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 Claims
Claims 11-24 are pending as of the response and amendments filed on 5/27/26. Claims 1-10 and 25-26 have been canceled.
The 103 rejection over claims 25-26 over Brattsand, US 3929768 is withdrawn as these claims have been canceled.
Upon further consideration, new rejections under 35 USC 103 are made, discussed below. As the new rejections are not necessitated by the amendments, this action is non-final.
Claims 11-24 were examined. Claims 11-18 and 20-22 are rejected. Claims 19 and 23-24 are objected to.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 11-17 and 20-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brattsand et. al., US 3929768, patented 12/30/1975 (of record) in view of Lira et. al., Tetrahedron Lett., vol. 54, pp. 1690-1692, publ. 2013.
Brattsand teaches steroids having the following structural formula, and methods of preparation, wherein the steroids have activity pharmacologically for treating inflammation (title & abstract; col. 1, lines 1-36):
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, wherein X and Y are independently hydrogen or fluorine; Z=hydroxyl or esterified hydroxyl group; R=straight or branched hydrocarbon group having 2-10 carbon atoms. Budesonide is encompassed by formula (I), having X and Y = hydrogen; Z=OH; and R= n-propyl. Furthermore, Brattsand teaches preparing the compounds as phosphate esters, i.e., 21-phosphate esters, utilizing phosphoroxy chloride in the presence of a tertiary base, followed by hydrolysis, as well as conversion into the alkali phosphate salts, such as sodium salts, by contacting the 21-phosphate ester with an alkali metal hydroxide, such as NaOH (col. 2, lines 30-38). Brattsand further provides two example compounds which are the 21-phosphate disodium salts of formula (I), and preparation and isolation of these compounds, involving methanol as a solvent (cols. 5-6. Exs. 37-38). Budesonide 21-phosphate disodium is included within formula (I) above, having X and Y both hydrogen; R=n-propyl; and Z=-OPO3- 2Na+.
Brattsand doesn’t teach the claimed phosphorylation process.
Lira teaches a one-pot procedure for the phosphorylation of alcohols to provide phosphate monoesters in improved yields utilizing tetrabutylammonium hydrogen phosphate and trichloroacetonitrile in acetonitrile; the reaction is carried out at room temperature with stirring for 2 hours or until all starting material is consumed, and part of the synthesis is carried out at a pH of 8.0 (abstract; p. 1691, Scheme 1 & left col., last para-right col., top para; p. 1692, see note 13):
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. Lira teaches the phosphorylation process as straightforward and applicable to a wide range of primary and secondary alcohols (p. 1691, right col., last para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have prepared budesonide 21-phosphate as taught by Brattsand using the phosphorylation process taught by Lira. Brattsand teaches the preparation of steroids, inclusive of budesonide, as well as preparing 21-phosphate esters of these steroids, and their disodium salts using NaOH in methanol solvent. Lira teaches a simpler process of phosphorylation of a primary alcohol involving reaction of the alcohol with Cl3CCN and tetrabutylammonium dihydrogen phosphate, at room temperature in acetonitrile, which provides improved yields. Additionally, Lira teaches the process can be used to phosphorylate a wide range of primary or secondary alcohols. Therefore, one of ordinary skill in the art would have been motivated to have prepared budesonide 21-phosphate by the instantly claimed process, i.e., combining budesonide with Cl3CCN and tetrabutylammonium dihydrogen phosphate, at room temperature in acetonitrile solvent, for the advantages taught by Lira, and have had a reasonable expectation of success.
Regarding instant claims 17 and 20, it would have been prima facie obvious to have isolated budesonide 21-phosphate or budesonide 21-phosphate disodium salt after synthesis, e.g., removal of unreacted material or intermediates.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brattsand et. al., US 3929768, patented 12/30/1975 (of record) in view of Lira et. al., Tetrahedron Lett., vol. 54, pp. 1690-1692, publ. 2013 as applied to claims 11-17 and 20-22 above, and further in view of Chen et. al., Crystal Growth & Design, vol. 11, pp. 887-895, publ. 2011.
The disclosures of Kern and Lira as discussed previously are incorporated herein. However, crystallization of budesonide 21-phosphate is not explicitly taught or suggested.
Chen teaches crystallization as important in the separation and purification of chemical products in the fine chemical, food, and pharmaceutical industries, typically functioning as the final step in the preparation of pharmaceutical ingredients (abstract; p. 887, Intro para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have added the step of crystallizing budesonide 21-phosphate to the synthetic process, as Chen teaches crystallization as important in the isolation and purification of chemicals and pharmaceuticals. One of ordinary skill in the art would have carried out the step of crystallization of budesonide 21-phosphate as part of a routine process of isolating and purifying the product.
Claim Objections
Claims 19 and 23-24 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH PIHONAK whose telephone number is (571)270-7710. The examiner can normally be reached Monday-Friday 9:00-5:30 EST.
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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