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 .
This is a Final Office Action.
Claims 29 and 33-51 are pending and claims 29, 33-38 and 49-51 are under examination. Claims 50 and 51 are new claims. Claims 38-48 are withdrawn based on the lack of unity.
Election/Restrictions
Applicant elected, without traverse, Group (II) and process a) in the reply filed on March 31, 2025, drawn to a method for preparation of 25-OH cholesterol and 25-OH vitamin D3 (calcifediol), embraced by claims 28-38 and 49.
Specification
The objection to the title of invention is withdrawn based on the amendments.
The objection to the disclosure because of the blurry schemes in the specification is withdrawn based on the amendments.
The substitute specification filed October 27, 2026 has been entered because it conforms to 37 CFR 1.125(b) and (c).
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.
Claim 51 is 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 pre-AIA the applicant regards as the invention.
Claim 51 is broader than claim 50, from which it depends. The term “comprising” is found in claim 51 but not claim 50. Thus, claim 51 is indefinite.
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 33, 35 and 49-51 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Zhang et al. (CN 109021059) in view of Schmitterberger et al. (Tetrahedron Letters, 1996, 37(1), 29-32), DeLuca et al. (US 7241909), and Zhang et al. (US 8962660).
The present application claims a process of making 25-OH cholesterol comprising the reactions provided in the scheme below.
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Zhang et al. (‘059) teaches the conversion of iodide compound 5 to the ethyl ester, compound 6, which is completed with pyridine, ethyl acrylate, nickel chloride hexahydrate and zinc powder by heating to 65ºC, see page 12, paragraph 0057-0058; and see the WIPO translation on pages 10/19 – 11/19. The ethyl ester is converted to the alcohol 7 by way of a Grignard reagent, MeMgBr, at 10 ºC and warmed to RT, followed by dehydration with an acid, p-TSA, see pages 4, 15 and 18; and pages 14/19 and 18/19 of the WIPO translation.
Zhang does not teach 1) the first reaction of compound 3 to compound 5; 2) the second step between Zn and nickel chloride at 50º C as currently amended; and 3) the Grignard reaction at 50 to 90 ºC, which is found in the present claim 32.
Schmittberger et al. teaches the conversion of alcohol 3 to the corresponding iodide compound 5 with PPh3-I2-imidazole in ether/acetonitrile, see page 30, compounds 4 and 5 and page 32, reference/note 7, last sentence.
Claim 49 has been amended and claims 50-51 are drawn to “preparing a reaction product of zinc and ethyl acrylate in the presence of nickel chloride, wherein reaction is started at a temperature of 50 º C; cooling the reaction product of zinc and ethyl acrylate to 25º C; reacting the (20S)-20-iodo methyl - 6β- methoxy-3[α],5-cyclo-5 α -pregnane with the reaction product of zinc and ethyl acrvlate in the presence of a first base to obtain ethyl 1(S)- 6β -methoxy-3α,5-cyclo-5 α -cholesta-25-oate at a temperature of up to 25º C.”
DeLuca et al. teaches the same reaction but with different starting materials, i.e. isopropyl acrylate instead of ethyl acrylate:
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, see columns 21-22 and column 15, which is also shown below. The reaction between zinc powder, pyridine and isopropyl acetate is warned to 50º C, then nickel chloride is added.
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Zhang et al. (‘660 patent) also teaches the same reaction with different starting materials, i.e. methyl acrylate instead of ethyl acrylate:
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Thus, the reaction of zinc in pyridine with nickel chloride at 50º C, then cooling the reaction before the addition of the acrylate, followed by increasing the temperature to about 65º C is well-known in the art for this reaction. The main differences are 1) the different starting materials; and 2) the cooling temperature, 0º C versus Applicant’s 25º C.
The use of analogous reactants in a known process is prima facie obvious unless there is evidence to the contrary, see In re Durden, 226 USPQ 359 (1985). Once the general reaction has been shown to be old, the burden is on Applicants to present reasons or authority for believing that a group on the starting material would take part in or affect the basic reaction and thus alter the nature of the product or the operability of the process. In looking at the instant claimed process as a whole, as stated in In re Ochiai, 37 USPQ 2d 1127 (1995), the claimed process would have been suggested to one skilled in the art.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the solvents taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Claim 32 requires the Grignard reaction to be done at 50 to 90 ºC compared to the Zhang reference at 10ºC and warmed to RT. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the solvents taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Claim 49 has been amended to “preparing a reaction product of zinc and ethyl acrylate in the presence of nickel chloride, wherein reaction is started at a temperature of 50 º C; cooling the reaction product of zinc and ethyl acrylate to 25º C; reacting the (20S)-20-iodo methyl - 6β- methoxy-3[α],5-cyclo-5 α -pregnane with the reaction product of zinc and ethyl acrvlate in the presence of a first base to obtain ethyl 1(S)- 6β -methoxy-3α,5-cyclo-5 α -cholesta-25-oate at a temperature of up to 25º C.”
Thus, the claims are rendered obvious by Zhang et al. in view of Schmitterberger et al, Deluca et al., and Zhang et al.
Claims 29, 33-38 and 49-51 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Zhang et al. (CN 109021059) in view of Schmitterberger et al. (Tetrahedron Letters, 1996, 37(1), 29-32), DeLuca et al. (US 7241909), Zhang et al. (US 8962660) and Uskokovic et al. (US 3993675) and Nishikawa et al. (US 4388243) and Fuse et al. (Organic & Biomolecular Chemistry, 2012, 10, 5205-5211) and Stevens et al. (US 4686023).
The present application claims a process of making 25-OH vitamin D3 (calcifediol) comprising preparing the 25-OH cholesterol as noted above and shown below in the scheme.
The 103 rejection above is incorporated here.
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Uskokovic et al. (‘675) teaches the acetylation step from compound 7 to compound 8, with a compound similar in structure to compound 7, see column 2 and Example 1 and below.
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The only difference between the present compound and compound I above is the OH group at position 1 of the steroid core. This OH group also undergoes the protection with acetic anhydride and pyridine as a base at 100ºC and is converted into an acetyl group with the other two OH groups at positions 3 and 25 of structure I. Uskokovic further teaches the reaction can be done from about 25ºC to the boiling point of the reaction medium see column 3, lines 59-61.
MPEP 2109 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Nishikawa et al. (‘243) teaches the allylic bromination step of the compound shown below, which is the same compound made by the acetylation reaction in the Uskokovic reference with 1,3-dibromo-5,5-dimethylhydantoin (DDH) under irradiation of infrared (IR), see column 15, Comparative Example 3. The reference further teaches the bromination step may be done with a small amount of a radical initiator, e.g., AIBN, see column 4, line 26.
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The final step of converting the diene of compound 9 to calcifediol is done using a high-pressure mercury lamp in presence of a sensitizer, e.g. 5-(3-pyridyl)-2,2'-bithiophene, anthracene, or 9-acetyl anthracene, as found in claim 37.
Stevens teaches the photochemical conversion of 7-dehydrocholesterol (7-DHC) to previtamin D3 by irradiation in the presence of anthracene as a photosensitizer, see columns 1-2 and below.
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Again, these compounds are similar in structure and are expected to have the same properties as the presently claimed compounds.
Thus, based on the above references, the process as claimed is rendered obvious.
Applicant traverses by stating, “Schmittberger does not show conversion of iodide 5 to an ethyl ester by reaction with ethyl acetate.”
This is not persuasive. The Schmittberger reference was used to for the following step:
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. As noted in the rejection, Schmittberger et al. teaches the conversion of alcohol 3 to the corresponding iodide compound 5 with PPh3-I2-imidazole in ether/acetonitrile, see page 30, compounds 4 and 5 and page 32, reference/note 7, last sentence.
Applicant refers to the TAMORE DECLARATION by stating, “As set forth in Para. 4, "[in] the process of Zhang, the nickel chloride, ethyl acrylate, and zinc were heated to 65º C at the start of the reaction. The resulting reaction product was purified by flash preparative chromatography (eluent: ethyl acetate-n-hexane) to give the desired ethyl ester in a yield of 69%." According to Para. 6 of the TAMORE DECLARATION, "a vigorously stirred mixture of 25.7 g (0.4 mol) of zinc dust and 25.7 mL (36.0 g 0.36 mol) of ethyl acrylate in 60 mL of pyridine was [treated with] 18.0 g (0.075 mol) of NiC126H2O. The mixture was heated to 50°C, whereupon an exotherm ensued, and stirring was continued at 650 C for 30 min."
According to the TAMORE DECLARATION, "initiating reaction between zinc and ethyl acrylate in the presence of nickel chloride at 500 C and then allowing the temperature to increase exothermically to 650 C resulted in a reddish brown solution. Initiating reaction between zinc and ethyl acrylate in the presence of nickel chloride at 600 C and then maintaining a constant temperature resulted in a black solution. The black color of the solution is indicative of decomposition of the catalytic nickel complex." TAMORE DECLARATION, Para. 7.
In Para. 8. of the TAMORE DECLARATION, it is stated that decomposition of the Ni(0) catalyst leads to undesired side reactions, including beta-elimination of iodide from the 20- iodomethyl pregnane derivative 5 and dimerization of ethyl acrylate, "forming a polymer that consumes the starting material and acts as a significant impurity."”
This is not persuasive. The critical step which is highlighted in the declaration is the following step:
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.
The declaration goes on to emphasize the reaction between zinc, pyridine, nickel chloride and ethyl acrylate is heated to 50º C, which is the temperature where an exothermic reaction occurs. The reaction is then heated to a higher temperature of 65º C for a period of 30 minutes, then cooled prior to the iodo-compound being added. As noted in the amended rejection, these steps are not unknown for this reaction, see the DeLuca and Zhang (‘066 patent) reference. A person of ordinary skill in the art would follow this same procedure as outlined in the art. Thus, the TAMORE DECLARATION was considered but not found to provide unexpected results.
Therefore, the rejections are maintained.
Conclusion
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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/SUSANNA MOORE/Primary Examiner, Art Unit 1624