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.
Election/Restrictions
Applicant's election without traverse of Group (I) in the reply filed on December 11, 2026 is acknowledged. Group (I), drawn to a mass production of sodium taurodeoxycholate, embraced by claims 1-14 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Claims 1, 3-11, 14 and 15 are pending and claims 1, 3-11 and 14 are under examination. Claim 15 is withdrawn based on the restriction requirement.
Drawings
The objection to the drawings has been withdrawn based on the amendments.
Information Disclosure Statement
The Hoffman reference submitted with the drawings was not cited on an information disclosure statement and therefore, has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Objections
The objection to claim 6 because the term “to” should be replaced with “or” in line 3, is withdrawn based on the amendments.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), second paragraph, as being indefinite for the phrase, “stirring the solution while adjusting a temperature” is withdrawn based on the amendments.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.
Claim 1, 3-11 and 14 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.
In claim 1, the phrase, “heating the solution to 30°C to 100°C and cooling the solution to 0°C to 30°C” is vague. If the temperature is heated to 30°C, then does the reaction require cooling? Therefore, due to the dependency of the claims, all claims are rejected.
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, 3-11 and 14 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Lack et al. (Journal of Lipid Research, 1973, 14, 367-370) in view of, Tserng et al. (Journal of Lipid Research, 1977, 18, 404-407, cited on the IDS), Campanelli et al. (Journal of Lipid Research, 1987, 28, 483-489), 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 present application is drawn to the mass production method of sodium taurodeoxycholate comprising:
1) synthesizing crude sodium taurodeoxycholate by reacting sodium taurate, deoxycholic acid, and EEDQ;
2) washing the crude sodium taurodeoxycholate with an organic solvent;
3) purifying sodium taurodeoxycholate with a solution containing isopropyl alcohol further comprising heating, cooling and filtering 1the recrystallized solid; and
4) another purifying step which is drawn to recrystallizing form a solution containing acetone.
Lack et al. teaches the synthesis of deoxycholic acid in a mixture of bile acids, in a mixture coupled with taurine as the sodium salt in the presence of EEDQ as a coupling agent, see page 367, left-hand column, third paragraph, see also page 369, right-hand column.
The Lack reference further teaches maintaining the reaction mixture at 40°C, followed by partitioning between ethyl acetate and water, to recover the sodium salt of the bile acid from the water solution, and then recrystallizing the final product. The reference refers to the specific example using sodium taurochenodeoxycholate as an example, see page 367, right-hand column. Said specific example dissolves the crude final product in warm ethanol, followed by recrystallization from ethyl acetate, see page 368, left-hand column, first paragraph.
The next paragraph states the reaction may be done by boiling the solution for the coupling reaction, followed by cooling, see page 368, left-hand column, second paragraph. The reference also states the preparations can be conveniently scaled in either direction, see page 369, left-hand column, third paragraph.
The Lack reference does not teach step 3) solution containing isopropyl alcohol; and 4) the recrystallization or purification with a solution containing acetone.
Tserng et al. teaches the synthesis of sodium salts of taurine conjugates of deoxycholate, that are recrystallized from ethanol, see page 405, right-hand column, third paragraph.
Isopropyl alcohol and ethanol are homologues and are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
The M.P.E.P. states (2144.09): 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).
Campanelli et al. teach the recrystallization of sodium taurodeoxycholate with an acetone-water solution, see page 484, left-hand column.
Claims 3-11 are drawn to different solvents for the washings and crystallization step, repeating the crystallization step, temperatures for heating and cooling, and ratios of different solvents. These are conventional and routine in an organic chemistry lab for purifying products by filtration and crystallization, unless there is evidence to the contrary. More specifically, claims 3-13 can also be addressed by 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 ethanol and acetone. 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 remarks regarding the Xu reference is now moot since the reference is no longer applied in the 103 rejection.
Applicant traverses the Lack reference by stating, “Lack's teachings do not undermine Hofmann's established findings at least because Lack's teachings do not relate to purification at the mass production scale. The bile acid-taurine conjugation reaction using N-ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline (EEDQ), as described in Lack, is merely a reaction conducted on a laboratory scale. Such laboratory-scale reactions cannot necessarily be scaled up to an industrial-scale purification process like that recited in claim 1. In particular, hydrophobic impurities, such as quinoline-based by-products or DCA ethyl ester that may be generated after the EEDQ reaction, interact with amphiphilic bile acids or are easily entrapped within aggregates or micelles. Due to these characteristics, said impurities are not easily removed solely by a conventional recrystallization method, which would lead to considerable difficulty in securing a high-purity compound.”
This is not persuasive. The Lack reference provides the synthesis of making sodium taurodeoxycholate. Said reference also states the reaction may be scaled-up or scaled-down.
Applicant further states, “To the contrary, the effectiveness of a solvent in the recrystallization process requires a precise solubility window, based on the difference in solubility between the target compound and impurities, in which only the target compound is selectively precipitated. This requires careful consideration of the structural characteristics of the target compound and the physicochemical behavior of the impurities. Accordingly, the appropriateness of solvent will depend on the specific structure of the target compound to be purified. In this regard, a person having ordinary skill in the art would not have considered the solvent system of Xu, which is optimized for TCA-Na, to be directly applicable to purification of TDCA-Na with any reasonable expectation of success. Even if one were to consider isopropyl alcohol as to be equivalent to the organic solvents used in Xu's method, it would not have been obvious to have used that solvent for the purification of TDCA- Na.”
This is also not persuasive. As noted in the rejection, isopropyl alcohol and ethanol are considered equivalent since said compounds are homologues, unless there is evidence to the contrary.
Applicant further notes, “The Examples and Experimental Examples of the present specification provide experimental data confirming that the unknown impurity content of the sodium taurodeoxycholate prepared according to the process of claim 1 is 0.0648% or less on average, and that other unknown impurities are also maintained at extremely low levels ranging from 0.0006% to 0.0036%. See Table 4 of the specification, reproduced below.
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538
642
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.”
This is also unpersuasive. The table only compares different runs of the same reaction. What is Test 1-3 being compared to? What is the control? How do we know these results are unexpected?
The rejection has been modified based on the amendments, which makes this a new rejection.
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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