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 (IDS) submitted on 01/11/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 1-20 are pending in this application.
Claim Objections
Claims 5-6, 8, 12, and 17-20 objected to because of the following informalities:
Claims read: “C1-20 amino group”. This limitation should read “C1-20 alkylamino” and/ or “C1-20 amino alkyl group” or something to that effect.
Claims also read: “C3-9 silyl group”. This limitation should read “C3-9 alkyl silyl” and/ or “C3-9 silyl alkyl” or something to that effect.
Appropriate correction is required.
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 5-13 and 17-20 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.
Claims 5 and 17-19 are indefinite because, in Equations 1-5, when at least one of R1-20 is a hydrocarbon alkyl chain (such as methyl or ethyl), it is unlikely that deuteration will occur selectively at the indicated positions without giving mixtures of deuterated products at other benzylic positions.
Claim 7 is rejected for depending upon the limitations of claim 5.
Claims 6 and 20 are indefinite because, in Equation 6 (shown below), when one of R21-23 is aryl and the other two variables are H, it is unlikely that the deuterated product indicated below will be the major product obtained, since benzylic deuteration will be favored, as in Example 29 of the spec. (page 24) and Equations 3-4 of claim 5.
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Further regarding claims 6 and 20, claims are indefinite because when applicant states “R21-23 can be connected into aliphatic hydrocarbon rings or aromatic rings”, it is unclear how these three groups can be connected to form an aromatic ring when the carbon alpha to the sulfur is shown as an sp3 carbon. Examiner suggests amending to specify that only two of R21 to R23 connect to form aliphatic or aromatic rings, and that when two of R21 to R23 are connected to form an aromatic ring, then the other group is absent.
Claim 8 is indefinite because, in Equations 8-12, when any of R29-34 is a hydrocarbon alkyl chain (such as ethyl or methyl), it is unlikely that deuteration will occur selectively at the indicated positions without giving mixtures of deuterated products or complete deuteration (see Examples 33-34, page 27 of the spec.).
Claim 9 is rejected for depending upon the limitations of claim 8.
Claim 10 is indefinite because it is unclear, particularly for equations 14 and 15 (shown below), how selective deuteration of the indicated positions is achieved when any of R36-40- are alkyl groups (e.g. methyl, ethyl). For example, when R39 or R40 are alkyl groups, the benzylic C-H bonds will be more easily activated, and therefore, deuteration will be favored at these positions over the positions indicated below.
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Similarly, when R36-40 are H, it is unclear how Applicant intends to stop at mono-deuteration, since multi-deuteration appears to be favored in relevant Examples 38-42 (pages 29-32 of spec.).
Claim 13 is rejected for depending upon the limitations of claim 10.
Claim 11 has the same issue described for claim 10 above, but for equations 16-17. Deuteration will be preferred at the carbon immediately attached to the aryl groups of these equations when either of R36-37 are alkyl (e.g. methyl, ethyl). This is demonstrated in Example 23 of the specification (shown below) where deuteration occurs on the methyl instead of the position indicated in Equation 16:
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(Example 23, page 21 of spec.)
Claim 12 has the same issue described for claims 10-11 above, with equation 18. In this case, deprotonation would be preferred in the allylic position (instead of the vinylic position – as shown in the equation) when R41-42 are alkyl.
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This is demonstrated in Example 50 of the specification, wherein one of the vinylic positions is deuterated on account of also being benzylic; however, the vinylic position β-to the phenyl (indicated with a solid arrow) is not benzylic or allylic, and therefore remains intact, while the allylic position (indicated with a dashed arrow) is effectively deuterated.
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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.
Claims 1-5 and 14-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”).
Regarding claims 1-2, 14, Xu discloses a reaction for toluene (a compound containing C-H bonds) deuteration with D2 (g) and 5 mol% KH (potassium hydride – alkali metal hydride catalyst) (see page 11051, Scheme 2).
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Regarding claims 3-4, Xu discloses benzyl potassium (alkali metal hydrocarbon), formed after C-H activation of toluene with KH (“alkali metal salt”) (page 11053).
Regarding claims 5, 17-19, Xu’s deuteration is described by instant “Reaction Equation 1” (shown below) when R1-5 are H; and X1 is C.
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Regarding claim 15, Xu discloses their reaction with 5 atm of D2, which is about 5 bar.
Regarding claim 16, Xu’s reaction is done under solvent free conditions, as toluene is the reactant and not a solvent in this case.
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.
Claims 5, 7, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”); as applied to claims 1-5 and 14-19.
The teachings of Xu are disclosed in the 102-section above and incorporated herein.
Xu further discloses their conditions for deuteration with D2 and alkali metal base catalyst, wherein the Lewis acidic alkali metal center (potassium) is demonstrated to interact with H2, HD, or D-2 (page 11053, col. 2, last para.), leading to formation of KH and/ or KD species, which can further undergo Xu’s reaction shown in Schemes 2D and 1B-C; specifically, KH and KD can deprotonate benzylic substrates (“activate benzylic C-H bonds” for deuteration) (page 11052, col. 2, last para.).
Regarding claims 5 and 17-19, specifically equations 3 and 5, wherein a benzylic position is deuterated, while Xu does not disclose these substrates specifically, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to use Xu’s conditions for the deuteration of benzylic positions. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Xu discloses their conditions for deuteration of the benzylic methyl of toluene, and mentions they are continuing to explore the potential applications of benzylic C-H activation (beyond toluene).
Regarding claim 7, Xu discloses KN(SiMe3)2 in deuterated benzene scrambled H-D to produce KH, KD, H-N(SiMe3)2, and D-N(SiMe3)2. Xu discloses that these species are in equilibrium with KN(SiMe3)2, H2, D2, and H-D.
Therefore, while Xu doesn’t specifically disclose deprotonation of the benzylic position of toluene with KN(SiMe3)2 to produce benzyl potassium, it would have been prima facie obvious to one of ordinary skill to swap KH for KN(SiMe3)2 in Xu’s Scheme 2D reaction, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Xu’s teachings that KN(SiMe3)2 is capable of activating H-D to generate KH and KD in situ, which can go on to react as shown in their Scheme 2.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”); as applied to claims 1-5, 7, and 14-19; in view of Wenchi et al. (CN109020849A – Pub. Date: Dec. 18th, 2018) (“Wenchi”).
The teachings of Xu are disclosed in the 102 and 103-sections above and incorporated herein.
While Xu doesn’t teach: (i) deuteration of alkyl sulfoxides or sulfates (claim 8); or (ii) using a sodium/ potassium hydroxide catalyst (claim 9); the teachings of Wenchi are relied upon for these disclosures.
Wenchi discloses a method for the preparation of deuterated DMSO (reading on the “Reaction Equation 8” below when R29 is C1 hydrocarbon) with a potassium hydroxide or sodium hydroxide base catalyst and D2O and heating at 90-95 °C for 1-3 h (page 1 of translated document).
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Therefore, regarding claims 8-9, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare deuterated-DMSO with D2 as a deuterium source, and potassium hydroxide as a base in view of the teachings of Xu and Wenchi. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because of Xu’s disclosure of their conditions for deuteration with D2 and alkali metal base catalyst, wherein the Lewis acidic alkali metal center (such as potassium) is demonstrated to interact with H2, HD, or D-2 (page 11053, col. 2, last para.), leading to formation of KH and/ or KD species, which can further undergo Xu’s reaction shown in Schemes 2D and 1B-C. Further because Wenchi discloses their method of DMSO deuteration with an alkali metal hydroxide catalyst.
Claims 10-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”); as applied to claims 1-5, 7, and 14-19; in view of Salamanca et al. (Eur. J. Org. Chem. 2020, 3206–3212) (“Salamanca”).
The teachings of Xu are disclosed in the 102 and 103-sections above and incorporated herein.
While Xu doesn’t teach deuteration of fluorobenzene (claim 10); the teachings of Salamanca are relied upon for these disclosures.
Salamanca teaches the general reaction scheme 1 below (page 3207) for the deuteration of fluorobenzenes with alkali metal carbonates, K3PO4, or NaOH (Table 2, page 3208) and D2O and deuterated DMSO as deuterium sources. Salamanca specifically discloses compound 7 as the deuteration product of fluorobenzene under these conditions. Salamanca also teaches deuteration of thiophene and furan under their reaction conditions (see Table 2, entries 11-12; and page 3209, col. 1, para. 4) – reading on instant claim 11, “reaction equation 17” when R36-37 are H and X5 is S or O.
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Therefore, regarding claim 10, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare deuterated fluorobenzene 7 with D2 as a deuterium source, and an alkali metal base catalyst in view of the teachings of Xu and Salamanca. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because of Xu’s disclosure of their conditions for deuteration with D2 and alkali metal base catalyst, wherein the Lewis acidic alkali metal center (such as potassium) is demonstrated to interact with H2, HD, or D-2 (page 11053, col. 2, last para.), leading to formation of KH and/ or KD species, which can further undergo Xu’s reaction shown in Schemes 2D and 1B-C. Further because Salamanca discloses their method of fluorobenzene deuteration with an alkali metal base catalyst.
Regarding claim 11, Salamanca discloses deuteration of thiophene and furan with their reaction conditions (see Table 2, entries 11-12; and page 3209, col. 1, para. 4) – reading on instant claim 11, “reaction equation 17” when R36-37 are H and X5 is S or O.
Regarding claim 13, Xu discloses KN(SiMe3)2 as effective in their reaction (Scheme 1B).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”); as applied to claims 1-5, 7, and 14-19; in view of Puleo et al. (J. Am. Chem. Soc. 2019, 141, 1467−1472) (“Puleo”).
The teachings of Xu are disclosed in the 102 and 103-sections above and incorporated herein.
While Xu doesn’t teach deuteration of alkenes; the teachings of Puleo are relied upon for these disclosures.
Puleo discloses α-selective deuteration of alkenes with a KOtBu base catalyst and with deuterated DMSO as a deuterium source (see Table 1). Puleo specifically discloses their deuterated compound 20, which reads on instant Reaction equation 19 when R41-42 are both pyridine (reading on aryl) – the instant specification does not define “aryl”, therefore the term “aryl” has been assumed to encompass heteroaryls.
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Therefore, regarding claim 12, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare a vicinal deuterated alkene like 20 with D2 as a deuterium source, and a potassium base catalyst in view of the teachings of Xu and Puleo. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because of Xu’s disclosure of their conditions for deuteration with D2 and alkali metal base catalyst, wherein the Lewis acidic alkali metal center (such as potassium) is demonstrated to interact with H2, HD, or D-2 (page 11053, col. 2, last para.), leading to formation of KH and/ or KD species, which can further undergo Xu’s reaction shown in Schemes 2D and 1B-C. Further because Puelo discloses their method of vinyl deuteration with a potassium tert-butoxide catalyst.
Claims 6, 8, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Angew. Chem. Int. Ed., 2018, 57, 11050 –11054) (“Xu”); as applied to claims 1-5, 7, and 14-19; in view of Salamanca et al. (Eur. J. Org. Chem. 2020, 3206–3212) (“Salamanca”); further in view of Evans et al. (Obtained from studylib.net [retrieved on 12/20/2025] <URL:https://studylib.net/doc/8126126/pka-table.1> - Published Nov. 4th, 2005) (“Evans”).
The teachings of Xu are disclosed in the 102 and 103-sections above and incorporated herein.
Xu discloses their conditions for deuteration with D2 and alkali metal base catalyst, wherein the Lewis acidic alkali metal center (potassium) is demonstrated to interact with H2, HD, or D-2 (page 11053, col. 2, last para.), leading to formation of KH and/ or KD species, which can further undergo Xu’s reaction shown in Schemes 2D and 1B-C; specifically, KH and KD can deprotonate benzylic substrates (“activate benzylic C-H bonds” for deuteration).
While Xu does not specifically teach deuterations corresponding to instant Reaction Equations 6-7, 9-13, 15-16 (claims 6, 8, 10-11, and 20); the teachings of Salamanca and Evans are relied upon for these disclosures.
Salamanca teaches deuteration conditions for fluorobenzenes with alkali metal carbonates, K3PO4, or NaOH (Table 2, page 3208) and D2O and deuterated DMSO as deuterium sources. Salamanca further discloses that the deuteration reaction is controlled by the acidity of the substrate (fluorobenzenes in their case) with the more acidic C-H bond being the one that is more favorably deuterated (Figure 2; and page 3209, col. 1, para. 5- end of page). Salamanca discloses that for the less acidic C-H bonds (pKa ≥ 35 in their calculations) stronger bases are required and that those arenes that could not be deuterated with their conditions have calculated pKas of about 40 (in DMSO).
Evans discloses common pKa values of a number of common functional groups. Evans discloses the pKa of toluene to be about 43 in DMSO (page 3, col. 1, 8th from top) – yet toluene was successfully deuterated with Xu’s conditions.
Regarding Reaction Equations 6-7 (claims 6 and 20), Evans teaches the pKa of PhSCH2Ph is about 31 (page 4, col. 2, entry 1). While Evans doesn’t specifically teach the pKa of PhSCH3 (as in instant claims when R21-22 are connected into an aromatic ring and R23 is absent – see 112(b)); comparing the pKa of -CH2Ph and -CH3 sulfoxides and sulfones (col. 3 and 4, page 4), one can see that the difference of pKa of -CH2Ph and -CH3 sulfoxides and sulfones is of about 4-6 pKa units. Therefore, the pKa of a C-H in the methyl of PhSCH3 can be estimated to be roughly around 35-37, which would still be expected to be acidic enough for Xu’s conditions, which worked for the deuteration of toluene, which has a pKa of 43 in DMSO.
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Regarding Reaction Equations 9-12 (claim 8), Evans teaches the pKa values for the sulfones and sulfoxides above, reading on instant R29 being C1 alkyl or aryl; R30 being alkyl or aryl; and C31-34 being H.
Therefore, regarding claims 6, 8, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare deuterated sulfides, sulfoxides, and sulfones, in view of Xu, Salamanca, and Evans. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Xu’s disclosure of their deuteration conditions comprising D2 as a deuterium source and an alkali metal base as catalyst, which work for the deuteration of toluene (with a pKa of 43 in DMSO); further because Salamanca teaches deuteration reaction is controlled by the acidity of the substrate, with the more acidic C-H bond being the one that is more favorably deuterated; further because Evans discloses pKa values of common functional groups, including sulfides, sulfoxides, and sulfones, all of which have pKa values lower than 43, and are therefore expected to be successfully deuterated under Xu’s conditions.
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627