for less than 5 minutes (pg. 5055, Figure 2C). Each of these values are within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Stauber and Ma render claim 11 obvious.
Regarding claim 12, Stauber teaches that the bioconjugation reactions proceed with nearly quantitative conversion efficiency (>99%) (pg. 5055, last paragraph through pg. 5056, first paragraph). Therefore, the examiner interprets this to mean that the conjugation of the 18F-aryl group from the Au(III) organometallic complex to the cysteine of a polypeptide as taught in the combined method would proceed with ~99% conversion efficiency. If ~99% of the 18F-aryl group is successfully transferred to the peptide, this would result in an RCY of ~99%. Furthermore, Ma teaches that 30 minute radiolabeling reactions can achieve RCY of ~90% (Table 2). As the gold organometallic system of Stauber can perform an analogous peptide modifying reaction in under 5 minutes (Figure 2C), it would be expected that the loss of radiolabel in the final product due to 18F radioactive decay would be minimal. Additionally, Ma teaches optimization of RCY by varying solvent components and reagent amounts (Table 2). This suggests that achieving high RCY values can be achieved by varying concentrations of reaction components, which amounts to routine optimization (MPEP § 2144.05(II)). For these reasons, the combined teachings of Stauber and Ma render claim 12 obvious.
Regarding claim 13, Stauber teaches the use of p-fluoro aryl iodide in the preparation of the Au(III) organometallic complex (Figure 2A; and pg. 5055, right column, first paragraph). The examiner interprets this to be preparing an oxidative addition reagent using an F-modified aryl iodide. Additionally, incorporating the above described modification by replacing the fluorine of Stauber with the 18F moiety of Ma would result in the use of an 18F-labelled aryl iodide. Therefore, the combined teachings of Stauber and Ma render claim 13 obvious.
Claims 14 and 15 re rejected under 35 U.S.C. 103 as being unpatentable over Stauber and Ma as applied to claims 1-13 above, and further in view of Lesniak (Lesniak, W. G.; et al., Mol. Imag., 2019).
As described above, Stauber teaches Au(III) organometallic complexes and their use in cysteine S-arylation (pg. 5054, Abstract). More specifically, Stauber teaches multiple (P,N)Au(III) complexes with different (P,N) ligands and various aryl groups (pg. 5055, Figures 1 and 2; pg. 5056, Scheme 1 and Figure 3; pg. 5057, Figure 4; and pg. 5058, Figure 6). Stauber teaches using these organometallic complexes to conjugate aryl groups to cysteine residues in polypeptides (Figure 2; Figure 3; Scheme 1; Figure 5; and Figure 6). Stauber teaches that the reagent used to generate the aryl-modified gold complex is an aryl iodide (Figures 2, 3, 4, and 6) and that this is an oxidative addition (pg. 5054, right column, first paragraph; and pg. 5058; right column, first paragraph). Stauber teaches that the aryl group may be modified with fluorine (Figure 2A). Additionally, Ma teaches the addition of 18F-modified aryl groups to cysteines in peptides using [18F]fluoro-4-(vinylsulfonyl)benzene ([18F]FVSB (pg. 530, Abstract). Ma teaches using [18F]FVSB to radiolabel a peptide (pg. 532, Table 2). Ma teaches that radiolabeled peptides are important PET imaging tools (pg. 530, left column, first paragraph). Ma teaches that [18F]FVSB can be used to prepare 18F-labeled peptides for PET molecular imaging(pg. 531, left column, paragraph 2). Furthermore, as described above, the combined teachings of Stauber and Ma render obvious the oxidative addition reagent of claims 1, 6, and 10 and the methods of claims 6 and 10.
The combined teachings of Stauber and Ma fail to teach performing positron emission tomography imaging of a biological target.
Lesniak teaches an 18F-labeled PET imaging peptide (pg. 1, Abstract). More specifically, Lesniak teaches labeling cyclic peptide WL12 with an 18F-labeled pyridine ring to make [18F]FPy-WL12 (Figure 1A). Lesniak teaches that an 18F label is well-suited to PET imaging (pg. 2, left column, first paragraph). Lesniak teaches using [18F]FPy-WL12 for PET imaging in mice (pg. 6, Figure 2; and pg. 4; right column, paragraph 2).
A person of ordinary skill in the art would recognize that each of Stauber, Ma, and Lesniak teach methods of attaching aromatic rings containing functional groups to peptides. Additionally, it would be recognized that each of Stauber, Ma, and Lesniak teach that these aromatic rings can be modified with fluorine. It would further be recognized that both Ma and Lesniak teach radiolabeling polypeptides using 18F-labelled aromatic moieties. It would be recognized that Ma teaches that 18F-labeled peptides can be used for PET imaging applications and that Lesniak teaches administering 18F-labeled peptides to a mouse and performing PET imaging.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the 18F-radiolabeled polypeptide (the composition and the method of making) taught by the combination of Stauber and Ma by additionally using the radiolabeled peptide for performing PET imaging as taught by Lesniak because Lesniak demonstrates that 18F labeled peptides can be used for PET imaging and because Ma teaches that such peptides are useful for this function (MPEP § 2143(I)(G)). This would predictably result in a method including using an 18F radiolabeled polypeptide for PET imaging.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because the 18F radiolabel of Lesniak is similar to that taught by the combination of Stauber and Ma in that it is an 18F moiety attached to an aromatic ring. Additionally, Ma suggests that such radiolabeled peptides are suitable for this use.
The skilled artisan would have been motivated to make this modification because Ma teaches that 18F-labeled products can be used for PET imaging in biomedical applications and Lesniak demonstrates the efficacy of such a use. Thus, using peptides conjugated to 18F-labeled aryl groups by the gold complex system of Stauber would enable fast and efficient radiolabeling of peptides for biomedical imaging use.
Regarding claim 14, as described above, the combined teachings of Stauber and Ma render the method of claim 10 obvious. Additionally, Ma teaches that radiolabeled peptides are important PET imaging tools (pg. 530, left column, first paragraph). Ma teaches that 18F labeling on cysteine using aromatic groups can be used to prepare peptides for PET molecular imaging (pg. 531, left column, paragraph 2). Furthermore, Lesniak teaches using an 18F-labeled peptide for PET imaging in mice (pg. 6, Figure 2; and pg. 4; right column, paragraph 2). Therefore, the combined method of these teachings would be a method comprising using the 18F coupled polypeptide in a PET imaging process. Therefore, the combined teachings of Stauber, Ma, and Lesniak render claim 14 obvious.
Regarding claim 15, as described above, the combined teachings of Stauber and Ma render obvious the method of claim 6 and therefore an 18F-labeled polypeptide product of this method. Additionally, Ma teaches that radiolabeled peptides are important PET imaging tools (pg. 530, left column, first paragraph). Ma teaches that 18F labeling on cysteine using aromatic groups can be used to prepare peptides for PET molecular imaging (pg. 531, left column, paragraph 2). Furthermore, Lesniak teaches using an 18F-labeled peptide for PET imaging in mice (pg. 6, Figure 2; and pg. 4; right column, paragraph 2). The method of Lesniak involves administering an 18F-radiolabeled peptide to a mouse and allowing it to bind PD-L1 (which the examiner interprets as combining an 18F labeled imaging agent with a biological target) and performing PET scanning to image the target (pg. 6, Figure 2; and pg. 4; right column, paragraph 2). Therefore, the combined method of these teachings would be a method comprising using the 18F coupled polypeptide in a PET imaging process.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. 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).
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Claims 1-4, 6-7 and 10-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 22-27 of copending Application No. 18/336,776 in view of Ma (Ma, G.; et al., Org. Lett., 2021 – provided by applicant in IDS filed November 20, 2024).
The conflicting claims of copending Application No. 18/336,776 (the ‘776 application) are drawn to a composition comprising a polypeptide having at least one cysteine residue and a gold(III) aryl complex. The gold(III) aryl complex further comprises a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group. The conflicting claims are also drawn to methods of preparing a cysteine-aryl conjugated polypeptide comprising contacting the gold(III) aryl complex and the polypeptide.
The conflicting claims of copending Application No. 18/336,776 do not teach an aryl or heterocycle ring coupled to an 18F or 11C moiety.
As described above, Ma teaches the addition of 18F-modified aryl groups to cysteines in peptides using [18F]fluoro-4-(vinylsulfonyl)benzene ([18F]FVSB (pg. 530, Abstract). Ma teaches 18F radiolabeling of an aryl group to synthesize [18F]FVSB (pg. 531, Table 1). Ma teaches using [18F]FVSB to radiolabel a peptide (pg. 532, Table 2). Ma teaches optimization of reaction conditions for radiolabeling comprising varying the aqueous buffering reagent, pH, presence of an organic solvent additive, and amount of organic solvent additive to improve radiochemical yield (Table 2). Ma teaches that such reactions can be used to radiolabel a wide variety of peptide molecules specifically at cysteine residues (pg. 533, Figure 2). Ma teaches that the radiolabeling of the aryl group can be performed in 30 minutes and achieve over 90% RCY (Table 1) and that the peptide labeling can be done in 30 minutes and achieve RCY of about 90% (Table 2). Ma teaches that radiolabeled peptides are important PET imaging tools (pg. 530, left column, first paragraph). Ma teaches that [18F]FVSB can be used to prepare 18F-labeled peptides for PET molecular imaging(pg. 531, left column, paragraph 2).
A person of ordinary skill in the art would recognize that both Ma and copending ‘776 application are drawn to methods of attaching aryl ring containing functional groups to peptides specifically at cysteine residues. It would further be recognized that Ma teaches that 18F-labeled peptides can be used for PET imaging applications.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the aryl ring group of copending Application No. 18/336,776 with the 18F atom label of Ma in place of the PEG group because Ma teaches that such a radionuclide label enables the use of reagents to site-specifically radiolabel peptides, allowing for the use of the peptide products for biomedical imaging applications (MPEP § 2143(I)(C)). This would predictably result in an 18F-labeled aryl group being attached to a gold organometallic complex and subsequently coupled to a cysteine in a polypeptide.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Ma teaches that aryl groups can be modified with 18F moieties.
The skilled artisan would have been motivated to make this modification because Ma teaches that 18F-labeled products can be used for PET imaging in biomedical applications. Thus, using 18F-labeled aryl groups in the gold complex system of the copending ‘776 application would enable fast and efficient radiolabeling of peptides for biomedical imaging use.
Regarding instant claim 1, conflicting claim 6 of the copending ‘776 application is drawn to a composition comprising an Au(III) complex comprising Au(III), a bidentate ligand comprising a phosphine bound to Au(III), and an aryl ring coupled to a functional group. Conflicting claim 11 supports that this gold complex can be used to transfer an aryl group to a cysteine on a protein and conflicting claim 14 supports that this is a modification to the sulfur of the cysteine. Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the PEG group of conflicting claim 1 of the copending ‘776 application with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety.
Regarding instant claim 2, conflicting claim 1 of the copending ‘776 application requires a polypeptide having at least one cysteine residue. As cysteine contains a sulfur atom, such a polypeptide comprises a sulfur atom.
Regarding instant claim 3, Ma teaches that peptide radiolabeling can be performed in aqueous media with buffering agents and alcohols (Table 2).
Regarding instant claim 4, as described above, conflicting claim 11 of the copending ‘776 teaches that the gold complex of conflicting claim 1 transfers an aryl group to a polypeptide. As also described above, the modification of the copending ‘776 application with the teachings of Ma would predictably result in an 18F radiolabeled aryl group. Thus, the transfer of the aryl group of the copending ‘776 application to a cysteine in a polypeptide would result in a composition comprising a polypeptide coupled to an 18F moiety.
Regarding instant claim 6, conflicting claim 6 of the copending ‘776 application is drawn to a composition comprising an Au(III) complex comprising Au(III), a bidentate ligand comprising a phosphine bound to Au(III), and an aryl ring coupled to a functional group. Conflicting claim 11 is a method of using such a complex by contacting it with a polypeptide containing a cysteine residue (which has a sulfur atom). Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the PEG group of conflicting claim 1 of the copending ‘776 application with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety.
Regarding instant claim 7, Ma teaches that peptide radiolabeling can be performed in aqueous media with buffering agents and alcohols (Table 2).
Regarding instant claim 10, conflicting claim 6 of the copending ‘776 application is drawn to a composition comprising an Au(III) complex comprising Au(III), a bidentate ligand comprising a phosphine bound to Au(III), and an aryl ring coupled to a functional group. Conflicting claim 11 is a method of using such a complex by contacting it with a polypeptide containing a cysteine residue (which has a sulfur atom). Additionally, Ma teaches [18F]FVSB (Figure 1), which comprises an 18F radiolabeled aryl group for conjugation to thiol groups in peptides (Table 2) to enable use in PET imaging (pg. 531, left column, paragraph 2). As described above, it would have been prima facie obvious to replace the PEG group of conflicting claim 1 of the copending ‘776 application with the 18F fluorine atom of Ma. The resulting combination would produce an oxidative addition reagent wherein the aryl ring attached to the Au(III) is coupled to an 18F moiety. Furthermore, per conflicting claims 11 and 14, the resulting use of such a gold complex would result in the transfer of the 18F aryl group to a sulfur atom in the polypeptide.
Regarding instant claim 11, conflicting claim 12 of the copending ‘776 application is drawn to a method of aryl modification of cysteine in a polypeptide wherein the temperature of the reaction is less than 30°C. Additionally, conflicting claim 13 is drawn to such a reaction wherein the time of the reaction is less than 5 minutes.
This is a provisional nonstatutory double patenting rejection.
Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
As pertinent art, the examiner cites Messina (Messina, M. S.; et al, J. Am. Chem. Soc., 2018). Messina teaches organometallic Au(III) complexes and their use in arylation of cysteine in peptides (pg. 7065, Title and Abstract). Messina teaches that such modification can be made on unprotected peptides and proteins in reactions that are shorter than 5 minutes (pg. 7065, Abstract). Messina teaches that such a reaction can be optimized in terms of the concentrations of reagents, pH, and solvent system used in order to increase yield of the desired products (pg. 7066, Figure 1). Messina teaches that aromatic groups attached to the Au(III) in the organometallic complex that can be subsequently coupled to peptides can have a variety of structures, including aryl groups modified with fluorine-containing groups and aromatic heterocycles (pg. 7066, Figure 2). The examiner notes that this reference teaches very similar Au(III) organometallic complexes to the instant application and similar reactions using the gold complexes to perform S-arylation of peptides at cysteine residues.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
