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.
Applicant requested an interview in their Remarks received by the office on October 13, 2025, see the attached interview summary.
Claims 1-3 are pending and under consideration.
Election/Restrictions
Applicant's election without traverse the following species: method A and sodium metabisulfate.
Claim Objections
The objection to claim 1 because the blurry formulas in claim 1, is withdrawn based on the amendments.
Claim Rejections - 35 USC § 112
Claims 1 and 2 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the term “fed” is withdrawn based on the amendments.
Claims 1 and 2 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “namely an initial reaction treated product or the progesterone crude product,” is withdrawn based on the amendments.
Claims 1 and 2 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “specifically comprises” is withdrawn based on the amendments.
Claims 1 and 2 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “M represents… or more” is withdrawn based on the amendments.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 1 has been amended to the ratio of solvent A to solvent B in step 1.2, from (0.5-2):1 to 0.5:1-2, which is a different ratio that is not supported by the specification. Thus, this is a new matter rejection.
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 1-3 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Furigay et al. (Journal of Visualized Experiments, 2018, 134, e57639, 1-10) further in view of Taub et al. (Journal of the American Chemical Society, 1954, 76, 4094-4097).
The present application is claiming a process of removing aldehyde impurities from a reaction mixture which comprises progesterone and the aldehyde impurities. The process comprises treating the reaction mixture with a sulfurated nucleophile, i.e. the elected species is sodium metabisulfite, to convert the aldehyde impurities to a highly polar hydroxysulfonate, which can be removed more readily.
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The Taub et al. reference teaches the conversion of aldehyde V to the sulfite addition compound VI, see page 4095, and page 4097, left-hand column for the experimental section. Compound V is different from the aldehyde impurities 2 and 3 shown above by the substitutions at C-12, OH versus Applicant’s H; and C-20, OH versus Applicant’s methyl. However, the hydroxy group is not affected by the reaction conditions as can be seen in compound VI. The use of analogous reactants in a known process is prima facie obvious. 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.
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The experimental section for compound VI teaches the purification of compound VI from the reaction mixture, see page 4097, left-hand column.
Additionally, Furigay et al. teaches the use of bisulfite to separate aldehydes from mixtures by an extraction protocol. Furigay teaches ”[t]he purification method for organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer by generating a charged structure provides an opportunity to use extraction as a simple purification technique. By combining the use of a miscible organic solvent with saturated sodium bisulfite, aldehydes and reactive ketones can be successfully transformed into charged bisulfite adducts that can then be separated from other organic components of a mixture by the introduction of an immiscible organic layer. Here, we describe a simple protocol for the removal of aldehydes, including sterically-hindered neopentyl aldehydes and some ketones, from chemical mixtures. Ketones can be separated if they are sterically unhindered cyclic or methyl ketones. For aliphatic aldehydes and ketones, dimethylformamide is used as the miscible solvent to improve removal rates. The bisulfite addition reaction can be reversed by basification of the aqueous layer, allowing for the re-isolation of the reactive carbonyl component of a mixture,” see the abstact. Therefore, this technique is known 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.
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. Thus, the claims are rendered obvious.
Applicant traverses by stating, “Furigay discloses separation of aldehydes and reactive ketones from mixtures using a bisulfite extraction protocol. Particularly, Furigay teaches "by combining the use of a miscible organic solvent with saturated sodium bisulfite, aldehydes and reactive ketones can be successfully transformed into charged bisulfite adducts that can then be separated from other organic components of a mixture by the introduction of an immiscible organic layer" (see abstract). Furigay teaches "this method is applicable to the separation of aldehydes and sterically-unhindered cyclic and methyl ketones from molecules that do not contain these functional groups (see last paragraph on page 1). Regarding the methyl ketones, compounds 34 and 35 are listed as reactive ketone substrates, while compound 26 is listed as unreactive ketone
substrate. Furigay does not explicitly disclose or teach the ketone compound of progesteron in the present application is the unreactive ketone substrate, which does not react with saturate sodium bisulfite.”
This is correct. However, based on the results achieved with the different aldehydes and ketones, this reference provides a method for the separation of aldehydes from ketones.
Applicant further states, “By comparison, current claim 1 differs from Furigay at least in that Furigay fails to disclose: 1) the possibility and feasibility of separating progesterone from impurities 2 and 3; 2) "cooling down to -20 to 5°C to obtain an initial reaction treated product of the progesterone crude product" in step 1.1; or step 1.2, or step 1.3; and 3) "step 2, adding water having a volume 0.5 to 5 times the weight of the progesterone crude product to the initial reaction treated product of the progesterone crude product obtained in step 1, filtering, washing a filter cake with water until neutral, and drying to obtain highly pure progesterone".
This is not persuasive. Again, based on the results achieved with the different aldehydes and ketones, this reference provides a method for the separation of aldehydes from ketones. Moreover, as noted in the rejection, 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.
Applicant further notes, “Regarding the difference (2) in step 1.1, after reaction, Taub teaches "concentrating under vacuum until a granular precipitate appeared, adding water and continuing concentrating until methanol had been removed completely, filtering the precipitate, washing with water..." Therefore, it is axiomatic that in order to recover the unreacted aldehyde compound V, Taub requires the complete removal of methanol, which teaches away from the present application.”
The Taub reference procedure does remove all the methanol from the reaction, however, the obviousness rejection is based on the combination of references.
Applicant further notes, “Regarding the difference (2) in step 1.2, Furigay teaches "the key to achieving reactivity between bisulfite and the carbonyl is the use of a water-miscible solvent, which allows the reaction to take place prior to the separation into separate phases" (see first paragraph in section Introduction). Thus, Furigay explicitly teaches the necessity of miscible solvent during the reaction to improve removal rate. To realize a high removal rate, a person of ordinary skill in the art would not modify Furigay by introducing the immiscible solvent before reaction, because such modification would render modified Furigay unsatisfactory for its intended purpose of high removal rate.”
The present claims provide two separate alternative methods in step 1, the first reaction only requires solvent A, although the process is not limited to only solvent A; and the alternate reaction that requires solvent A and B, but not limited to said solvents.
Applicant further states, “Regarding the difference (3), the purification of compound VI from the reaction mixture disclosed by Taub just means the separation of reaction product VI from the reaction system free of or containing little reactant compound V. By contrast, in the present application, progesterone that is not reacted with sulfurated nucleophile still exists in the reaction system, hence, a person of ordinary skill in the art would not be motivated to apply the purification method of Taub to a mixture system different from that of Taub.”
The Examiner is not sure what is the point being raised here. Purification methods are well-known in the art and conventional.
Applicant further notes, “In addition, the method of present application has achieved unexpected technical effects, i.e., high progesterone yield, and high purity of progesterone product. Such unexpected technical effects have been demonstrated by Examples. As shown in table below, Example 1 (falling within the scope of current claim 1) achieves higher yield meanwhile high purity, achieving an overall yield compared with Examples 2-3 (outside of the scope of current claim 1), which are unexpected in view of cited references. Examples 5-7 of the present application, where a mixed solvent of organic solvents A and B is used, the defined solvent B being obviously water-immiscible solvent, have achieved high yield and purity (shown in table below), which is unexpected in view of Furigay.”
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This is unpersuasive. Is the product yield calculated on the weight of only progesterone or is the product yield based on the crude material weight (progesterone and aldehyde impurities)? What was the purity prior to the purification steps?
Thus, the rejection is maintained over claims 1-2 and applied to newly submitted claim 3.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624