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 1-3 and 6-11 are pending and under consideration.
Claim Objections
The objection of claim 6 because of the term “and” is withdrawn based on the amendments.
The objection of claims 8 and 9 because of the term “and” is required between the last two steps in the claim, is withdrawn based on the amendments.
The objection of claim 11 because of the term “and” is required between E.5) and E.6), is withdrawn based on the amendments.
Claim Rejections - 35 USC § 112
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “the derivatives of osmium,” is withdrawn based on the amendments.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “possibly of catalytic amounts” is withdrawn based on the amendments.
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 1-3 and 6-11 are 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.
With regards to claim 1, the newly amended phrase is separated with the term “and”:
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The solvents cannot be selected from various solvents, and then only pyridine. Thus, claims 1-3 and 6-11 are indefinite and vague. All claims are rejected since the deficiency is not remedied in the dependent claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites a broad recitation, and the claim also recites “preferably…” which is the narrower statement of the range/limitation. See section E.2), E.3) and E.4) of claim 11. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 1 and 6 were amended to remove said term, however, the rejection is maintained for claim 11.
Regarding claim 11, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention, see E.3). See MPEP § 2173.05(d).
This rejection was not addressed, and is therefore, maintained.
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 does not further limit claim 1. Claim 1 is drawn to a process of synthesizing estetrol. Claim 11 is drawn to a process of making estetrol monohydrate. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
This rejection was not addressed, and is therefore, maintained.
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 § 102
The rejection of claim(s) 1-4, 7, 9 and 10 under 35 U.S.C. 102(a)(2) as being anticipated by Lovas et al. (WO 2021044302) is withdrawn based on the amendments.
The rejection of claim(s) 12 under 35 U.S.C. 102(a)(2) as being anticipated by Lovas et al. (WO 2021044302) is withdrawn based on the amendments.
The rejection of claim(s) 13 under 35 U.S.C. 102(a)(2) as being anticipated by Lovas et al. (WO 2021044302) is withdrawn based on the amendments.
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 and 6-10 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Lovas et al. (WO 2021044302).
The present application claims a method of making estetrol by a similar method as the ‘302 publication as noted below with the following wherein clause:
wherein in step B) the exhaustive acetylatin2 reaction from intermediate 2 to intermediate 3' is carried out using acetic anhydride as a reactant in a solvent selected from isopropyl acetate, ethyl acetate, tetrahydrofuran, pyridine and toluene, in the presence of an inorganic or organic base, of a catalyst and catalytic amounts of trifluoroacetic anhydride, and wherein the exhaustive acetylatin2 reaction from intermediate 2 to intermediate 3' of step B) is carried out in pyridine as a solvent, 4-dimethylaminopyridine as a catalyst, operating at a temperature between 20 and 30 °C for a time of at least 4 hours.
Note the 112b rejection for claim 1 since the newly submitted amendments are indefinite and vague.
The ‘302 publication teaches the oxidation with PVP-OsO4 of the 3-benzyl ether, intermediate I, to produce intermediate 2, as a 15α, 16 α, 15β, 16 β isomeric mixture with a ratio of 90/10 in 99% yield, see page 4, or with OsO4 on pages 12-13 (bridged), which produced a 94/6 ratio in a 91% yield, or with K2OsO4 2H2O with trimethylamine N-oxide dihydrate to produced 90/10 ratio in a 95% yield, see page 14 and 15 and below:
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Acylation of intermediate 2 provides intermediate 3 or (III) in ethyl acetate, triethylamine and 4-dimethylaminopyridine at 35-40ºC for 3 hours, where intermediate 3’ was made since the isomeric mixture was used without isolation from the oxidation, see pages 15-16, Method B. Intermediate 3 was purified by recrystallization, see page 16:
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The ‘302 publication teaches the acylation maybe carried out “preferably in pyridine,” see page 8, line 15.
Intermediate 3 was deprotected by hydrogenation using H2 and Pd/C to afford intermediate 4, see page 17, Example 2:
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Intermediate 4 is converted to estetrol by the removal of the three acetyl groups using potassium carbonate at 20-25ºC for 3 hours, see page 19, Example 5:
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Lovas further teaches the estetrol was precipitated from water by distilling the methanol (hot) and cooling the aqueous solution to 0-5ºC, see page 19, Example 5 work-up.
With regards to claims 2 and 3, the oxidation of step A) is carried out at between the temperatures of 35 and 60ºC for at least 12 or 16 hours. These are result-effective variables, and unless there is evidence to the contrary, are considered obvious as noted below.
Generally, differences in time 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., reaction times and temperatures which are result effective variables), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan.
With regards to claim 6, the present claim is drawn to a recrystallization of intermediate 3 from methanol. The ‘302 publication teaches intermediate 3 is recrystallized from methanol but does not give specific details. Techniques to crystalize or recrystallize compounds are well-known in the art and the ‘302 publication provides an example of a hot-cold crystallization of the final product estetrol, see page 19, lines 16-28. There are many other examples of recrystallizations throughout the ‘302 publication as this process is commonly used to purify compounds.
Thus, claims 1-3 and 6-10 are obvious over Lovas et al.
Applicant traverses by stating, “Applicant submits that Lovas fails to teach or suggest at least "wherein the exhaustive acetylating reaction from intermediate 2 to intermediate 3' of step B) is carried out in pyridine as a solvent, 4-dimethylaminopyridine as a catalyst, operating at a temperature between 20 and 30 0C for a time of at least 4 hours," as recited in amended Claim 1.”
This is not persuasive. First of all, the newly submitted amendments are vague and indefinite as noted above. Secondly, pyridine is taught as a preferable solvent and dimethylpyridine is taught as a catalyst as noted in the rejection. The temperatures and times are result-effective variables, unless there is evidence to the contrary. However, there is nothing in the specification that indicates otherwise.
Thus, the rejection is maintained.
Claims 1-3 and 6-11 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Lovas et al. (WO 2021044302), Ferreiro et al. (WO 2015040051) and Pascal (WO 2013050553) in view of Jurczak et al. (Pharmaceutics 2020, 12, 959, 1-25), Hardwood et al. ((Experimental Organic Chemistry, Standard and Microscale, 2nd Edition, 1998, pp. 131-143) and Perrin et al. (Purification of Laboratory Chemicals, 3rd Edition, 1988, pp. 12-41).
The 103 rejection over claims 1-3 and 6-10 are incorporated here.
Claim 1 is drawn to a process of making estetrol.
Claim 11 is drawn to a method of transforming estetrol to estetrol monohydrate by dissolving the estetrol in a water-miscible organic solvent, e.g., methanol, adding water, removing the organic solvent by distillation, stirring the suspension at 5 to 20ºC for at least 15 minutes, filtering the solid from the suspension and drying the solid for at least 5 hours at a minimum of 40ºC and reduced pressure.
The ‘302 reference teaches a process of preparing estetrol, see page 21, claim 1. The ‘302 reference teaches water was added to estetrol in methanol, followed by the distillation of methanol, where estetrol precipitated as crystals, that were then filtered and dried at 40C under vacuum, see page 19, lines 23-27.
This process is similar to the claimed process, but the ‘302 reference does not teach that the monohydrate was formed.
The ‘051 reference teaches a process of preparing estetrol, hydrates or solvates thereof, see the abstract and page 38, claim 1. The ‘051 reference teaches estetrol was precipitated from methanol and water and dried in an oven at 50ºC, see page 34, lines 8-15.
The ‘051 reference further teaches that the solvation methods are generally known in the state of the art, see page 14, lines 23-26.
This process is similar to the claimed process, but the ‘051 reference does not teach that the monohydrate was formed.
The ‘553 reference teaches a process of preparing estetrol, hydrates or solvates thereof, see the abstract and page 30, claim 1. The reference further teaches the recrystallization from methanol and water to afford estetrol, see page 24, lines 11-12.
This process is similar to the claimed process, but the ‘553 reference does not teach that the monohydrate was formed.
Jurczak et al. teaches that “[h]ydrates are of particular interest among solid APIs solvates for several reasons. First, the unique character of the water molecule—its relatively small size and the possibility to form the interactions as both a donor and acceptor of H-bonding, sometimes simultaneously, make it an important “building material” in the field of crystal engineering. Further, from the pharmaceutical point of view, it is a non-toxic substance, in contrast to most of the other organic solvents. Finally, owing to the present of the moisture in the air, spontaneous hydration may occur at any stage of drug production or storage, leading to hydrate formation,” see page 2, first full paragraph. Thus, in the present of water, hydrates may spontaneously form.
Even if a hydrate is not spontaneously made, making hydrates is well-known in the art and is a conventional procedure in the lab. More specifically, claims 1-4 can also be addressed with crystallization or recrystallization references.
Crystallization or recrystallization is a commonly used technique in organic chemistry to purify solid compounds. “The simplest and most effective technique for the purification of solid organic compounds is crystallization. Crystalline compounds are easy to handle, their purity is readily assessed… and they are often easier to identify than liquids or oils. Crystals can be obtained in one of three ways: from the melted
solid on cooling, by sublimation… or from a supersaturated solution. The last method is by far the most common in the organic laboratory,” see the Crystallization paragraph on page 131 of the Hardwood reference.
Hardwood goes on to state, “The process involves five stages: dissolution[,]
Filtration[,] crystallization[,] collection of the crystals[,] and drying the crystal,” see the last two lines on page 131. On page 132, the reference states, “The technique involves dissolving the impure solid in the minimum volume of a hot solvent and filtering to remove insoluble impurities. The resulting hot saturated solution of the compound, together with any soluble impurities, is set aside to cool slowly, whereupon crystals of pure compound will separate from solution,” see the bottom paragraph on page 132.
The Perrin reference teaches solvents commonly used for crystallizations, see page 40, Table 5, which teaches methanol and water. The Perrin reference goes on to state, “Where a substance is too soluble in one solvent and too insoluble in another, for either to be used for recrystallisation, it is often possible (provided they are miscible) to use them as a mixed solvent. (In general, however, it is preferable to use a single solvent if this is practicable.) Table 6 comprises many of the common pairs of miscible solvents,” see page 15, first paragraph and page 41. Thus, purification of the same general approach used for single-solvent dissolution is followed when mixed solvents (solvents and anti-solvents) are employed.
The solution is allowed to cool to allow for crystal formation (crystallization will be better if this step takes place slowly). After the system reaches room temperature, cooling it in an ice bath may improve the yield. Then the solid product is isolated by filtration. The crystals normally are washed with a small amount of cold solvent during the filtration step. The solid may be heated at reduced pressure to remove solvents with higher boiling points.
The choice of solvent is perhaps the most critical step in the process of crystallization since the correct solvent must be selected to form a product of high purity and in good recovery or yield. This is considered routine optimization unless there is evidence to the contrary. 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). 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.
Thus, the claims are rendered obvious.
Applicant traverses by stating, “Applicant submits that Lovas, Ferreiro, Pascal, Jurczak, Harwood, and Perrin fail to teach or suggest at least "wherein the exhaustive acetylating reaction from intermediate 2 to intermediate 3' of step B) is carried out in pyridine as a solvent, 4-dimethylaminopyridine as a catalyst, operating at a temperature between 20 and 30 °C for a time of at least 4 hours," as recited in amended Claim 1.”
This is not persuasive for the same reasons noted above in the first 103 rejection, which is equally applicable here. Thus, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1 and 11 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-4 of copending Application No. 17763267. Although the conflicting claims are not identical, they are not patentably distinct from each other because the presently claimed process drawn to a method of making estetrol further comprising making estetrol monohydrate. The claims in the ‘267 application are drawn to a process of making estetrol monohydrate, which are a subset of the present process.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicant states, “Applicant submits that the clarification of Claims 1 and 11 render these provisional rejections moot.”
This is not persuasive for the same reasons noted above in the first 103 rejection, which is equally applicable here. Thus, the rejection is 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.
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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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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