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 .
Status of the Claims
Claims 1-3, 5, 8, 10, 11, and 13-18 are currently pending.
Claims 4, 6, 7, 9, and 12 were previously cancelled.
Response to Amendments
Applicant’s amendments filed 26 June 2026 are acknowledged.
Claim 11 is not currently amended to differ from the immediate prior version of the claim; however, the claim includes a marking indicating changes that have been made relative to the immediate prior version of the claim in line 2, “formula (Ia)”. See the claim objection below.
Response to Arguments
Applicant’s arguments filed 26 June 2026 have been fully considered but they are not persuasive.
Applicant’s argue that Kitamura, Birkhahn, and MIT do not disclose the limitations as recited in claims 1 and 11. These arguments have been considered but are not persuasive for the reasons set forth in the maintained in modified form grounds of rejection below and the response to arguments below.
In response to applicant’s arguments on pages 9-11 of the remarks submitted on 26 June 2026 that “Kitamura expressly recognizes that, in multifunctionalized ketones, competitive ligation of functional groups to ruthenium tends to decrease enantioselectivity, and that the directivity of the functional groups is critically affected by donor ability, orientation of nonbonding orbitals, steric bulk, and kinetic properties of the resulting chelate complexes. … Kitamura does not provide a general teaching that any 3-ketoester, regardless of structure or functionality, can be substituted into Kitamura's reaction scheme with predictable stereochemical results. To the contrary, Kitamura teaches that the outcome for multifunctionalized substrates is not a matter of routine substitution, but depends on the particular substrate and its specific coordination behavior. … The claimed compound of formula (IV) is not a simple monofunctional 3-ketoester and is not merely a small diketone. It is a glycerol tri-acetoacetate containing three 3-ketoester groups on the same glycerol scaffold. … Kitamura does not teach that its reported results for selected functionalized ketones would predictably transfer to Birkhahn's glycerol tri-acetoacetate substrate, nor does Kitamura provide a reasonable expectation that all three stereogenic centers would be formed selectively in the R configuration”.
““The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).” ““Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).” ““Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….”. In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”, see MPEP 2123.
In this case, Kitamura teaches “with the BINAP-Ru(II) complexes effecting highly enantioselective hydrogenation of β-keto carboxylic esters in hand, we are now in the stage to extend the scope and application of this chiral multiplication method. As disclosed herein, the BINAP-Ru-catalyzed hydrogenation exhibits wider scope than reactions with any other chiral transition-metal complexes so far designed and is capable of producing a variety of functionalized alcohols in synthetically useful enantiomeric excesses. With many substrates, this homogeneous hydrogenation procedure is superior to the heterogeneous version and compares well with the biochemical transformations, whose chemical and optical yields are often variable. … As exemplified in Table I, excellent levels of enantioselection have been observed with a wide range of functionalized ketones” substrates with “nitrogen- and oxygen-containing directing groups include dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc.”, where the “oxygen-triggered hydrogenation was accomplished smoothly with the halogen-containing Ru complexes as catalysts, whereas the reaction of more basic amino ketones was effected equally well with the Ru dicarboxylate complexes. With the multifunctionalized ketones, the competitive ligation of the functionalities to Ru tends to decrease the enantioselectivity. The overall directivity of functionalities is critically affected by the donicity and orientation of the nonbonding orbitals of X or Y, bulkiness of the functional groups, and, of course, kinetic properties of the resulting chelate complexes. … Hydrogenation of acetylacetone (6) catalyzed by RuCl2[(R)-binap] produced first the (R)-hydroxy ketone 11 (98.5% ee at 10% conversion), as expected from eq 2, and then resulted in a 99:1 mixture of (R,R)-diol 8 in 100% ee and meso-diol 10. … Thus the BINAP-Ru complexes have excellent kinetic chiral recognition ability and are capable of hydrogenating a series of functionalized ketones in a predictable manner and with satisfactory chemical and chiral efficiency. The high synthetic applicability is obvious”, see Pgs. 629-631; Table I.
Therefore, Kitamura is directly drawn to and expressly teaches the BINAP-Ru(II) complexes effecting highly enantioselective hydrogenation of β-keto carboxylic esters with the selection of reaction conditions depending upon “the donicity and orientation of the nonbonding orbitals of X or Y, bulkiness of the functional groups, and, of course, kinetic properties of the resulting chelate complexes” leading to “a series of functionalized ketones in a predictable manner and with satisfactory chemical and chiral efficiency”. Kitamura does not criticize, discredit, or otherwise discourage the use of a variety of β-keto carboxylic esters as the substrate. On the contrary, Kitamura teaches “excellent levels of enantioselection have been observed with a wide range of functionalized ketone” substrates with “nitrogen- and oxygen-containing directing groups include dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc.”
Furthermore, an “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, see MPEP 2145 X.B. Since Kitamura teaches highly enantioselective hydrogenation of β-keto carboxylic esters with nitrogen- and oxygen-containing directing groups including dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc. by BINAP-Ru(II) complexes leads to excellent levels of enantioselection, see Kitamura, Table I; Pg. 630, the prior art contains “detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful”, see MPEP 2145 X.B.; therefore, it would have been obvious for one of ordinary skill in the art at the time the invention was made to try the claimed compound of formula (IV), a glycerol tri-acetoacetate containing three 3-ketoester groups on the same glycerol scaffold, as the substrate of Kitamura in a highly enantioselective hydrogenation with BINAP-Ru(II) complexes.
For the reasons indicated above, Applicant’s above arguments regarding Kitamura not teaching that any 3-ketoester, regardless of structure or functionality, can be substituted into Kitamura's reaction scheme with predictable stereochemical results and Kitamura teaches away from the use of a glycerol tri-acetoacetate as a substrate are not persuasive.
In response to applicant’s arguments on pages 10-11 of the remarks submitted on 26 June 2026 that “even if Birkhahn is considered to disclose a substrate and product framework corresponding to formulas (IV) and (Ia), the cited art still fails to disclose or suggest the claimed method as a whole”. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art, see In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981) and MPEP 2145.
In this case, as stated above, Kitamura teaches the BINAP-Ru(II) complexes effecting highly enantioselective hydrogenation of β-keto carboxylic esters with nitrogen- and oxygen-containing directing groups including dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc. by the selection of reaction conditions depending upon “the donicity and orientation of the nonbonding orbitals of X or Y, bulkiness of the functional groups, and, of course, kinetic properties of the resulting chelate complexes” leads to “a series of functionalized ketones in a predictable manner and with satisfactory chemical and chiral efficiency”.
Birkhahn is not applied to teach the claimed method as a whole. As stated on pages 11-15 of the previous office action dated 17 April 2026 (hereinafter POA), Birkhahn is applied to teach ““the reaction of glycerol or a protected glycerol and an acetoacetate ester or acetoacetate precursor, yielding an acetoacetyl glycerol which is thereafter reduced, providing a glycerol ester of 3-hydroxybutyric acid”, see Abstract.” “The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense”, see MPEP 2143 I.E. Since patents are part of the literature of the prior art relevant for all they contain, see MPEP 2123, and Kitamura and Birkhahn both teach hydrogenation reactions involving β-keto carboxylic esters, a person of ordinary skill in the art has good reason to modify Kitamura by relying upon Birkhahn before the effective filing date of the claimed invention for knowledge generally available within the hydrogenation of β-keto carboxylic esters art, see MPEP 2143 B & G and 2141, for the benefit of efficiently producing β-keto carboxylic esters that are optically pure “containing a majority of the composition in the form that is more readily metabolized by the body”, see Birkhahn, Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7; and, MPEP 2141 and 2143 I. B-D.”
For the reasons indicated above, Applicant’s above arguments are not persuasive.
In response to applicant’s arguments on pages 12-13 of the remarks submitted on 26 June 2026 that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper, see In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971) and MPEP 2145 X.A. Only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made has been applied to determine obviousness.
For the reasons indicated above, applicant’s above argument is not persuasive.
In response to applicant’s arguments on pages 13-19 of the remarks submitted on 26 June 2026 that “MIT's generic extraction guidance is materially different from the claimed purification sequence” which is “a staged low-salt/high-salt purification of an aqueous solution of the claimed formula (Ia) compound using different solvent operations before and after increasing the salt concentration”, the “Office Action does not identify an articulated reason why a person of ordinary skill in the art would have modified Kitamura's purification procedure, Birkhahn's disclosure, or any combination thereof to arrive at the particular sequence recited in claim 8”, and the “Examiner has not shown that MIT's generic brine-washing guidance would have led a skilled person to this low-salt/high-salt staged purification of the presently claimed amphiphilic triester system. Nor has the Examiner shown that a person of ordinary skill would have had a reasonable expectation that MIT's generic guidance would apply to the specific formula (Ia) system in the manner claimed.” It is noted that instant claim 8 is directed to 0% w/w NaCl in a washing and greater than 5% w/w NaCl in a washing. The claim is not directed to any low-salt/high-salt washing. The claim is directed to a no NaCl washing and a greater than 5% w/w NaCl washing.
Additionally, in response to the arguments that “Kitamura's distillation of a small diol does not render obvious the claimed purification of the present formula (Ia) triester system, particularly where the claimed compound is understood to have a very high boiling point and distillation would be expected to require high-vacuum conditions with attendant concerns regarding degradation, yield, and process cost.” It is noted distillation, vacuum conditions, degradation, yield, and production costs are not instantly claimed.
As stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art, see In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981) and MPEP 2145.
“A reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention)”, see MPEP 2141.01(a).
In this case, as stated on page 16 of the POA, “Kitamura teaches “[t]he solvent of the bright yellowish orange solution was removed under reduced pressure. The residue was distilled to give (2R,4R)-pentanediol in 100% ee”, see Pg. S2, Lns. 3-6” … Kitamura teaches a product purification by adding ether and water to a crude reaction mixture, then adding ether and washing with HCl, NaOH, water, and then brine followed by drying over anhydrous sodium sulfate, see Pg. S2.” Kitamura does not only teach distillation. Kitamura also teaches washing with 1 N sodium hydroxide, a strong base, water, a neutral base, and brine, a salt solution. Therefore, Kitamura teaches washing with differing solutions with differing concentrations to isolate and purify the desired product.
Birkhahn teaches “[i]n an attempt to remove trace metals, this oil (750.2 g) was dissolved in saturated aqueous sodium chloride (800 mL). This aqueous solution was extracted in a separatory funnel with ethyl acetate (800 mL). The organic phase was extracted with an additional portion of saturated aqueous sodium chloride (100 mL). … A second extraction of the combined aqueous sodium chloride phases provided an additional batch of DL-tris-betahydroxybutyryl glycerol (61.78 g, 93% combined weight recovery) … to provide Compound 2 as a clear oil (518.9 g, 84% recovery)”, see Col. 14, Ln. 30-Col. 15, Ln. 33, Example 6. As stated on pages 12-13 of the POA, “where compound 2, tris(β-hydroxybutyryl) glycerol, is preferably optically pure containing a majority of the composition in the form that is more readily metabolized by the body, such that the tris(β-hydroxybutyryl) glycerol is the isomer tris(D-β-hydroxybutyryl) glycerol in a concentration of at least 50%, i.e., instantly claimed formula (Ia) R, R, R configuration, see Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7”. Therefore, Birkhahn is in the known prior art field of hydrogenation reactions involving β-keto carboxylic esters and teaches the isolation of formula (Ia) by multiple NaCl extractions.
As stated on pages 16-17 of the POA, “MIT is in the known prior art field of product purification by “standard extraction and washing protocols that can be applied to virtually any crude reaction mixture”, see Pg. 61, Overview”, and teaches organic, no salt, high salt, and water washings to isolate the desired product, see all of MIT.
As stated on page 18 of the POA, “[t]he rationale to support a conclusion that the claim would have been obvious is that a particular known technique was recognized as part of the ordinary capabilities of one skilled in the art. One of ordinary skill in the art would have been capable of modifying the purification and washing techniques of Kitamura by choosing the known purification and washing techniques as taught by MIT with a reasonable predictability of success for the purpose of efficiently purifying the crude mixture through use of NaCl to “disrupt any emulsions” and to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see MIT, Pg. 61, Overview; Pg. 62, 6); and, MPEP 2143 I. B-D.” “Since patents are part of the literature of the prior art relevant for all they contain, see MPEP 2123, and Kitamura and MIT both teach purification and washing techniques of a crude mixture, a person of ordinary skill in the art has good reason to modify Kitamura by relying upon MIT before the effective filing date of the claimed invention for knowledge generally available within the purification and washing techniques art, see MPEP 2143 B & G and 2141, for the benefit of efficiently purifying the crude mixture through use of NaCl to “disrupt any emulsions” and to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see MIT, Pg. 61, Overview; Pg. 62, 6); and, MPEP 2143 I. B-D.”
Furthermore, an “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, see MPEP 2145 X.B. Since Kitamura, Birkhahn, and MIT all teach purification and washing techniques of a crude mixture of an aqueous layer and an organic layer with differing solutions of organics, water, salt, and brine, the prior art contains “detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful”, see MPEP 2145 X.B.; therefore, it would have been obvious for one of ordinary skill in the art at the time the invention was made to try the washing techniques of all of Kitamura, Birkhahn, and MIT to isolate and purify the compound of formula (Ia).
For the reasons indicated above, applicant’s above arguments are not persuasive.
Therefore, the rejections of:
Claims 1-3, 5, 11, and 13-18 under 35 U.S.C. 103 as being unpatentable over Kitamura et al. (“Homogeneous Asymmetric Hydrogenation of Functionalized Ketones”, published 1988, Journal of the American Chemical Society, Vol. 110, Pgs. 629-631 and S1-S14, hereinafter Kitamura) in view of Birkhahn et al. (US5693850, published 02 December 1997, hereinafter Birkhahn); and,
Claims 8 and 10 under 35 U.S.C. 103 as being unpatentable over Kitamura et al. (“Homogeneous Asymmetric Hydrogenation of Functionalized Ketones”, published 1988, Journal of the American Chemical Society, Vol. 110, Pgs. 629-631 and S1-S14, hereinafter Kitamura) in view of Birkhahn et al. (US5693850, published 02 December 1997, hereinafter Birkhahn), as applied to claims 1-3, 5, 11, and 13-18 in the 35 USC 103 rejection above, in further view of MIT (“8.4 – Extraction and Washing Guide”, published January 2012, 5.301 Chemistry Laboratory Techniques, Pgs. 61-63),
are all maintained in modified form.
In the Spirit of Compact Prosecution
Throughout prosecution the examiner has attempted to identify all objections and clarity issues amongst the claims, applicant is advised that some objections and clarity issues may still remain. Going forward, the examiner respectfully requests applicant to perform a detailed review of the claims regarding clarity, grammar, antecedent basis, word spacing, and spelling issues.
New and Maintained Rejections in Modified Form Based on the reply filed on 26 June 2026
Claim Objections
Claim 11 is objected to because of the following informalities:
Claim 11 is not currently amended to differ from the immediate prior version of the claim; however, the claim includes a marking indicating changes that have been made relative to the immediate prior version of the claim in line 2, “formula (Ia)”. The marking requires removal.
Appropriate correction is required.
For clarity between the maintained and modified rejections, the specific modified rejections below are in italics.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5, 11, and 13-18 stand rejected in modified form under 35 U.S.C. 103 as being unpatentable over Kitamura et al. (“Homogeneous Asymmetric Hydrogenation of Functionalized Ketones”, published 1988, Journal of the American Chemical Society, Vol. 110, Pgs. 629-631 and S1-S14, hereinafter Kitamura) in view of Birkhahn et al. (US5693850, published 02 December 1997, hereinafter Birkhahn).
Kitamura is in the known prior art of the hydrogenation of functionalized ketones, such as β-keto carboxylic esters, over BINAP-Ru catalysts, see Pg. 629, Col. 2, Last Para. – Pg. 630, Col. 2; Table 1.
Regarding the limitations of instant application claims 1-3, 11, 13, 14, 16, and 17, Kitamura teaches the hydrogenation of various ketones, such as 1 is methylolacetone
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and
2 is 2,4 pentanedione
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,
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over the catalysts RuCl2[(R)-binap] in “degassed anhydrous ethanol” at a hydrogen pressure of 40-100 atm or 40.5 to 101.3 bar to yield “(2R,4R)-pentanediol in 100% ee”, see Pg. 629, Col. 2, Last Para. – Pg. 630, Col. 2; Table 1; Pgs. S1, General-S3, Figure 1, where the “structures of the initially created hydroxy ketones including chirality of the stereogenic center (substrate control). Hydrogenation of acetylacetone (6) catalyzed by RuCl2[(R)-binap] produced first the (R)-hydroxy ketone 11 (98.5% ee at 10% conversion), as expected from eq 2, and then resulted in a 99:1 mixture of (R,R)-diol 8 in 100% ee and meso-diol 10.”, see Pg. 631, Col. 1, meeting:
The method of preparing a compound, having all stereogenic centers with a configuration (R) by the hydrogenation reaction of a compound in the presence of RuCl2[(R)-binap] and within the hydrogen pressure range in instant application claim 1 and instant application claim 11; and,
The solvent consists of ethanol in instant application claim 2, in instant application claim 3, in instant application claim 13, in instant application claim 14, in instant application claim 16, and in instant application claim 17.
Regarding the limitations of instant application claim 5, Kitamura teaches the reaction is carried out at a temperature of 20-32 °C, see Pg. 629, Col. 2, Last Para. – Pg. 630, Col. 2; Table 1; Pgs. S1, General-S3, Figure 1. See current specification, Pg. 8, Lns. 11-13 stating the temperature is about 25° C to the reflux temperature of the solvent, and Example 3 with an ethanol solvent and a reaction temperature of 40-45° C., meeting within the temperature range in instant application claim 5.
Regarding the limitations of instant application claims 15 and 18, Kitamura teaches the HPLC analysis of “asymmetrically synthesized (2R,4R)-pentanediol” with a purity of about 100%, see Pg. S3, Figure 1 right as compared to Figure 1 left; Pg. 629, Col. 2, Last Para. – Pg. 630, Col. 2; Table 1; Pgs. S1, General-S3, Figure 1, meeting within the HPLC purity in instant application claim 15 and in instant application claim 18.
Kitamura does not teach:
The instant application claims 1 and 11 limitations of formula (Ia) and formula (IV).
Birkhahn is in the known prior art field of “the reaction of glycerol or a protected glycerol and an acetoacetate ester or acetoacetate precursor, yielding an acetoacetyl glycerol which is thereafter reduced, providing a glycerol ester of 3-hydroxybutyric acid”, see Abstract, where 3-hydroxybutyrate and acetoacetate are “so-called ketone bodies”, see Col. 1, Lns. 53-60, and the reaction is the reduction of 1,2,3-propanetriyl acetoacetate under hydrogen pressure in the presence of a catalyst to produce tris(D-β-hydroxybutyryl) glycerol, see Col. 3, Ln. 54-Col. 4, Ln. 7; Col. 6, Ln. 55-Col. 7, Ln. 28, Scheme 2.
Regarding the limitations of instant application claims 1 and 11, Birkhahn teaches a method of preparing a compound of formula (I)
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as a single enantiomer, where 1,2,3-propanetriyl acetoacetate
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aka instantly claimed formula (IV) is reacted under hydrogen pressure in the presence of a catalyst to produce
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compound 2, see Col. 6, Ln. 55-Col. 7, Ln. 28, Scheme 2; Col. 13, Ln. 30-Col. 15, Ln. 33, Example 5 and Example 6, where compound 2, tris(β-hydroxybutyryl) glycerol, is preferably optically pure containing a majority of the composition in the form that is more readily metabolized by the body, such that the tris(β-hydroxybutyryl) glycerol is the isomer tris(D-β-hydroxybutyryl) glycerol in a concentration of at least 50%, i.e., instantly claimed formula (Ia) R, R, R configuration, see Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7, meeting formula (Ia) and IV in instant application claim 1 and in instant application claim 11.
In reference to the above claims, it would have been obvious to one of ordinary
skill in the art, before the effective filing date of the claimed invention, to have modified the functionalized ketone substrate of Kitamura to choose the functionalized ketone body substrate as taught by Birkhahn with a reasonable predictability of success for the purpose of efficiently producing β-keto carboxylic esters that are optically pure “containing a majority of the composition in the form that is more readily metabolized by the body”, see Birkhahn, Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7.
The rationale to support a conclusion that the claim would have been obvious is that a particular known technique was recognized as part of the ordinary capabilities of one skilled in the art. One of ordinary skill in the art would have been capable of modifying the functionalized ketone substrate of Kitamura by choosing the known functionalized ketone body substrate as taught by Birkhahn with a reasonable predictability of success for the purpose of efficiently producing β-keto carboxylic esters that are optically pure “containing a majority of the composition in the form that is more readily metabolized by the body”, see Birkhahn, Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7; and, MPEP 2143 I. B-D.
“Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103.”, see MPEP 2112 III. In this case, the chiral product of Kitamura is synthesized in a solvent consisting of ethanol in contact with a RuCl2[(R)-binap] catalyst. A person of ordinary skill in the art would naturally be lead to the reasonable expectation that the Kitamura synthesis procedures starting with the instantly claimed formula (IV) substrate would lead to the instantly claimed formula (Ia) with all three stereogenic centers in the R, R, R configuration.
The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense”, see MPEP 2143 I.E. Since patents are part of the literature of the prior art relevant for all they contain, see MPEP 2123, and Kitamura and Birkhahn both teach hydrogenation reactions involving β-keto carboxylic esters, a person of ordinary skill in the art has good reason to modify Kitamura by relying upon Birkhahn before the effective filing date of the claimed invention for knowledge generally available within the hydrogenation of β-keto carboxylic esters art, see MPEP 2143 B & G and 2141, for the benefit of efficiently producing β-keto carboxylic esters that are optically pure “containing a majority of the composition in the form that is more readily metabolized by the body”, see Birkhahn, Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7; and, MPEP 2141 and 2143 I. B-D.
As stated in Sakraida v. Ag Pro, Inc., 425 U.S. 273, 189 USPQ 449, reh’g denied,
426 U.S. 955 (1976), “[w]hen a work is available in one field of endeavor, design
incentives and other market forces can prompt variations of it, either in the same field
or a different one. If a person of ordinary skill can implement a predictable variation, §
103 likely bars its patentability. For the same reason, if a technique has been used to
improve one device, and a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the technique is obvious unless its
actual application is beyond his or her skill”, see MPEP 2141.
Selection of a known material, such as a β-keto carboxylic ester to hydrogenate, based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), see MPEP 2144.07.
In addition, “[i]t is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree,” such as all three stereogenic centers in the R, R, R configuration, “or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions. In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929)”, see MPEP 2144.05.
In additional reference to the above claims, Kitamura teaches “with the BINAP-Ru(II) complexes effecting highly enantioselective hydrogenation of β-keto carboxylic esters in hand, we are now in the stage to extend the scope and application of this chiral multiplication method. As disclosed herein, the BINAP-Ru-catalyzed hydrogenation exhibits wider scope than reactions with any other chiral transition-metal complexes so far designed and is capable of producing a variety of functionalized alcohols in synthetically useful enantiomeric excesses. With many substrates, this homogeneous hydrogenation procedure is superior to the heterogeneous version and compares well with the biochemical transformations, whose chemical and optical yields are often variable. … As exemplified in Table I, excellent levels of enantioselection have been observed with a wide range of functionalized ketones” substrates with “nitrogen- and oxygen-containing directing groups include dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc.”, where the “oxygen-triggered hydrogenation was accomplished smoothly with the halogen-containing Ru complexes as catalysts, whereas the reaction of more basic amino ketones was effected equally well with the Ru dicarboxylate complexes. With the multifunctionalized ketones, the competitive ligation of the functionalities to Ru tends to decrease the enantioselectivity. The overall directivity of functionalities is critically affected by the donicity and orientation of the nonbonding orbitals of X or Y, bulkiness of the functional groups, and, of course, kinetic properties of the resulting chelate complexes. … Hydrogenation of acetylacetone (6) catalyzed by RuCl2[(R)-binap] produced first the (R)-hydroxy ketone 11 (98.5% ee at 10% conversion), as expected from eq 2, and then resulted in a 99:1 mixture of (R,R)-diol 8 in 100% ee and meso-diol 10. … Thus the BINAP-Ru complexes have excellent kinetic chiral recognition ability and are capable of hydrogenating a series of functionalized ketones in a predictable manner and with satisfactory chemical and chiral efficiency. The high synthetic applicability is obvious”, see Pgs. 629-631; Table I.
Therefore, Kitamura is directly drawn to and expressly teaches the BINAP-Ru(II) complexes effecting highly enantioselective hydrogenation of β-keto carboxylic esters with the selection of reaction conditions depending upon “the donicity and orientation of the nonbonding orbitals of X or Y, bulkiness of the functional groups, and, of course, kinetic properties of the resulting chelate complexes” leading to “a series of functionalized ketones in a predictable manner and with satisfactory chemical and chiral efficiency”. Kitamura does not criticize, discredit, or otherwise discourage the use of a variety of β-keto carboxylic esters as the substrate. On the contrary, Kitamura teaches “excellent levels of enantioselection have been observed with a wide range of functionalized ketone” substrates with “nitrogen- and oxygen-containing directing groups include dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc.”
In reference to the above claims, an “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, see MPEP 2145 X.B. Since Kitamura teaches highly enantioselective hydrogenation of β-keto carboxylic esters with nitrogen- and oxygen-containing directing groups including dialkylamino, hydroxyl, alkoxyl, siloxyl, keto, alkoxycarbonyl, alkylthiocarbonyl, dialkylaminocarbonyl, carboxyl, etc. by BINAP-Ru(II) complexes leads to excellent levels of enantioselection, see Kitamura, Table I; Pg. 630, the prior art contains “detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful”, see MPEP 2145 X.B.; therefore, it would have been obvious for one of ordinary skill in the art at the time the invention was made to try the claimed compound of formula (IV), a glycerol tri-acetoacetate containing three 3-ketoester groups on the same glycerol scaffold, as taught by Birkhahn, as the substrate of Kitamura in a highly enantioselective hydrogenation with BINAP-Ru(II) complexes.
Claims 8 and 10 stand rejected in modified form under 35 U.S.C. 103 as being unpatentable over Kitamura et al. (“Homogeneous Asymmetric Hydrogenation of Functionalized Ketones”, published 1988, Journal of the American Chemical Society, Vol. 110, Pgs. 629-631 and S1-S14, hereinafter Kitamura) in view of Birkhahn et al. (US5693850, published 02 December 1997, hereinafter Birkhahn), as applied to claims 1-3, 5, 11, and 13-18 in the 35 USC 103 rejection above, in further view of MIT (“8.4 – Extraction and Washing Guide”, published January 2012, 5.301 Chemistry Laboratory Techniques, Pgs. 61-63).
Regarding the limitations of instant application claim 10, Kitamura teaches “[t]he solvent of the bright yellowish orange solution was removed under reduced pressure. The residue was distilled to give (2R,4R)-pentanediol in 100% ee”, see Pg. S2, Lns. 3-6, meeting purification without chromatography in instant application claim 10.
Kitamura and Birkhahn do not teach the limitations of instant application claim 8.
Kitamura teaches a product purification by adding ether and water to a crude reaction mixture, then adding ether and washing with HCl, NaOH, water, and then brine followed by drying over anhydrous sodium sulfate, see Pg. S2.
MIT is in the known prior art field of product purification by “standard extraction and washing protocols that can be applied to virtually any crude reaction mixture”, see Pg. 61, Overview.
Regarding the limitations of instant application claim 8, MIT teaches in order to purify a product from an aqueous crude reaction mixture, the reaction mixture is first contacted with an appropriate organic solvent, such as ether or ethyl acetate, see Pgs. 61-62, Overview-4), meeting step a. one or more washings of the aqueous solution with organic solvent S1 ether or ethyl acetate and 0% NaCl in instant application claim 8;
After the washings, saturated NaCl is added to the solution to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see Pg. 62, 6), meeting step b. increasing the concentration of NaCl within the range of higher than 5% w/w in instant application claim 8; and,
The solution is concentrated and dissolved in another higher boiling point solvent and dichloromethane repeatedly to isolate the product, see Pgs. 62-63, 10)-13), meeting steps c. and d. and the organic solvent S2 dichloromethane in instant application claim 8.
In reference to the above claims, it would have been obvious to one of ordinary
skill in the art, before the effective filing date of the claimed invention, to have modified the purification and washing techniques of Kitamura to choose the purification and washing with NaCl as taught by MIT with a reasonable predictability of success for the purpose of efficiently purifying the crude mixture through use of NaCl to “disrupt any emulsions” and to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see MIT, Pg. 61, Overview; Pg. 62, 6).
The rationale to support a conclusion that the claim would have been obvious is that a particular known technique was recognized as part of the ordinary capabilities of one skilled in the art. One of ordinary skill in the art would have been capable of modifying the purification and washing techniques of Kitamura by choosing the known purification and washing techniques as taught by MIT with a reasonable predictability of success for the purpose of efficiently purifying the crude mixture through use of NaCl to “disrupt any emulsions” and to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see MIT, Pg. 61, Overview; Pg. 62, 6); and, MPEP 2143 I. B-D.
The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense”, see MPEP 2143 I.E. Since patents are part of the literature of the prior art relevant for all they contain, see MPEP 2123, and Kitamura and MIT both teach purification and washing techniques of a crude mixture, a person of ordinary skill in the art has good reason to modify Kitamura by relying upon MIT before the effective filing date of the claimed invention for knowledge generally available within the purification and washing techniques art, see MPEP 2143 B & G and 2141, for the benefit of efficiently purifying the crude mixture through use of NaCl to “disrupt any emulsions” and to ““dry” the organic layer by extracting water that may have dissolved in the organic phase”, see MIT, Pg. 61, Overview; Pg. 62, 6); and, MPEP 2143 I. B-D.
As stated in Sakraida v. Ag Pro, Inc., 425 U.S. 273, 189 USPQ 449, reh’g denied,
426 U.S. 955 (1976), “[w]hen a work is available in one field of endeavor, design
incentives and other market forces can prompt variations of it, either in the same field
or a different one. If a person of ordinary skill can implement a predictable variation, §
103 likely bars its patentability. For the same reason, if a technique has been used to
improve one device, and a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the technique is obvious unless its
actual application is beyond his or her skill”, see MPEP 2141.
In addition, “[t]he 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”, such as the concentration of the NaCl, “is the optimum combination of percentages.” In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969), see MPEP 2144.05.
Selection of a known material, such as a NaCl salting out, based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), see MPEP 2144.07.
In additional reference to the above claims, as stated above, “Kitamura teaches “[t]he solvent of the bright yellowish orange solution was removed under reduced pressure. The residue was distilled to give (2R,4R)-pentanediol in 100% ee”, see Pg. S2, Lns. 3-6” … Kitamura teaches a product purification by adding ether and water to a crude reaction mixture, then adding ether and washing with HCl, NaOH, water, and then brine followed by drying over anhydrous sodium sulfate, see Pg. S2.” Kitamura does not only teach distillation. Kitamura also teaches washing with 1 N sodium hydroxide, a strong base, water, a neutral base, and brine, a salt solution. Therefore, Kitamura teaches washing with differing solutions with differing concentrations to isolate and purify the desired product.
Birkhahn teaches “[i]n an attempt to remove trace metals, this oil (750.2 g) was dissolved in saturated aqueous sodium chloride (800 mL). This aqueous solution was extracted in a separatory funnel with ethyl acetate (800 mL). The organic phase was extracted with an additional portion of saturated aqueous sodium chloride (100 mL). … A second extraction of the combined aqueous sodium chloride phases provided an additional batch of DL-tris-betahydroxybutyryl glycerol (61.78 g, 93% combined weight recovery) … to provide Compound 2 as a clear oil (518.9 g, 84% recovery)”, see Col. 14, Ln. 30-Col. 15, Ln. 33, Example 6. As stated above, “where compound 2, tris(β-hydroxybutyryl) glycerol, is preferably optically pure containing a majority of the composition in the form that is more readily metabolized by the body, such that the tris(β-hydroxybutyryl) glycerol is the isomer tris(D-β-hydroxybutyryl) glycerol in a concentration of at least 50%, i.e., instantly claimed formula (Ia) R, R, R configuration, see Col. 3, Ln. 65-Col. 4, Ln. 7; Col. 5, Lns. 5-7”. Therefore, Birkhahn is in the known prior art field of hydrogenation reactions involving β-keto carboxylic esters and teaches the isolation of formula (Ia) by multiple NaCl extractions.
As stated above, “MIT is in the known prior art field of product purification by “standard extraction and washing protocols that can be applied to virtually any crude reaction mixture”, see Pg. 61, Overview”, and teaches organic, no salt, high salt, and water washings to isolate the desired product, see all of MIT.
In reference to the above claims, an “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, see MPEP 2145 X.B. Since Kitamura, Birkhahn, and MIT all teach purification and washing techniques of a crude mixture of an aqueous layer and an organic layer with differing solutions of organics, water, salt, and brine, the prior art contains “detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful”, see MPEP 2145 X.B.; therefore, it would have been obvious for one of ordinary skill in the art at the time the invention was made to try the washing techniques of all of Kitamura, Birkhahn, and MIT to isolate and purify the compound of formula (Ia).
Conclusion
No claims are allowed.
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/YO/Examiner, Art Unit 1692
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
