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
This office action is in reply to the Applicant’s Arguments and Amendment filed 04 March 2026. Claims 1 and 8 are amended. Claims 6-7 and 9-18 are canceled. Currently, claims 1-5 and 8 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 25 February 2026 was filed after the mailing date of the application on 07 July 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
REJECTIONS – MAINTAINED & NEW
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(New) Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hutchinson et al. (Synthesis of alkylated methylene bisphosphonates via organothallium intermediates, J. Organometallic Chem. 1985, 291, 145-151; entered into the IDS on 22 December 2023).
In pursuit of halogenated methylene bis-phosphonic acids, Hutchinson discloses a method to obtain medronic acid through the hydrolysis of tetraisopropyl esters of methylene bis-phosphonic acids through the use of bromotrimethylsilane, added under dry nitrogen, stirred for ≥20 hours, lyophilized, then dissolved in aqueous methanol which was removed in vacuo. This last procedure was repeated four times, then the residues dissolved in water and isolated via ion exchange chromatography (pg. 151, section – viii). This reaction is best illustrated by Scifinder© as the reference itself provides little in the way of visual representation:
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As the claim does not specify exact reaction conditions, Hutchinson reads upon the claim where medronic acid tetraisopropyl ester, contacted with trimethylsilyl bromide to form a mixture, and treating the mixture with a liquid comprising water, thereby forming medronic acid. As such, Hutchinson anticipates claim 1.
(New) With regards to the limitations of claim 2, wherein the compound of the formula (A) is reacted with trimethylsilyl bromide or trimethylsilyl iodide, are met as Hutchinson uses trimethylsilyl bromide to deprotect medronic acid tetraisopropyl ester.
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 non-obviousness.
(New) Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Hutchinson et al. (Synthesis of alkylated methylene bisphosphonates via organothallium intermediates, J. Organometallic Chem. 1985, 291, 145-151) in view of Vaghefi et al. (Synthesis of certain nucleoside methylenediphosphonate sugars as potential inhibitors of glycosyltransferases, J. Med. Chem. 1987, 30, 8, 1391-1399).
Hutchinson discloses a method of deprotecting medronic acid tetraisopropyl ester using trimethylsilyl bromide followed by hydrolysis with aqueous methanol.
Hutchinson does not, however, teach where the compound of the formula (A) is reacted with trimethylsilyl chloride and an alkali metal iodide or bromide.
Vaghefi addresses this by teaching deprotection of medronic acid diisopropyl ester diphenyl ester 8 using trimethylsilyl chloride with sodium iodide to yield medronic acid diphenyl ester 5:
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As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of trimethylsilyl chloride with sodium iodide to perform deprotection of isopropyl phosphonic acid esters, in light of the teachings of Veghefi, and apply these same conditions to the deprotection of medronic acid tetraisopropyl ester.
Regarding the limitation of claim 4, wherein an alkali metal iodide is utilized and is sodium iodide, is met as Veghefi teaches the use of sodium iodide with trimethylsilyl chloride in phosphonic acid ester deprotection.
(New) Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Hutchinson and Veghefi as applied to claims 3-4 above, and further in view of Erion et al. (Thyroid hormone receptor agonist and use thereof, WO 2017/184811 A1, 2017).
Hutchinson discloses a method of deprotecting medronic acid tetraisopropyl ester using trimethylsilyl bromide followed by hydrolysis with aqueous methanol. Veghefi further expands this by teaching deprotection using trimethylsilyl chloride and sodium iodide.
They do not, however, teach where the alkali metal iodide utilized is potassium iodide.
Erion fixes this shortcoming by teaching the use of potassium iodide with trimethylsilyl chloride in the deprotection of diisopropyl phosphonic acid ester 1G to give the resulting phosphonic acid 1I (pg. 40 – scheme 1, para. 0134):
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As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of potassium iodide as an alternative to sodium iodide along with trimethylsilyl chloride to perform deprotection of isopropyl phosphonic acid esters, in light of the teachings of Erion, and apply this condition to the deprotection of medronic acid tetraisopropyl ester.
(New) Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Hutchinson et al. (Synthesis of alkylated methylene bisphosphonates via organothallium intermediates, J. Organometallic Chem. 1985, 291, 145-151) in view of Chiminazzo et al. (Challenging synthesis of bisphosphonate derivatives with reduced steric hindrance, Tet. Lett. 2021, 70, 153012; entered in the IDS 22 December 2023).
Hutchinson discloses a method of deprotecting medronic acid tetraisopropyl ester using trimethylsilyl bromide followed by hydrolysis with aqueous methanol.
Hutchinson does not, however, teach post alkylation by further comprising reacting the medronic acid with an alkylating compound of the formula HC(OR)3, wherein R is a methyl.
Chiminazzo rectifies this deficiency by teaching alkylation, using trimethyl orthoformate, of bis-phosphonic acid 8 to give medronic acid tetramethyl ester 5 under refluxing conditions yielding 71% (pg. 2, scheme 2). Once again, this is best illustrated by Scifinder© as scheme 2 in the reference includes more elements than is required and does not fit well into this office action:
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As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to apply the same experimental conditions as taught by Chiminazzo to medronic acid to obtain medronic acid tetramethyl ester using trimethyl orthoformate.
Summary
Claim 1 is rejected under 35 U.S.C. 102(a)(1). Claims 2-5 and 8 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622