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 .
DETAILED ACTION
Claims 1 and 5 of K. Tamura, et al, US 17/058,221 (May 20, 2019) are pending, under examination on the merits. Claims 1 and 5 are rejected.
Election/Restrictions
Applicant previously elected Group (I), (claims 1-6) without traverse in the Reply to Restriction Requirement filed on March 7, 2024. Claims 7-18 to non-elected inventions of Groups (II) - (IV) are canceled by Applicant. The restriction/election requirement is maintained as FINAL.
Pursuant to the election of species requirement Applicant elected, without traverse, the species of:
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for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Claims 1 and 5 read on the elected species. The elected species were searched and determined to be unpatentable as indicated in the § 103 rejection rejections below. The search/examination was not extended to additional species. MPEP § 803.02 (III)(C)(2). The provisional election of species requirement is given effect and no claims are withdrawn from consideration as not reading on the elected species. MPEP § 803.02(III)(A).
Claim Interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution. See, MPEP § 2111. Claim interpretation is updated from the previous Office action to account for claim amendments.
Independent claim 5 (which is narrower than independent claim 1) is summarized below.
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Where, per claim 5, in the above scheme “n denotes an integer of 0”; “X denotes a bromine atom” and “R2 and R3 each denote a methyl group or at-butyl group; and R2 and R3 are different”.
Claim 5 further requires the step of crystallizing above optically active intermediate (3):
Claim 5 . . . a crystallization step of crystallizing the optically active phosphinobenzene borane derivative obtained by the reaction step (A) to obtain an optically active phosphinobenzene borane derivative crystal . . .
Note that in the above scheme, structures in brackets are undefined in the claims, but are drawn in by the Examiner based on the teachings of the specification, in order to better compare the claims to the prior art.
Instant claim 1 is directed to the synthesis of “optically active phosphinobenzene borane derivative crystal” (i.e., optically active (3)) and recites the identical step (A) language of claim 5, including the crystallization step.
Interpretation of the Claim 1 and 5 Term “adding liquid B to liquid A”
Notably, independent claims 1 and 5 both require the limitation of “adding the liquid B to the liquid A”. The specification teaches that the step of “adding the liquid B to the liquid A” is advantageous. Specification at page 5, [0013]. The specification defines this phrase as follows:
Here, in the present invention, adding the liquid B to the liquid A refers to such an addition manner that the liquid B is little by little dividedly added to the total amount of the liquid A.
Specification at page 17, [0056]. In working Examples 1 and 2 (directed to the claimed addition method), the specification teaches that “liquid B was dropwise charged in the liquid A over 15 min at -80°C maintained” (Example 1, 84% yield) and “same operation as in Example 1, except for dropwise charging the liquid B to the liquid A at -10°C maintained” (Example 2, 70% yield). Specification at pages 67-70 (data in Table 1, page 73).
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Specification at pages 67-70 (data in Table 1, page 73).
In Comparative Examples 1 and 2, the same procedure was performed, “except for dropwise charging the liquid A to the liquid B” (the opposite of the claimed addition method) (Comparative Example 1, 65% yield; Comparative Example 2, 24% yield). Specification at pages 72(data in Table 1, page 73).
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Specification at pages 71 (data in Table 1, page 73).
The independent claim 1 and claim 5 phrase “adding liquid B to liquid A” is interpreted in accordance with the specification definition:
adding the liquid B to the liquid A refers to such an addition manner that the liquid B is little by little dividedly added to the total amount of the liquid A.
Specification at page 17, [0056].
In view of the foregoing, the claim limitation of “adding the liquid B to the liquid A” is broadly and reasonably interpreted, consistently with the specification, as requiring that portions (for example, pouring in or dropwise addition) of liquid B (which is the lithiated/deprotonated boranyl compound of claim 1 formula (2)) are added to a bulk liquid A (which is the compound of claim 1 formula (1)).
Maintained 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 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 AIA 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.
Claims 1 and 5 and the elected species are rejected under 35 U.S.C. 103 as obvious over K. Tamura et al., 12 Organic Letters, 4400-4403 (2010) (“Tamura”) in view of W. Li et al., 67 Journal of Organic Chemistry, 5394-5397 (2002) (“Li”); N.G. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT, “CHAPTER 5, Running the Reaction”, 113-143, (2000); and V. Gessner et al., 15 Chemistry, A European Journal, 3320-3334 (2009) (“Gessner”)
K. Tamura et al., 12 Organic Letters, 4400-4403 (2010) (“Tamura”)
Tamura teaches that chiral phosphine ligands have played an important role in transition metal-catalyzed asymmetric reactions, and numerous ligands have been designed and synthesized over the past four decades. Tamura at page 4400, col. 1.
Tamura teaches that that enantiopure 1,2-bis(tert-butylmethylphosphino)benzene (named BenzP*) (1) would exhibit excellent enantioselectivities high catalytic activities. Tamura at page 4400-4401, col. 2.
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Tamura demonstrates significant utility for, and motivates one of ordinary skill to explore methods of synthesizing BenzP*, because Tamura teaches that the optically active rhodium complex 4 derived from BenzP* is useful in asymmetric hydrogenations of prochiral substrates. Tamura at page 4402, Table 1.
Tamura teaches the following synthesis of above BenzP*.
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Tamura at page 4401, col. 1, Scheme 1; Experimental at pages S2-S4. Per the crystallization recited in step (A) of instant claims 1 and 5:
Claims 1 and 5 . . . a crystallization step of crystallizing the optically active phosphinobenzene borane derivative obtained by the reaction step (A) to obtain an optically active phosphinobenzene borane derivative crystal . . .
Tamura teaches crystallizing above optically active intermediate (3):
The solvent was evaporated and the residual pasty oil was triturated with hexane to form white crystalline solid, which was collected by filtration and washed with hexane. Yield: 1.43 g (52%). filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate (10:1) as the eluent to give another crop of product (0.35 g, 13%). Pure compound was obtained by the recrystallization from hexane.
Tamura at lines bridging pages S2-S3.
Tamura Scheme 1 meets each and every limitation of claims 1 and 5 (and the elected species) regarding chemical structure and reagents employed. The first part of Tamura Scheme 1 meets each and every reagent/product limitation of claim 1 as well as the first part of claim 5 (“reaction step (A) of claim 5). The second part of Tamura Scheme 1 meets alternative reaction (B1) of claim 5.
The claim 1 and claim 5 concentration limitation of “the first mole larger than the second mole”:
Claims 1 and 5 . . . obtaining liquid B comprising a first mole of n-butyllithium and a second mole of an optically active phosphine borane compound obtained by deprotonating, the first mole larger than the second mole, an optically active hydrogen-phosphine borane compound . . .
is met by Tamura because Tamura employs 11 mmol of n-butyllithium and 10 mmol of (S)-tert-butylmethylphosphine–borane. Tamura at page S2.
Tamura further meets the claimed “optically active” limitations because (per the Scheme above, Tamura starts with enantiopure 2, isolates compound 3 in 99.8 %, and designates each chiral center as “R”.
Differences between Tamura and Claim 1 and 5
Tamura does not meet the claim 1 and claim 5 addition order and temperature-range limitations of:
Claims 1 and 5 . . . adding the liquid B to the liquid A at -20°C to 0°C . . .
because Tamura adds liquid A to liquid B (reverse of the claim 1 and claim 5 order) at -80 °C. See Tamura at page S2 “Preparation of (R)-2-(boranato-tert-butylmethylphosphino)bromobenzene (3)”. In sum, the sequence of reagent addition as well as the addition temperature (claimed -20 °C to 0 °C versus Tamura’s -80 °C) in the following step are the only differences between Tamura and claims 1 and 5:
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W. Li et al., 67 Journal of Organic Chemistry, 5394-5397 (2002) (“Li”)
Li teaches a study towards optimizing the synthesis of 3-pyridylboronic acid (3) based on the addition order of reactants 3-bromopyridine (1), triisopropyl borate (2) and n-butyl lithium, per Scheme 1. Li at page 5394, col. 2.
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Li at page 5395, Scheme 1. Li teaches that “the order of addition of the reagents was the key to a successful preparation”. Li at page 5394, col. 2.
Li teaches that when 3-bromopyridine was treated with n-butyllithium at -78 °C followed by triisopropyl borate (2), the product was isolated in poor yield (20-30%). Li at page 5394, col. 2.
Li teaches that the “reverse” addition procedure, in which 3-bromopyridine was added to a solution of n-butyllithium followed by addition of triisopropyl borate, gave better yields, but the reaction must be run at low temperatures (below -70 °C) in order to get consistent results, making it inconvenient for largescale preparation. Li at page 5394, col. 2.
In the experiment most relevant to the instant facts, Li teaches that adding n-butyllithium to a solution of 3-bromopyridine and triisopropyl borate followed by an acid quench was superior in that not only did it consistently afford good yields but it also proved to be temperature tolerant, giving the best yields (90-95%) at -40 °C and a respectable 80% yield even at 0 °C. Li at page 5394, col. 2.
This was probably because the lithium-halogen exchange on 3-bromopyridine is much faster than the reaction between n-butyllithium and triisopropyl borate. The 3-lithiopyridine intermediate thus generated reacts rapidly with the borate in the reaction mixture, thereby minimizing the chance for 3-lithiopyridine to undergo undesired side reactions.
Li at paragraph bridging page 5394 and 5395 (emphasis added).
In sum, Li teaches that having the electrophile present as the n-BuLi was added enabled high yields and the reaction to be run at a higher temperature than is normally used for a lithium-halogen exchange.
T. Rathman et al., 13 Organic Process Research & Development, 144-151 (2009) (“Rathman”)
In a review of optimization of organolithium reactions, Rathman teaches that order of addition organolithium reagents to an electrophile is parameter that should be considered. Rathman at pages 146-147 (“Order of Addition”). Rathman cites Li (reference Li is discussed above), stating that:
The practice of conducting the lithiation step in the presence of an electrophile may also be applied in the case of a Li-halogen exchange reaction. For example, as illustrated in Scheme 8, the reaction of 3-bromopyridine with n-BuLi may be conducted in the presence of triisopropyl borate.17 Having the electrophile present as the n-BuLi was added enabled the reaction to be run at a higher temperature than is normally used for a lithium-halogen exchange.
Rathman at page 146, col. 2 (citing, in footnote 17, W. Li et al., 67 Journal of Organic Chemistry, 5394-5397 (2002)) (emphasis added”).
N. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT, “CHAPTER 5, Running the Reaction”, 113-143, (2000) (“Anderson”).
Anderson teaches that determining the optimal addition sequence of reagents is important. N.G. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT, “CHAPTER 5, Running the Reaction”, 113-143, (2000) (see Anderson at page 114, Table 5.2; Id. at page 122 (“[t]he sequence of adding starting materials, reagents, and solvents usually must be optimized for each reaction”); Id. at page 128-129. Anderson teaches that the addition sequence may determine the primary reaction course or influence impurity formation. Anderson at page 128.
In one example, Anderson teaches that in the preparation of amide 42, a precursor to saquinavir (Figure 5.15), two addition sequences were investigated. Anderson at page 128. Anderson teaches that the preferred procedure was to add pivaloyl chloride (PivCl) to a solution of carboxylic acid 39 in EtOAc, followed by the addition of Et3N. Anderson at page 128. Anderson teaches that this cleanly generated the mixed anhydride 40, which reacted with L-asparagine (41) to afford 42 in 90% yield. When pivaloyl chloride was added to a solution of 39 and Et3N, some of the symmetrical anhydride 44 was generated, and coupling with 41 led to lower yields of 42 since only half of 44 can form the desired amide. The gist of Anderson is that, in some cases, the addition sequence is expected to affect the reaction parameters.
Anderson further teaches that reaction temperatures and reagent addition rates are important optimizable parameters. Anderson at pages 124-128.
Anderson also teaches optimization of addition temperatures. Anderson at pages 124-128. Anderson teaches that adding a reagent to the reactor containing the starting material often results in an exothermic reaction, and the chemist usually wants to maintain the reaction within a desired temperature range. Anderson at page 124. To reduce the rate heat is evolved, one can add the reagent in portions or at a steady rate over an extended period. Anderson at page 124. Generally, the key is to balance the heat generated by the addition against the cooling provided by the vessel utilities. Sometimes the addition is extended to prevent buildup of the reagent and formation of by-products (see Figure 13.9). Anderson at page 124.
V. Gessner et al., 15 Chemistry, A European Journal, 3320-3334 (2009) (“Gessner”).
Gessner teaches that due to the strongly polarized lithium–carbon bond, organolithium compounds are used as highly reactive nucleophiles and strong bases. Gessner at page 3321, col. 1.
Obviousness Rationale
Claims 1 and 5 and the elected species are obvious in view of the cited art for the following reasons.
The Claimed Addition Order “adding the liquid B to the liquid A” Is Obvious over the Cited Art
The claim 1 and 5 order-of-addition limitation “adding the liquid B to the liquid A at -20°C to 0°C” is obvious for the following reasons.
It is first noted that the case of obviousness is very strong because one of ordinary skill can readily envisage the claimed reaction addition order simply as the inverse of Tamura’s addition. MPEP § 2131.03(III) (citing Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962))). And one of ordinary skill is apprised that sequence of reagent addition is an optimizable, result-effective parameter. See Li, Rathman and Anderson as discussed above.
One of ordinary skill seeking 1,2-bis(tert-butylmethylphosphino)benzene (named BenzP*) (1), in view of its catalytic utility in asymmetric synthesis as taught by Tamura, is motivated to modify/investigate the method of Tamura by reversing the order of addition; i.e., by adding the THF solution of deprotonated (S)-tert-butylmethylphosphine–borane (i.e., deprotonated 2) to the THF solution of o-dibromobenzene thereby arriving at optically active (3). One of ordinary skill is so motivated because such modification simply represents suitable alternative order of addition of regents. MPEP § 2144.04 (IV)(C).1 More significantly, one of ordinary skill is motivated to optimize Tamura by investigating the sequence of addition as taught by Li, Rathman, and Anderson. MPEP § 2144.05(II). For example, one of ordinary skill (apprised of the high reactivity of lithiated organics by Gessner and Li) is motivated to investigate reversing the order of addition (as taught Li, Rathman, and Anderson) and slowly add cooled reactive lithiated compound (2) (liquid B) (for example dropwise addition) to the dibromobenzene (liquid A) so that cooled, reactive lithiated 2 is consumed as it is added (rather than Tamura’s addition order where the bulk of unreacted lithiated intermediate is present in the reaction mixture). Based on the teachings of Li and Gessner, one of ordinary skill would reasonably postulate that in this manner, the concentration of the highly reactive lithiated anion (i.e., compound (2)/liquid B) within the reaction mixture would be lower over time than in the Tamura addition order. One of ordinary skill could reasonably expect that under such reverse-order conditions, a lower reaction-mixture concentration of the reactive lithiated intermediate may lead to fewer side products and/or higher yield similar to the teachings of Li. MPEP § 2144.05(II) citing In re Williams, 36 F.2d 436, 438 (CCPA 1929); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). When making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the relevant time, and on what such a person would have reasonably expected to have been able to do in view of that knowledge; regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. MPEP § 2141(II) (discussing the flexible approach of KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Here, one of ordinary skill would reasonably consider the concentration of the reactive lithiated intermediate in the reaction mixture.
The Claimed Addition Temperature Range “-20°C to 0°C” Is Obvious Over the Cited Art
The claim 1 and 5 addition-temperature limitation “adding the liquid B to the liquid A at -20°C to 0°C” is obvious for the following reasons.
Tamura effectively teaches reaction temperature range of -80 °C to 0 °C, which overlaps with the claimed temperature range of “-20°C to 0°C”. That is, Tamura’s addition temperature and subsequent temperature elevation is shown by the following paragraph in Tamura:
Preparation of (R)-2-(boranato-tert-butylmethylphosphino)bromobenzene (3)
To a solution of (S)-tert-butylmethylphosphine–borane (1.18 g, 10 mmol) in THF (10 mL) was added n-butyllithium (7.0 mL of 1.57 M hexane solution, 11 mmol) at –80 °C under argon. To the resulting solution was added a solution of o-dibromobenzene (3.54 g, 15 mmol) in THF (5 mL) during 15 min. The bath temperature was gradually elevated to 0 °C during 2 h . . .
Tamura at page S2 (emphasis added).2 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. MPEP § 2144.05(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)). Here, one of ordinary skill in the art is motivated to develop workable or optimum ranges for addition temperature, where Applicant can rebut a prima facie case of obviousness by showing the criticality (unexpected result) of the range. MPEP § 2144.05; see also, In re Boesch, 617 F.2d 272,276 (CCPA 1980); In re Aller, 220 F.2d 454, 456 (CCPA 1955). Here, respecting the highly reactive lithiated intermediate (liquid B), addition temperature is clearly a result-effective variable as taught by Li. One of skill in the art it motivated to balance the cost-benefit of lower addition temperatures versus higher (perhaps at the cost of selectivity). For example, while one of ordinary skill may reasonably expect a lower yield at the claimed addition temperature of -20 °C, such may be offset by the costs (equipment availability/costs and power costs) of maintaining Tamura’s lower -80 °C addition temperature. On the other hand, one of ordinary skill may reasonably expect to mitigate yield losses by slower addition of one cooled reagent to the other.
Further, one of ordinary skill is motivated to investigate reaction-mixture temperature with respect to a change in addition order because Li teaches that having the electrophile present as the n-BuLi was added enabled high yields and the reaction to be run at a higher temperature than is normally used for a lithium-halogen exchange. Li at page 5394, col. 2. Li teaches that the “reverse” addition procedure, in which 3-bromopyridine was added to a solution of n-butyllithium followed by addition of triisopropyl borate, must be run at low temperatures (below -70 °C) in order to get consistent results, making it inconvenient for largescale preparation. Li at page 5394, col. 2.
One of ordinary skill apprised by Tamura of the general reaction is free to develop workable temperature and addition protocols.
APPLICANT’S ARGUMENT
(I) Applicant’s Argument Respecting the Claimed Addition Temperature
Applicant argues that Tamura, prepares the lithiated phosphine-borane reagent first and then adds a solution of o-dibromobenzene to that lithiated solution at -80 °C, followed only thereafter by warming toward 0 °C and therefore does not disclose the critical reaction manner required by the pending claims, namely adding liquid B to liquid A at -20 °C to 0 °C. Reply at page 6. Applicant argues that by adopting the claimed addition manner, the desired product can be obtained at a substantially warmer temperature than Tamura's -80 °C condition, while maintaining high optical purity and achieving a yield equal to or greater than Tamura's reported yield. Reply at page 9. Applicant cites specification the higher yield ([Symbol font/0x7E]70%) of Examples 2 and 5 (claimed addition order of liq. B added to A at -10 °C) versus the yield (24%) of comparative Example 2 (Tamura addition order of liq. A added to B at -10 °C). Reply at pages 9-10. The Specification Examples are summarized by the Examiner below.
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Where the following Table compares the claimed temperature/addition order versus the prior art (Tamura) addition order of comparative Examples 1 and 2.
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Applicant argues that these data clearly show that the claimed addition manner provides not only a much higher yield than the conventional addition manner at the same elevated temperature, but also a qualitatively different isolation result because crystallization is achieved under the claimed process but not under the conventional process. Reply at page 10. Applicant thus notes the lack of crystal formation in specification Comparative Example 2 (Tamura addition order of liq. A added to B at -10 °C).
In this regard, the Examiner notes that specification Comparative Example 2 states that:
(R)-2-(boranato) (t-butyl)methylphosphino-1-bromobenzene (a3) was obtained as in Example 2, except for dropwise charging the liquid A to the liquid B. Since no crystal deposited by the same recrystallization operation as in Example 2, an objective substance was obtained by subjecting the whole amount of a crude product after the post-treatments to the column treatment. The yield was 24%.
Specification at page 72, [0187] (emphasis added).
Applicant argues that Tamura does not teach or suggest that such results would be obtained at -10 °C, because Tamura performs the key addition at -80 °C, not at the substantially higher temperatures (i.e., -20 °C to 0 °C) recited in the pending claims
Examiner Response
Applicant’s argument is not persuasive for the following reasons. As stated above, one of ordinary skill is motivated to explore/optimize Tamura with respect to the reverse addition order as taught by Li, Rathman, and Anderson. MPEP § 2144.05(II). For example, one of ordinary skill (apprised of the high reactivity of lithiated organics by Gessner and Li) is motivated to investigate reversing the order of addition (as taught Li, Rathman, and Anderson) and slowly add cooled reactive lithiated compound (2) (liquid B) (for example dropwise addition) to the dibromobenzene (liquid A) so that cooled, reactive lithiated 2 is consumed as it is added (rather than Tamura’s addition order where the bulk of unreacted lithiated intermediate is present in the reaction mixture). Based on the teachings of Li and Gessner, one of ordinary skill would reasonably postulate that in this manner, the concentration of the highly reactive lithiated anion (i.e., compound (2)/liquid B) within the reaction mixture would be lower over time than in the Tamura addition order. One of ordinary skill could reasonably expect that under such reverse-order conditions, a lower reaction-mixture concentration of the reactive lithiated intermediate may lead to fewer side products and/or higher yield similar to the teachings of Li.
One of ordinary skill exploring optimization of Tamura’s process, by reversing the addition order, naturally arrives at the conclusion that the claimed higher addition temperatures are workable ranges. Respecting addition temperature, one of ordinary skill is motivated to develop workable or optimum ranges respecting addition temperatures as taught by Anderson. MPEP § 2144.05; In re Aller, 220 F.2d 454, 456 (CCPA 1955). For example, one of ordinary skill is motivated to balance the cost-benefit of lower addition temperatures versus higher (perhaps at the cost of selectivity). For example, while one of ordinary skill may reasonably expect a lower yield at the claimed addition temperature of -20 °C, such may be offset by the costs (equipment availability/costs and power costs) of maintaining Tamura’s -80 °C addition temperature. One the other hand, one of ordinary skill may reasonably expect to mitigate yield losses by slower addition of one cooled reagent to the other.
(II) Applicant’s Argument Respecting Reference Li
Applicant argues that Li does not support the § 103 rationale premise that the claimed order of addition would have been an immediately apparent or routine modification of Tamura or by itself is a predictable solution that can be transferred generally from one reaction system to another. Reply at page 11.
Applicant argues that Li expressly states that its "reverse" addition procedure must be run below -70 °C in order to obtain consistent results. Reply at page 12 (citing Li at page 5394, col. 2). The Examiner notes here that Applicant is citing the following Li excerpt.
When 3-bromopyridine was treated with n-butyllithium at -78 °C followed by triisopropyl borate (2), the product was isolated in poor yield (20-30%).
The “reverse” addition procedure, in which 3-bromopyridine was added to a solution of n-butyllithium followed by addition of triisopropyl borate, gave better yields, but the reaction must be run at low temperatures (below -70 °C) in order to get consistent results, making it inconvenient for largescale preparation.
Li at page 5394, col. 2 (emphasis added).
Applicant argues even in Li's own system, a change in order of addition does not suggest that the reaction can be moved to a much warmer temperature range. Reply at page 12. Applicant argues that Li’s teaching points away from, rather than toward, the expectation that Tamura' s reaction could be inverted and successfully carried out at the presently claimed range of -20 °C to 0 °C while still obtaining high optical purity and high yield. Reply at page 12.
Applicant further comments on what the previous Office action referred to as Li’s most relevant Experiment, where Li teaches that adding n-butyllithium to a solution of 3-bromopyridine and triisopropyl borate followed by an acid quench was superior in that not only did it consistently afford good yields but it also proved to be temperature tolerant, giving the best yields (90-95%) at -40 °C and a respectable 80% yield even at 0 °C. Reply at page 13 (citing Li at page 5394, col. 2). Applicant argues that the arrangement in Li is not analogous to Tamura because Li uses a premixed solution containing 3-bromopyridine and triisopropyl borate, followed by n-butyllithium addition and an acid quench. Reply at page 13
Examiner Response
This argument is not persuasive because, although Li is directed to a different system, Li still emphasizes the concept that a lower reaction-mixture concentration of the reactive lithiated intermediate may lead to fewer side products and/or higher yield and/or permitting warmer reaction temperatures.
As noted in the § 103 rationale, the experiment most relevant to the instant facts, Li teaches that adding n-butyllithium to a solution of 3-bromopyridine and triisopropyl borate followed by an acid quench was superior in that not only did it consistently afford good yields but it also proved to be temperature tolerant, giving the best yields (90-95%) at -40 °C and a respectable 80% yield even at 0 °C. Li at page 5394, col. 2.
Li states
This was probably because the lithium-halogen exchange on 3-bromopyridine is much faster than the reaction between n-butyllithium and triisopropyl borate. The 3-lithiopyridine intermediate thus generated reacts rapidly with the borate in the reaction mixture, thereby minimizing the chance for 3-lithiopyridine to undergo undesired side reactions.
Li at paragraph bridging page 5394 and 5395 (emphasis added). Thus, Li (as a whole) does teach one of ordinary skill that warmer temperatures are predictable when the reactive lithiated intermediate is in the presence of a suitable electrophile concentration. This issue was noted by Rathman in citing reference Li as follows:
The practice of conducting the lithiation step in the presence of an electrophile may also be applied in the case of a Li-halogen exchange reaction. For example, as illustrated in Scheme 8, the reaction of 3-bromopyridine with n-BuLi may be conducted in the presence of triisopropyl borate.17 Having the electrophile present as the n-BuLi was added enabled the reaction to be run at a higher temperature than is normally used for a lithium-halogen exchange.
Rathman at page 146, col. 2 (citing, in footnote 17, W. Li et al., 67 Journal of Organic Chemistry, 5394-5397 (2002)) (emphasis added”). As noted in the § 103 rationale, one of ordinary skill could reasonably expect that under such reverse-order conditions, as applied to Tamura, a lower reaction-mixture concentration of the reactive lithiated intermediate may lead to fewer side products and/or higher yield and/or permitting warmer reaction temperatures similar to the teachings of Li. MPEP § 2144.05(II) citing In re Williams, 36 F.2d 436, 438 (CCPA 1929); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In any case, the overriding point of the § 103 rationale is that one of ordinary skill exploring optimization of Tamura’s process, by reversing the addition order, naturally arrives at the conclusion that the claimed higher addition temperatures are workable ranges. And respecting addition temperature, one of ordinary skill is motivated to develop workable or optimum ranges respecting reaction temperatures as taught by Anderson. MPEP § 2144.05; In re Aller, 220 F.2d 454, 456 (CCPA 1955).
(III) Applicant’s Argument Respecting the Additional Secondary Art
In summary, Applicant argues that secondary references Rathman and Anderson provide only general teachings respect reagent addition sequence and do not specifically provide guidance resecting Tamura’s lithiation. Reply at pages 14-15. Similarly, Applicant argues that secondary reference Gessner likewise does not cure the deficiencies of the cited combination and provides only general background that organolithium compounds are highly reactive nucleophiles and strong bases because of the strongly polarized lithium-carbon bond. Reply at page 16.
Examiner Response
This argument is not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. MPEP § 2145(IV). Here the § 103 rational relies on the combination of Li, Rathman, Anderson, and Gessner as motivating one of ordinary skill, seeking to employ Tamura’s lithiation to prepare the useful BenzP*) (1), to modify/investigate Tamura by reversing the order of addition; i.e., by adding the THF solution of deprotonated (S)-tert-butylmethylphosphine–borane (i.e., deprotonated 2) to the THF solution of o-dibromobenzene thereby arriving at optically active intermediate (3). Li, Anderson and Ratherman, while each not teaching the Tamura’s specific system, still provide the general motivation to explore addition order. Further, one of ordinary skill could reasonably expect that under such reverse-order conditions, as applied to Tamura, a lower reaction-mixture concentration of the reactive lithiated intermediate may lead to fewer side products and/or higher yield and/or permitting warmer reaction temperatures similar to the teachings of Li.
(IV) Applicant’s Argument Respecting Crystallization
Applicant argues that claims 1 and 5 are amended respecting variables R2 and R3 and to require a crystallization step so as to recite the system exemplified in the specification and therefore address any concern regarding commensurateness.3 Reply at page 17. Applicant argues that under the claimed addition manner, the product can be isolated as a crystal even when the reaction is carried out at -10 °C. Reply at page 17. Applicant argues that by contrast, Comparative Example 2 shows that, under the conventional addition manner (Tamura) at the same -10 °C, no crystal precipitates by the same recrystallization operation. Reply at page 18. Applicant argues that the claimed inverse addition order results in a practical difference in post-reaction isolation and purification between the claimed addition manner and the conventional addition manner at the same elevated temperature. Rely at page 18.
Examiner Response
This argument is not persuasive for the following reasons. One of ordinary skill exploring optimization of Tamura’s process, by reversing the addition order, naturally arrives at the conclusion that the claimed higher addition temperatures are workable ranges. Respecting addition temperature, one of ordinary skill is motivated to develop workable or optimum ranges respecting addition temperatures as taught by Anderson. MPEP § 2144.05; In re Aller, 220 F.2d 454, 456 (CCPA 1955). Further, one of ordinary skill would reasonably expect different addition sequences give different percent yields (as taught by the secondary references (particularly Li)) and that at higher reaction temperatures (e.g., -10 °C), side products may cause purity issues resulting in a product’s failure to crystallize, directly from the reaction mixture, thereby required additional purification. Further this non-crystal result at -10 °C has not been shown to extend to the full claimed range end point of -20 °C, nor has Applicant argued such. Although unexpected results are not argued here by Applicant, it is noted that differences of degree are not as persuasive as a difference in kind – i.e., if the range produces ‘a new property dissimilar to the known property, rather than producing a predictable result but to an unexpected extent. MPEP § 716.02 (citing UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023)).
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.
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 MPEP § 2144.04 (IV)(C) (citing Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
2 In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP § 2144.05(I) (citing In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)).
3 Applicant previously proffered the results of specification working Examples 1-5 (claimed addition method) versus specification Comparative Examples 1 and 2 (prior art inverse addition method) as probative of unexpected results to overcome the § 103 rejection. Reply dated June 9, 2025 at pages 9-10; 2nd Oohara Declaration (May 7, 2025) at page 4, ¶ 5-3. The Examiner found that the proffered results were not commensurate with claims scope. Office action dated July 3, 2025 at pages 21-22.
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