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 .
Status of the Claims
Claims 1-13 are currently pending and under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP21215313.4, filed on December 16 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 10 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
On page 18, Example 2 is titled “Ligand According to Structure IIIc,” but the body of the example states that dipropylene glycol dimethyl ether (DPGDME) was added. Elsewhere in the specification, compound IIIc is identified as diethylene glycol diethyl ether, whereas compound IIId is identified as dipropylene glycol dimethyl ether. Thus, Example 2 appears inconsistent with the earlier identification of compounds IIIc and IIId.
On page 19, Example 3 is titled “Ligand According to Structure IIId,” but the body of the example states that diethylene glycol diethyl ether was added. Elsewhere in the specification, compound IIId is identified as dipropylene glycol dimethyl ether, whereas compound IIIc is identified as diethylene glycol diethyl ether. Thus, Example 3 appears inconsistent with the earlier identification of compounds IIIc and IIId.
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 2 , 8-9, and 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.
Regarding claim 2, the phrase “wherein the compound of formula IIIa comprises or is a compound of formula IIIb, IIIc, IIId, IIIe” renders the claim indefinite because it is unclear whether formula IIIa must be exactly one of formula IIIb, IIIc, IIId, or IIIe, whether it may be a mixture including more than one of those compounds, or whether it encompasses a broader compound that merely includes one or more thereof. The absence of a coordinating conjunction between “IIIb, IIIc, IIId, IIIe” further renders the relationship among the listed alternatives unclear. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 8 recites ”stirring the reaction mixture, preferably for less than 1 h”, and claim 9 recites “wherein the temperature in step (b) is in the range of from 20 to 100 °C, preferably 30 to 80 °C”, It is unclear whether the preferred language further limits the claims or is only non-limiting exemplary language. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 13, the phrase “wherein the compound IIIf comprises or is” renders the claim indefinite because it is unclear whether the claim is limited to the specifically depicted compound or instead encompasses a broader compound that merely includes the depicted structure. Accordingly, the metes and bounds of the claim are unclear. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1–7 and 10–13 are rejected under 35 U.S.C. 103 as being unpatentable over Zinser et al. (WO2021151908A1) in view of Sakamoto et al. (JPH08245641A), and further in view of Molnar et al. (WO1997018179A1).
Zinser et al. teaches (See e.g. p. 14 III Reaction step b) a process for the synthesis of buprenorphine, and the Grignard reagent tert-butylmagnesium chloride in diethyl ether/toluene is used, Zinser et al. teaches (See e.g. p. 14 III Reaction step b) adding diglyme before addition of the buprenorphine ketone substrate. Zinsar et al. teaches (See e.g. p. 14 III Reaction step b) adding diglyme to a mixture of tert-butyl magnesium chloride solution in diethyl ether and toluene, then adding the substrate solution to that Grignard mixture. Zinser et al. therefore teaches the same reaction context as the present claims: a buprenorphine precursor ketone is reacted with t-ButylMgX in an ether/aromatic hydrocarbon medium, with the coordinating ether additive introduced before substrate addition.
Zinser et al. does not expressly teach replacing diglyme with the presently claimed formula IIIa ether family or the broader formula IIIf family.
Sakamoto et al. teaches (See e.g. p. 2 claim 1)exactly that missing solvent-class concept. It discloses a Grignard reagent comprising a polyalkylene glycol dialkyl ether solvent of formula [1]
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, where R1 and R2 are each C1–8 alkyl, R3 is H or methyl, and n is 1–6, and expressly identifies representative solvents including diethylene glycol diethyl ether, diethylene glycol ethyl methyl ether, and dipropylene glycol dimethyl ether. Sakamoto et al. further teaches (See e.g. p. 4 [0018]) that Grignard reagents can be prepared in such solvents in high yield, and that the same solvent system is useful in subsequent coupling reactions and downstream handling.
It would have been obvious to a person of ordinary skill in the art before the effect filing date of the invention, to modify Zinser et al.’s buprenorphine Grignard step by replacing the diglyme additive with one of the closely related polyalkylene glycol dialkyl ethers taught by Sakamoto et al., because Sakamoto et al. teaches those ethers as suitable coordinating media for Grignard reagents, teaches their use in subsequent coupling chemistry, and teaches operational advantages such as high-yield reagent formation and easier downstream handling. This would have been no more than the substitution of one known Grignard-coordinating ether medium for another closely related known Grignard-coordinating ether medium in the same type of carbonyl-addition chemistry, with a reasonable expectation of success.
Regarding claim 2, the instant application expressly identifies claim-2 species including IIIb = diethylene glycol methyl ethyl ether (DEGMEE), IIIc = diethylene glycol diethyl ether (DEGDEE), and IIId = dipropylene glycol dimethyl ether (DPGDME). Sakamoto et al. (See e.g. p. 2 [0006]) expressly lists diethylene glycol diethyl ether, diethylene glycol ethyl methyl ether, and dipropylene glycol dimethyl ether among its preferred polyalkylene glycol dialkyl ethers. Accordingly, Sakamoto et al. directly teaches the same named species family relied on by claim 2.
Regarding claims 3–6, the instant application recites a solvent selected from an ether, hydrocarbon, or aromatic hydrocarbon, including toluene/benzene, and further recites a mixture of diethyl ether and toluene. Zinser et al. expressly teaches (See e.g. p. 14 III Reaction step b) the buprenorphine Grignard reaction in diethyl ether/toluene, while Sakamoto et al. teaches (See e.g. p. 2 [0006]) adding hydrocarbon solvents including benzene, toluene, and xylene to the Grignard system and gives examples using toluene with the polyalkylene glycol dialkyl ether solvent. Thus, the solvent limitations of claims 3–6 would have been obvious from the combined teachings of Zinser et al. and Sakamoto et al.
Regarding claim 7, Zinser et al. teaches (See e.g. p. 14 III Reaction step b) the operative sequence of first introducing the coordinating ether additive into the Grignard solution and then adding the buprenorphine ketone substrate solution. Replacing Zinser et al.’s diglyme with the closely related Sakamoto et al.’s ether class preserves that same order of operations. Claim 7 is therefore rendered obvious by the same combination.
Regarding claim 10, Zinser et al. ( See e.g. p. 22, claim 1) is expressly directed to a process for the synthesis of buprenorphine, and the present application likewise states that the claim-1 method is used to make buprenorphine.
Regarding claims 11–12, claim 11 broadens from t-butylMgX to t-alkylMgX, and claim 12 returns to t-butyl. Sakamoto et al. expressly states (See e.g. p. 2 claim 1) that the Grignard residue R4 may be selected from many groups including t-butyl, while Zinser et al. (See e.g. p. 14 III Reaction step b) expressly uses tert-butylmagnesium chloride in the same buprenorphine Grignard step. Thus claims 11 and 12 are also rendered obvious by the combination.
Regarding claim 13, Molnar et al. teaches ( See e.g. p. 6 line 5) substituted tetrahydrofurfuryl ethers substituted tetrahydro-3-furan ethers
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as replacement solvents for reactions where THF or diethyl ether is used, and it expressly states that these substituted THF ethers are well suited for Grignard reagent chemistry.
Claims 8–9 are rejected under 35 U.S.C. §103 as being unpatentable over Zinser et al. (WO2021151908A1) in view of Allen et al. (US8232397B2).
Zinser et al. teaches (See e.g. p. 14 III Reaction step b) the same addition sequence of the processes for the production of buprenorphine, but its illustrated diglyme-based buprenorphine Grignard additions are carried out at 0–5°C or 5–10°C.
Zinser does not teach addition of the carbonyl compound at or above ambient temperature, further specifies 20–100°C.
Allen et al. teaches (See e.g. col. 42 line 50) in the same buprenorphine Grignard setting, teaches (See e.g. col. 12 line 25) forming a Grignard mixture comprising tert-butylmagnesium chloride, THF, and toluene, cooling the concentrate to 60°C, and then adding the ketone solution to that Grignard concentrate over about 31 minutes. The reaction is conducted (See e.g. p. 13 line 11) at a temperature that ranges from about 15° C. to about 100° C. In certain embodiments, the temperature of the reaction may be about 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, 90°, 95°, or 100° C.
It would have been obvious to a person of ordinary skill in the art before the effect filing date of the invention, to apply the known elevated-temperature buprenorphine Grignard addition conditions of Allen et al. to Zinser et al and Sakamoto et al. solvent-substitution combination, because Allen et al. demonstrates that the same kind of buprenorphine ketone addition to a tert-butyl Grignard system can be run from 20 to 100 °C with success.
Conclusion
No claims are allowed.
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/G.S./Examiner, Art Unit 1628 /AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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