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 application claims priority as follows:
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Receipt of claim amendments and arguments filed on 09/08/2026 is acknowledged.
Rejections and objections not reiterated herein have been withdrawn.
Claims 1-11 are currently pending and are the subject of this Final Office Action.
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 1-11 remain 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.
Claim 1, recites at steps A-C “in which the configuration … is not fixed” and, at step D) recites “(intermediate 5) in which the configuration of the carbon atoms 15 and 16 of the steroidal skeleton is fixed”. This is ambiguous. Compounds do not exist with bonds having a wiggly line and non-fixed configuration. It is unclear what is meant by “is fixed” and “is not fixed”.
Applicant argues that one of ordinary skill would understand that the expression “in which the configuration of the carbon atoms 15 and 16 of the steroidal skeleton is not fixed” refers to a mixture of 15α,16α,17β- and 15β,16β,17β-stereoisomers. That is not convincing because the wavy bond on the drawn structures indicates that the stereochemical configuration at those atoms is not specific. Because the stereochemical configuration at those atoms is not specific, the artisan would read it as encompassing any of the possible stereoisomers, as well as mixtures of stereoisomers at any ratio. It is unclear what the term “not fixed” adds to the claims. The artisan would not give such a narrow meaning as given by the applicant.
Applicant argues that the expression “in which the configuration of the carbon atoms 15 and 16 of the steroidal skeleton is fixed” refers to a single stereoisomer having the depicted configuration. That is unpersuasive because the recitation that the configuration is fixed describes the configuration of the compound; it does not specify the stereoisomeric purity of the product. A compound may have a defined configuration at each stereocenter and nonetheless be obtained as a mixture containing other stereoisomers. The phrase “the configuration … is fixed” identifies which stereoisomer is intended, but not the extent to which it is free of the other stereoisomers. Accordingly, the phrase does not inform one of ordinary skill in the art the degree of stereoisomeric purity (e.g. de, ee), if any, required by the claim. In addition, it’s confusing that the products of steps E and F do not recite that the “configuration … is fixed”, because the structures appear to have a defined configuration.
The examiner suggests deleting the phrases that contain “fixed” and “not fixed”; and, if the applicant wants a purity limitation, they should recite it in measurable terms supported by the specification.
In claim 9 the following phrase remains unclear: “under vacuum to the organic solvent to small volume”. There are two occurrences in claim 9.
The amendment filed on 09/08/2026 did not correct this issue.
Claim 10 recites the limitation "the solution of operation F.1)" and “in the water-miscible organic solvent”. There is insufficient antecedent basis for this limitation in the claim. Claim 10 depends of claim 1, which does not have operation F.1) and water-miscible organic solvent.
The amendment filed on 09/08/2026 did not correct this issue.
Dependent claims are rejected for containing the same issues.
Claim Objections
Claims 1, 3, 5, 8 and 9 are objected to. The term “and” is required between the last two steps in the claim.
The amendment filed on 09/08/2026 did not correct this issue.
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.
Claim(s) 1-8 and 10-11 remain rejected under 35 U.S.C. 103 as being unpatentable over Richter (WO2021/044302-cited in the International Search Report provided by applicants in the IDS of 03/22/2024), in view of Philips et al. (as below) and Kundu, N.; Grant, Michael (as below).
Richter teaches the same first step of oxidation of intermediate 1 to produce intermediate 2, using potassium osmate dihydrate as oxidant, trialkyl-amine N-oxide dihydrate as organic amine N-oxide co-oxidant, 2-butanone as solvent, at 20-25C for 28 under nitrogen atmosphere (p. 7-8 and 14-15):
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.
Acetylation of intermediate 2 (compound (II)) with acetic anhydride in toluene or ethyl acetate, in the presence of triethyl amine and 4-DMAP, with or without isolation, followed by purification by recrystallization, produced compound (III) in high isomeric purity, (p. 8 and 15-16) :
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. Removal of the 3-O-benzyl protecting group by catalytic hydrogenation in Pd/C in an alcohol, such as ethanol, produced compound (IV):
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(p.9). Removal of the acetyl protecting groups of compound IV by hydrolysis in presence of potassium carbonate, in a C1-3 alcohol as solvent at 20-25C, produced estetrol (p. 19, example 5):
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. Recovery of crystalline estetrol was performed in methanol by adding water, removal of methanol by distillation, and precipitation of crystals, cooling at 0 to 5C for 1 h, filtering, washing with water, and drying the crystals at 40C under vacuum (p. 19, lines 23-27, and see both method A and method B).
The recovery process of Richter must have obtained estetrol monohydrate
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since it is the same process that provided estetrol monohydrate in WO 2021/058716 (see page 16, Example 5).
Richter additionally taught that the protecting groups could be different (see R), and that intermediate 2 could be debenzylated by hydrogenation to produce intermediate 3:
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. These are the same conditions as claimed in claim 3.
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See page 3.
Ascertainment of the difference between the prior art and the claims (MPEP § 2141.02)
The difference between the process of Richter and the claims is that some of the reaction steps are reversed. In the instant claims the debenzylation step occurs before the acetylation and purification steps, while in the process of Richter the debenzylation step is carried out after the acetylation and purification steps.
Particularly, the instant claims have the following sequence of steps:
oxidation, debenzylation, acetylation, purification, hydrolysis and recovery of estetrol monohydrate.
While the prior art preparation of estetrol has the following steps:
oxidation, acetylation, debenzylation, purification, hydrolysis and recovery of estetrol monohydrate.
The tetra-acetylated intermediate 4 was know in at least Kundu, N.; Grant, Michael (Radioimmunoassay of 15α-hydroxyestriol (estetrol) in pregnancy serum. Steroids 1976, Volume 27, Issue 6, p. 785-796) and the 3rd reference provided by applicant in the IDS of 03/22/2024.
Finding of prima facie obviousness – rationale and motivation (MPEP § 2142-2413)
Someone performing these reactions would be trained in organic chemistry and would recognize that the reactions in prior art Richter are the same reactions as in this application. The same starting material, intermediates, reactions steps, purification steps, and reagents were known in the prior art in the production of estetrol. It would have been obvious to the ordinary artisan to select the reverse order of steps of Richter, that is, perform a debenzylation by hydrogenation first on intermediate 2 (II) of Richter, followed by the acetylation step, since each step and reagents were well known and would perform as was expected. The motivation arises from the general objective of improving a product or process and the normal desire of scientists or artisans to improve upon what is already generally known. In addition, Richter is evidence that carrying out the debenzylation (hydrogenation) step before acetylation would be envisioned by the artisan. See the comparative example.
In accordance with MPEP 2144.04 C: “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.” See Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959); and In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946).
The moving of the debenzylation step earlier in the overall process simply means that the 3-OH group is free during the next step of acetylation, and thus, that the free 3-OH group will be acetylated together with the other OHs groups. The skilled artisan would recognize that the 3-OH would simply be protected by another known protecting group (acetyl vs. benzyl) that would be removed together with all other acetyl groups after the obligatory hydrolysis step of Richter. Thus, the artisan would have expected that performing the different order of process steps would be inconsequential.
Regarding claims 2-4, 8, Richter taught all the reaction conditions claimed.
Regarding claims 5-7, in Richter, purification by crystallization and recrystallization of the acetylated intermediate was performed as follows:
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The operation was repeated once more for a
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See page 16. This process necessarily involves allowing the solution to cool for crystal formation, filtering and drying the recrystallized material. Optimizing recrystallization steps, such as temperatures, process for solvent removal, stirring times and times of crystallization and drying is considered routine optimization, moreover, since the general conditions were provided by the prior art. The same exact recrystallization solvents and similar conditions were used by Richter to recrystallize the acetylated intermediate at page 16. Techniques to crystalize or recrystallize compounds are well known in the art and Richter provides examples of various recrystallizations. This evidences that these are result-effective variables. See different crystallization conditions at page 15 and 19.
As stated in MPEP 2144.05 II:
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See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). This is what research chemists do, optimization of result-effective variables within prior art conditions and through routine experimentation (MPEP 2144.05 IIA and B). Currently, there is no evidence of criticality.
Regarding claim 10, if it refers to step F), the process of Richter taught distillation in methanol, which first involves heating the mixture to boiling (to reflux), which dissolves the compound.
Regarding claims 11 and 12, the synthesis of the prior art employed Pd catalysts. “The need to remove palladium (Pd) from API process streams is driven by International Conference on Harmonisation (ICH) Q3D guidelines which dictate the permissible levels of Pd allowed in the final drug product.” “Scavengers provide an excellent solution for Pd removal issues, particularly at low metal levels.” See Philips et al. (Johnson Matthey Technol. Rev., 2016, 60, (4), 277-286). They discuss the advantages of using Quadrasil® MP and how to screen for the most suitable scavenger for Pd impurity removal from a particular sample or application. See page 279. In view of Philips, it would have been prima facie obvious to find a suitable Pd scavenger disclosed by Philips, and it them to remove residual Pd from the pharmaceutical product of Richter.
Thus, pursuant to the Supreme Court rationales in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007), at least exemplary rationale (A) applies in this case:
(A) Combining prior art elements according to known methods to yield predictable results.
Response to Arguments
Applicant’s arguments have been carefully considered but are not found persuasive.
Applicant argues that the Reference Example of Richter is not an example of the disclosed prior art process. In response, a reference is prior art for all that it teaches, including nonpreferred and comparative embodiments. See MPE P 2123(II); In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). The Reference Example of Richter sets forth a complete worked procedure with starting materials, reagents, quantities, solvents, temperatures, workup and HPLC analysis. Reference Example is relied upon for its disclosure of exactly the same steps A and B of claim 1.
Applicants argues that the Reference Example was not carried forward to Estetrol. That is not correct because the Reference Example clearly states that it makes estetrol. See the title of the Reference Example:
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The HPLC shows 87.53% of 15α,16α,17β-isomer (estetrol).
Richter teaches that the deprotected compound cannot be effectively purified, and that acylated derivatives crystallize well and separate from the isomeric by-product with high selectivity. Thus, one of ordinary skill having made the mixture produced by the Reference Example would have been led to acylate it before purification, thereby performing steps C and D of instant claim 1.
Applicants argue
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This argument is not convincing because the Reference Example gave the desired estetrol with an HPLC purity of 87.53%. Second, because claims 1-6, 8 and 10-11 do not claim any desired purity as argued by Applicant. It is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In addition, the argument is not convincing because Richter shows that impurities are removable. Examples in Richter report crystallization followed by further recrystallization to give estetrol in above 99% purity and
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in 0.14% or less.
Applicant argues that Richter teaches away by stating that the tetrol “cements” with the crystals during recrystallization and that the isomer ratio cannot be improved by changing the recrystallization solvent. In response, instant claim 1 does not purify the tetrol. Applicant argues about an operation that the claims do not perform. It is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Currently, the reference does not discredit or criticize the solution claimed. Furthermore, Richter teaching that the tetrol “cements” with the crystals during recrystallization and that the isomer ratio cannot be improved by changing the recrystallization solvent gives precisely the reason to convert it to an acetyl ester before purifying. Richter showed that while the free tetrol cannot be purified, peracylated derivatives crystallize and reject the ββ-isomer. The reference identifies the problem and identifies esterification (acetylation) as the solution. Debenzylating first frees the 3-OH, so exhaustive acetylation necessarily gives the tetraacetate.
Applicant further relies on the statement that compounds of formulae (I) and (II) have unfavorable crystallization properties while compounds of formulae (III) and (IV) crystallize well, can be purified in high yields and can be separated from the isomeric by-product with high selectivity. However, this passage supports the rejection. Formula (IV) of Richter is the 3-hydroxy-15,16,17-triacylate, that is, a debenzylated, poly-acylated estetrol derivative differing from applicant’s intermediate 4 only in that the phenolic hydroxyl at position 3 is not acylated. Richter thus expressly teaches that a debenzylated, acylated estetrol derivative possesses favorable crystallization behavior and high selectivity over the isomeric by-product 15β,16β,17β. The examples confirm it, reporting about 0.04% of the by-product 15β,16β,17β-isomer. The distinction drawn by Richter is between acylated and non-acylated species at positions 15,16 and 17, not between benzylated and debenzylated species at position 3. The passage therefore supplies, rather than negates, a reasonable expectation of success in purifying Applicant’s intermediate 4.
Regarding Applicant’s arguments about Kundu, this reference is not relied upon for the separation of diastereomers. Kundu is relied upon for its teaching that estetrol tetraacetate intermediate 4 of the claims is a known compound, isolated and purified as a stable solid, and converted to estetrol by hydrolysis. The reasonable expectation of success in separating the 15α,16α,17β-isomer from the 15β,16β,17β-isomer by crystallization of an acylated derivative is supplied by Richter. That reference states that the compounds of general formulae (III) and (IV) crystallize well, can be purified in high yields and can be separated from the isomeric by-product with high selectivity. That teaching is demonstrated in the examples.
The compound crystallized in Example 2 of Richter differs from applicant’s intermediate 4 only in that the hydroxyl at position 3 is not acylated (making it a triacetate). The stereochemical difference between the two isomers resides at carbons 15 and 16, remote from position 3. One of ordinary skill in the art would have had a reasonable expectation that crystallization of the corresponding tetraacetate would likewise separate the 15α,16α,17β-isomer from the 15β,16β,17β-isomer, as demonstrated from the triacylated derivatives of Richter.
Conclusion
Claims 1-11 are rejected. No claim is in condition for allowance.
It is noted that the examiner found no prior art rejection for claim 9.
THIS ACTION IS MADE FINAL. 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 VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
