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
Claim 1 of P. Dalmases et al., App. No. 18/007,192 (Jul. 26, 2021) is pending and under examination on the merits. Claim 1 is rejected.
Claim Objections
Claim 1 is objected to on the grounds that is contains a period after step g) of the MIK crystallization, which should be replaced by a semicolon.
Maintained Claim Rejections - 35 USC § 103
The following is a quotation of AIA 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 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.
Claim 1 is rejected under AIA 35 U.S.C. 103 as being unpatentable over primary references R. Dammalapati et al., WO 2014/041565 (2014) (“Dammalapati”) and P. Box et al., US 7,361,787 (2008) (“Box”) in further view of Z. Wu et al., 18 CrystEngComm, 2222-2238 (2016) (“Wu”) in view of secondary references N.G. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT 81-111, 223—247, (2000) (“Anderson”) and/or B. Furniss et al., Vogel’s Textbook of Practical Organic Chemistry 135-154 (1989) (“Vogel”).
R. Dammalapati et al., WO 2014/041565 (2014) (“Dammalapati”)
Dammalapati teaches that vilanterol is useful in the treatment of respiratory diseases and the preferred pharmaceutically acceptable salt is the triphenyl acetate salt (vilanterol trifenatate). Dammalapati at page 1, lines 15-35. Dammalapati teaches that the triphenyl acetate salt is prepared in ethanol as follows:
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Dammalapati at page 1, line 35 through page 2, line 11 (referencing US 7,361,787).
Dammalapati teaches the following with respect to optimization of the above acid-base salt-forming reaction:
During optimization studies, salt formation with triphenylacetic acid was carried out as per reported condition in US’787 and observed an impurity on a higher side at 1.24 RRT. This impurity makes the final API combination not suitable for preparing the formulation, which demands a higher chemical and chiral pure. Further the reactions were performed in different alcoholic solvent such as methanol and isopropanol for the formation of desired salt which did not result in exceptional yields and also purity. The role of solvent system is has a major influence on the purity of the compound.
The preferred nonalcoholic solvent may be selected from the group consisting of halogenated solvents, esters, ethers, hydrocarbons, amides, ketones and nitriles or mixtures thereof Preferably the nonalcoholic solvent is selected from methylene chloride, ethyl acetate, THF, DMF, acetone, acetonitrile and the like; more preferably acetone.
Apart from above said alcoholic solvents, inventors herein, tried with ketone solvents such as acetone, methyl isobutyl ketone considering the results obtained in stage wherein the vilanterol was obtained (prefinal·stage). Reactions in acetone resulted in better yields with a decreased impurity profile with greater than 99.5% purity by HPLC, greater than 99.9% chiral pure and no single major impurity> 0.1 %.
Any conditions for the formation of acid addition salts of vilanterol or the free base form from solution may be used wherein acid addition salts of vilanterol formed, for example concentrated by subjecting the solution to heating, cooling the solution to precipitation, crystallization, solvent precipitation, drying and the like.
Dammalapati at page 13, lines 11-35 (referencing US 7,361,787) (emphasis added).
The portion of US 7,361,787 referenced by Dammalapati in the above-cited passage is clearly the following:
Triphenylacetic acid (1.81 g, 1 eq) was added to a solution of 4-(1-2-6-2-(2,6-dichlorobenzyloxy)-ethoxy-hexylamino-1-hydroxyethyl)-2-hydroxymethyl-phenol (3.28 g) in ethanol (20 mL) and the mixture heated to 80°C. to obtain a solution. The mixture was allowed to cool to ambient temperature, and the resulting product filtered, washed with a little ethanol, then dried in vacuo at 50° C to afford the title compound as a white crystalline solid (4.3 g). m.pt. (DSC) 131.9 134.2° C. The XRPD pattern of this product is shown in FIG. 1.
US 7,361,787 at col. 69, lines 40-50 (emphasis added). The above-cited WO 2014/041565 Dammalapati passage (i.e., Dammalapati at page 13, lines 11-35) specifically contemplates performing the US 7,361,787 acid-base salt-forming reaction in ketone solvents (naming acetone and methyl isobutyl ketone (MIK)), where the product precipitates/crystallizes from the reaction mixture itself. Dammalapati further more generally suggests the class of ketones as a recrystallization solvent.
As mentioned herein the embodiment, the process from steps (i) to (iv), includes the intermediates/products isolated from the reaction mixture by suitable techniques other than column chromatography including adopting various process modifications such as purification by washings, filtrations, trituration, precipitation crystallization, evaporation etc.
The suitable solvent includes but is not limited to alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, hydrocarbons, water and mixtures thereof.
Dammalapati at page 14, lines 14-22 (emphasis added).
In sum, Dammalapati teaches that crystallization of vilanterol trifenatate is a suitable method for its purification. Dammalapati at page 14, lines 14-22; see also Dammalapati at claim 17. Dammalapati specifically contemplates the class of ketones, as well as the ketone species methyl isobutyl ketone (MIK) as crystallization solvents. Dammalapati at page 13, lines 25-30; Id. at claim 17.
Indeed, as discussed in detail above, Dammalapati teaches “optimization studies, salt formation with triphenylacetic acid was carried out as per reported condition in US’787” where “[a]part from above said alcoholic solvents, inventors herein, tried with ketone solvents such as acetone, methyl isobutyl ketone”, whereby (per US 7,361,787) the vilanterol trifenatate crystallizes/precipitates from the salt forming reaction mixture. Dammalapati at page 13, lines 11-35 (referencing US 7,361,787 at col. 69, lines 40-50)).
Differences between the Claims and Dammalapati
Dammalapati differs from independent claim 1, in that Dammalapati does not teach the specific (times/temperatures) step-wise crystallization (seeding and temperature cycling) as indicated by strikeout text below.
1. A method for the purification of vilanterol trifenatate of formula (I)
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comprising a crystallization of vilanterol trifenatate from a solution of the vilanterol trifenatate in a ketone solvent selected from the group consisting of methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIK)
wherein crystallization carried out in MEK and comprises the following steps:
a) providing a suspension of vilanterol trifenatate in MEK;
b) heating the suspension of step a) until a solution is obtained;
c) cooling the solution
f) cooling the suspension
g) isolating vilanterol trifenatate crystals from the suspension of step f); or
wherein crystallization is carried out in MIK and comprises the following steps:
a) providing a suspension of vilanterol trifenatate in MIK;
b) heating the suspension of step a) until a solution is obtained;
c) cooling the solution
f) cooling the suspension
g) isolating vilanterol trifenatate crystals from the suspension of step f).
P. Box et al., US 7,361,787 (2008) (“Box”)
As discussed above, Box is cited in Dammalapati. Box teaches phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases. Box at col. 1, lines 13-16. In Example 78(i), Box teaches the following exemplary synthesis of the triphenyl acetate salt of 4-((R)-2-(6-(2-(2,6-Dichlorobenzyloxy)-ethoxy-hexylamino-1-hydroxyethyl)-2-hydroxymethyl-phenol:
Triphenylacetic acid (1.81 g, 1 eq) was added to a solution of 4-(I-2-6-2-(2,6-dichlorobenzyloxy)-ethoxy-hexylamino-1-hydroxyethyl)-2-hydroxymethyl-phenol (3.28 g) in ethanol (20 mL) and the mixture heated to 80°C. to obtain a solution. The mixture was allowed to cool to ambient temperature, and the resulting product filtered, washed with a little ethanol, then dried in vacuo at 50° C to afford the title compound as a white crystalline solid (4.3 g). m.pt. (DSC) 131.9 134.2° C. The XRPD pattern of this product is shown in FIG. 1.
Box at col. 69, lines 40-50, Example 78 (emphasis added). The Examiner summarizes the above process as follows
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In Example 78 (iii) and (iv), Box teaches the same acid addition salt forming but with methyl isobutyl ketone (MIBK) instead of ethanol as the solvent to form the respective 1-naphthoic acid or (R)-mandelic acid salts. Box at cols. 69-70.
iii 1-Naphthoate Salt
1-Naphthoic acid (0.16 g. 0.97 mmol) was added to a solution of 4-((R)-2-6-2-(2,6-dichlorobenzyloxy)- ethoxy-hexylamino-1-hydroxyethyl)-2-hydroxymethyl phenol (0.46 g) in MIBK (5 mL) and the resulting suspension warmed to 80°C. The resulting solution was allowed to cool slowly to ambient temperature and left to stir for 20 h. The product was filtered, washed with MIBK, then dried in vacuo at 50° C. to afford the title compound as a solid (0.49 g). m.pt. (DSC) 91.4–95.2°C.
The XRPD pattern of this product is shown in FIG. 3.
iv) (R)-Mandelate Salt
(R)-Mandelic acid (0.15 g) was added to a solution of 4-((R)-2-6-2-(2,6-dichlorobenzyloxy)-ethoxy-hexylamino-1-hydroxyethyl)-2-hydroxymethyl-phenol (0.48 g) in MIBK (5 mL) and the resulting suspension warmed to 80° C. The resulting solution was allowed to cool slowly to ambient temperature and left to stir for 20 h. The product was filtered, washed with MIBK, then dried in vacuo at 50° C. to afford the title compound as a solid (0.44 g).
The XRPD pattern of this product is shown in FIG. 4.
Box at col. 69, line 64 – col. 70 line 20.
This is summarized by the Examiner as follows:
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Here the formed salts were isolated from the reaction mixture in crystalline form, as evidenced by the fact that the XRPD was used as the analytical method, which requires crystalline materials.
Thus, Box teaches methyl isobutyl ketone (which can be termed either as MIK or MIBK) as a salt forming solvent for vilanterol, but with salts different (i.e., the 1-naphthoic acid or (R)-mandelic acid salts) than the triphenyl acetate salt as instantly claimed.
Z. Wu et al., 18 CrystEngComm, 2222-2238 (2016) (“Wu”)
Wu teaches that CSD [crystal size distribution] and crystal size are the key characteristics of crystal quality in industry and pharmaceuticals, because the downstream issues caused by filtration, drying and washing of crystals are always significantly affected by the size and CSD of crystals. Wu at page 2226, col. 1. Wu teaches that from a manufacturing perspective, larger crystals are preferred on considering the uniformity of the formulated product. Wu at page 2226, col. 1.
Wu teaches that implementation of temperature cycling during crystallization can improve crystal quality by improving crystal size.
During crystallization, the temperature cycling is implemented through successive heating–cooling cycles for dissolution and recrystallization in crystal suspension. Therefore, the fines crystals or one species are expected to dissolve out completely during the heating period, and the remaining crystals or dominant species continuously grow or nucleate during the cooling period. When such temperature cycling is facilitated during crystallization, the characteristics of crystal quality, including crystal size distribution, size, morphology, polymorphism and chirality, are well managed.
Wu at Abstract. With respect to applying alternate heating and cooling cycles during crystallization, Wu teaches that:
Thus, based on the manipulation of such key parameters during crystallization, many important techniques and strategies have been developed for controlling the characteristics of crystal quality in the solution state. For instance, the seeding technique is used during crystallization for controlling the size, CSD [crystal size distribution] and chiral purity, the programmed temperature profile technique is used to obtain the desired size and CSD, and fines destruction or temperature cycling is applied to control size, CSD, polymorph selection, chirality, and morphology. In particular, temperature cycling is considered to be a unique and important strategy for controlling the characteristics of crystal quality during crystallization.
. . .
Since then, temperature cycling has been developed to control the size, CSD, morphology, polymorphism and chirality of crystals. Here, to obtain the desired crystal quality, the defined temperature cycling in the solution state involves successive heating–cooling cycles that are employed in dissolution– recrystallization. Then, fines crystals or one classified species are destroyed by the heating temperature, and the remaining crystals or dominant species are expected to further grow circularly.
Wu at page 2223, col. 2 (emphasis added) (citations omitted); see also, Wu at page 2225, col. 2 (under “2.2. The basic protocol of temperature cycling during crystallization”).
With respect to the claim 1 concept of alternative heating and cooling steps with seeding. Wu teaches that,
During temperature cycling with an alternating successive heating–cooling program for CSD [crystal size distribution] and size control, external or in situ seed loading is also frequently employed, due to the flexible manipulation of supersaturation within the metastable zone limitation.
Wu at page 2226, col. 2 (emphasis added).
B. Furniss et al., Vogel’s Textbook of Practical Organic Chemistry 135-154 (1989) (“Vogel”)
Vogel teaches a section on recrystallization. Vogel at pages 135-154. Vogel teaches that solid organic compounds when isolated from organic reactions are seldom pure; they are usually contaminated with small amounts of other compounds (impurities) which are produced along with the desired product. Vogel at page 135. Vogel teaches that the purification of impure crystalline compounds is usually effected by crystallization from a suitable solvent or mixture of solvents. Vogel at page 135. Vogel teaches that acetone and butan-2-one (ethyl methyl ketone), are common solvents available for the recrystallisation. Vogel at page 137.
Vogel teaches that in practice, the choice of a solvent for recrystallisation must be determined experimentally if no information is already available. Vogel at page 138, lines 1-2. Vogel teaches a routine method for experimentally determining appropriate solvents (or solvent mixtures) for crystallization. Vogel at page 138, lines 1-36.
Anderson, Practical Process & Research Development 81-111, 223--247, (2000) (“Anderson”)
Anderson teaches that the chemist has many options for purifying and isolating intermediates and final products and that the operations preferred on scale differ from those routinely used in the laboratory. Anderson at page 223. Ander teaches that isolation of solid intermediates and final product is often achieved by crystallization. Anderson at page 223. Anderson teaches that intermediates may be upgraded by crystallization, decreasing the burden on the purification of the final product. Anderson at page 223. Under controlled conditions, crystallization generally provides the best purification of a product. Anderson at page 223. Anderson teaches that by adjusting solution conditions to decrease the solubility of the product within the metastable zone, the desired molecules can be “pressured” to come out of solution and crystallize. Anderson at page 227 (III.A.). Anderson teaches that crystallization is induce by applying a “pressure” to a solution of the subject compound, such as cooling a warmed solution. Anderson at page 229.
Anderson teaches removing by-products by crystallization or precipitation can ease work-up conditions and solvent ratios may be adjusted or solvents may be exchanged during work-up to remove by-products. Anderson at page 100.
Anderson teaches guidance on solvent selection. Anderson at page 81 et seq. Anderson teaches that solvents may be selected for the purpose of removing by-products by crystallization precipitation to increase productivity, yield, and product quality. Anderson at page 92, Table 4.5. Anderson teaches a table of solvents useful for scaleup, included methyl isobutyl ketone. Anderson at pages 86-87, Table 4.3.
With respect to Ostwald ripening, Anderson teaches that:
Particle size and particle size distribution can be controlled to a great extent by crystallization, using the techniques in Table 11.2. Small particles are filtered and washed during isolation more slowly than large crystals. Through gradual cooling, very small crystals (fines) dissolve and crystallize as part of the existing, larger crystals. This process is termed Ostwald ripening. By controlling cooling and other crystallization pressures, it is possible to control crystal size and quality.
Anderson at page 234 (emphasis added).
Obviousness Rational
Claim 1 is obvious for the following reasons. One of ordinary skill is motivated to purify and/or control the particle size and/or particle size distribution of vilanterol trifenatate by crystallization in view of Dammalapati’s teaching vilanterol is useful in the treatment of respiratory diseases and the preferred pharmaceutically acceptable salt is the triphenyl acetate salt (vilanterol trifenatate) (Dammalapati at page 1, lines 15-35), in further view of Wu’s teaching that CSD [crystal size distribution] and crystal size are the key characteristics of crystal quality in industry and pharmaceuticals, because the downstream issues caused by filtration, drying and washing of crystals are always significantly affected by the size and CSD of crystals. Wu at page 2226, col. 1.
For this purpose, one of ordinary skill is motivated to employ a ketone crystallization solvent, for example, methyl isobutyl ketone (MIBK or MIK) because Dammalapati and Box suggest that ketones as a class, in particular, methyl isobutyl ketone, are suitable solvents from which vilanterol acid addition salts crystallize. That is, Dammalapati teaches “optimization studies, salt formation with triphenylacetic acid was carried out as per reported condition in US’787” where “[a]part from above said alcoholic solvents, inventors herein, tried with ketone solvents such as acetone, methyl isobutyl ketone”, whereby (per US 7,361,787) the vilanterol trifenatate crystallizes/precipitates from the salt forming reaction mixture. Dammalapati at page 13, lines 11-35 (referencing US 7,361,787 at col. 69, lines 40-50)); see also, Box at col. 69, line 64 – col. 70 line 20 (teaching methyl isobutyl ketone for crystallization from a salt forming reaction of vilanterol with 1-naphthoic acid or (R)-mandelic acid salts). Further, Vogel teaches that acetone and butan-2-one (ethyl methyl ketone), are common solvents available for the recrystallisation. Vogel at page 137. One of ordinary skill thereby meets the following recitations of claim 1.
Claim 1 A method for the purification of vilanterol trifenatate of the formula (I) [structure] comprising a crystallization of vilanterol trifenatate from a solution of the vilanterol trifenatate in a ketone solvent selected from the group consisting of methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIK). . .
Neither Dammalapati nor Wu teach the specific claim 1 temperature ranges, cycling times and seeding as indicated by strikeout text below;
Claim 1 . . . wherein crystallization is carried out in MIK and comprises the following steps:
a) providing a suspension of vilanterol trifenatate in MIK;
b) heating the suspension of step a) until a solution is obtained;
c) cooling the solution
f) cooling the suspension
g) isolating vilanterol trifenatate crystals from the suspension of step f).
as well as the alternative claim 1 successive heating and cooling steps when methyl ethyl ketone (MEK) is employed as the crystallization solvent. However, these limitations do not lend patentability to claim 1 where Wu clearly teaches that crystallization temperatures, cycling times, and seeding are result-effective variables. MPEP § 2144.05(II)(B). That is, Wu teaches that
Thus, temperature control for dissolution and recrystallization plays an important role in adjusting the crystal growth and nucleation process to control the final quality of the products.
Wu at page 2225, col. 2 (emphasis added).
However, heating–cooling cycles, heating/cooling rate and optimal cycling time during laboratory crystallization also have significant influences on modulating the final morphology of crystals during the alternating heating–cooling cycles.
Wu at page 2230, col. 1.
Thus, based on the manipulation of such key parameters during crystallization, many important techniques and strategies have been developed for controlling the characteristics of crystal quality in the solution state. For instance, the seeding technique is used during crystallization for controlling the size, CSD [crystal size distribution] and chiral purity, the programmed temperature profile technique is used to obtain the desired size and CSD, and fines destruction or temperature cycling is applied to control size, CSD, polymorph selection, chirality, and morphology. In particular, temperature cycling is considered to be a unique and important strategy for controlling the characteristics of crystal quality during crystallization.
. . .
Since then, temperature cycling has been developed to control the size, CSD, morphology, polymorphism and chirality of crystals. Here, to obtain the desired crystal quality, the defined temperature cycling in the solution state involves successive heating–cooling cycles that are employed in dissolution– recrystallization. Then, fines crystals or one classified species are destroyed by the heating temperature, and the remaining crystals or dominant species are expected to further grow circularly.
Wu at page 2223, col. 2 (emphasis added) (citations omitted); see also, Wu at page 2225, col. 2 (under “2.2. The basic protocol of temperature cycling during crystallization”). And with respect to the claim 1 concept of alternative heating and cooling steps with seeding. Wu teaches that,
During temperature cycling with an alternating successive heating–cooling program for CSD [crystal size distribution] and size control, external or in situ seed loading is also frequently employed, due to the flexible manipulation of supersaturation within the metastable zone limitation.
Wu at page 2226, col. 2 (emphasis added).
Here, one of ordinary skill is motivated to optimize (or develop workable rages regarding) the number of successive heating and cooling steps, the cycling times and temperatures (for example, to within the parameters of claim 1) as directly taught by Wu for these result-effective variables. MPEP § 2144.05(II)(B).1
Claim 1 steps (a)-(g)) represent the standard temperature cycling during crystallization as discussed in detail above. Wu teaches that through such successive cycles of dissolution and recrystallization, the characteristics of crystal quality become more desirable. Wu at page 2224, col. 2 – 2225, col. 1.
Applicant’ Argument Respecting Unexpected Results
Applicant submits the Declaration under 37 C.F.R. § 1.132, executed by Angel Esquinas Garcia (January 19, 2026) (the Garcia Declaration). The Garcia Declaration proffers a comparison of crystallization of vilanterol trifenatate in methyl ethyl ketone (MEK) without using successive heating and cooling cycles (the prior art) versus specification Examples 7 and 8 (the claimed invention), respectively employing methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIK) as crystallization solvents.
The Proffered Prior Art Crystallizations
Prior Art (no successive heating and cooling steps) Crystallization in MEK with Seeding
The Garcia Declaration avers (2-10-2019) that vilanterol trifenatate (20 g) was dissolved in methyl ethyl ketone (MEK, 160 ml + 20 ml) at 62 °C and allowed to cool. Garcia Declaration at ¶ 4. At 55 °C, the solution was seeded with crystals obtained from recrystallization in MEK. Id. At 44 °C precipitation was noted and at 38 °C a thick precipitated was noted. Id. More MEK was added and the suspension maintained at 28 °C overnight. Id. The Garcia Declaration further avers (3-10-2019) that white suspension at 26 °C was filtered, crystals washed with MEK and dried at 45 °C for 8 hours. Id. The Garcia Declaration avers that the SEM analysis showed the vilanterol trifenatate crystals to have an ‘acicular’ shape (slender, needle-like of similar thickness). Garcia Declaration at ¶ 5. The Garcia Declaration avers that the obtained crystals were fragile, not readily manipulable, and not particularly suited for micronization. Garcia Declaration at ¶ 6.
Prior Art (no successive heating and cooling steps) Crystallization in MEK without Seeding
The Garcia Declaration avers that a second crystallization experiment was performed also using vilanterol trifenatate (20 g) and MEK (180 ml), but without seeding. Garcia Declaration at ¶ 7. The Garcia Declaration avers that the SEM analysis showed the vilanterol trifenatate crystals to have an acicular shape, 5-25 μm long and were forming aggregates. Garcia Declaration at ¶ 8. The Garcia Declaration avers that the obtained crystals similarly were fragile, not readily manipulable, and not particularly suited for micronization. Garcia Declaration at ¶ 9.
The Proffered Crystallizations Per Claim 1
Specification Example 7
In specification Example 7 (per claim 1), vilanterol trifenatate (100 g, 129 mmol) was suspended in methyl ethyl ketone (MEK) (850 ml). The suspension was heated to 55 °C until a solution was observed. Then, the system was cooled to 49°C, seeded with vilanterol trifenatate crystals. Then this resultant suspension was subjected to two successive heating–cooling cycles as follows.
1. the suspension was cooled to 40 °C and stirred at this temperature for 15 min;
2. the suspension was heated to 49 °C and stirred at this temperature for 15 min;
3. the suspension was cooled to 40 °C and stirred at this temperature for 15 min; and
4. the suspension was heated to 49 °C and stirred at this temperature for 15 min.
The obtained suspension was cooled to 20 °C and stirred at this temperature for 1 h where the white solid obtained was filtered and dried under reduced pressure at 55 °C for 24 h to give 88 g (114 mmol) of vilanterol trifenatate (I), (yield= 88%). A SEM image of the crystals obtained is shown in Fig. 1, where it can be seen that no aggregates are formed with MEK. Specification at page 13, lines 1-17.
Specification Example 8
In specification Example 8 (per claim 1), vilanterol trifenatate (20 g, 25,8 mmol) was suspended in methyl isobutyl ketone (MIK) (600 ml). The suspension was heated to 65-68 °C until a solution was observed. Then, the system was cooled to 57°C, seeded with vilanterol trifenatate crystals. Then this resultant suspension was subjected to two successive heating–cooling cycles as follows.
1. the suspension was cooled to 47 °C and stirred at this temperature for 15 min;
2. the suspension was heated to 57 °C and stirred at this temperature for 15 min;
3. the suspension was cooled to 47 °C and stirred at this temperature for 15 min; and
4. the suspension was heated to 57 °C and stirred at this temperature for 15 min.
The obtained suspension was cooled to 20 °C and stirred at this temperature for 1 h. The white solid obtained was filtered and dried under reduced pressure at 55 °C for 16 h. 17 g (21 ,9 mmol) of vilanterol trifenatate (I) were obtained (yield= 85%). A SEM image of the crystals obtained is shown in Fig. 2, where it can be seen that no 35 aggregates are formed with MIK. Specification at page 13, lines 19-36.
It is noted that neither of specification Examples 7 or 8 state the source of the vilanterol trifenatate crystals used for seeding, thus it is unclear if Examples 7 or 8 meet the claim 1 limitation of:
Claim 1 . . . wherein vilanterol crystals of step d) are obtained by crystallization or recrystallization of vilanterol trifenatate from a solution of the vilanterol trifenatate in a ketone solvent selected from the group consisting of methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIK).
The Garcia Declaration avers that by carrying out the crystallization according to claim 1, unexpectedly not only bigger crystals in good yield, high purity and uniform morphology were obtained without forming aggregates, but they also has a “columnar” particle shape particularly suited for micronization. Garcia Declaration at ¶ 10. Consequently, the quality of the resulting vilanterol trifenatate crystals was markedly improved. Garcia Declaration at ¶ 10.
Summary of Proffered Results
The Examiner summarizes the above-proffered results in the following table.
Examiner Summary of Proffered Results for
Crystallization of Vilanterol Trifenatate
Example
*Solvent concentration
of vilanterol trifenatate
heating-cooling cycles
Result
Garcia Declaration ¶ 4
MEK (with seeding)
0.111
none
Acicular, slender, needle-like crystals that were fragile, not readily manipulable, and not particularly suited for micronization
Garcia Declaration ¶ 7
MEK (without seeding)
0.111
none
Acicular, slender, needle-like crystals that were fragile, not readily manipulable, and not particularly suited for micronization. Forming aggregates
Ex. 7 (claimed)
MEK (with seeding)
0.118
Cool to 40 °C
Heat to 49 °C
Cool to 40 °C
Heat to 49 °C
88 % yield
bigger crystals, uniform morphology, no aggregates, a “columnar” particle shape particularly suited for micronization
Specification states that Fig. 1 shows no aggregates formed
Ex. 8 (claimed)
MIK (with seeding)
0.033
Cool to 47 °C
Heat to 57 °C
Cool to 47 °C
Heat to 57 °C
85 % yield
bigger crystals, uniform morphology, no aggregates, a “columnar” particle shape particularly suited for micronization
Specification states that Fig. 2 shows no aggregates formed
*Grams vilanterol trifenatate /ml solvent
The Proffered Results Art not Sufficient to Overcome the § 103 Rejection
Applicant has not demonstrated that the results are unexpected. MPEP § 716.02(a)(I)/(II). Here, in view of Wu, one of ordinary skill would expect that applying alternate heating and cooling cycles (temperature cycling) during crystallization would result in improved crystal properties, e.g., larger circular crystals. For example, Wu teaches that:
Thus, based on the manipulation of such key parameters during crystallization, many important techniques and strategies have been developed for controlling the characteristics of crystal quality in the solution state. For instance, the seeding technique is used during crystallization for controlling the size, CSD [crystal size distribution] and chiral purity, the programmed temperature profile technique is used to obtain the desired size and CSD, and fines destruction or temperature cycling is applied to control size, CSD, polymorph selection, chirality, and morphology. In particular, temperature cycling is considered to be a unique and important strategy for controlling the characteristics of crystal quality during crystallization.
. . .
Since then, temperature cycling has been developed to control the size, CSD, morphology, polymorphism and chirality of crystals. Here, to obtain the desired crystal quality, the defined temperature cycling in the solution state involves successive heating–cooling cycles that are employed in dissolution– recrystallization. Then, fines crystals or one classified species are destroyed by the heating temperature, and the remaining crystals or dominant species are expected to further grow circularly.
Wu at page 2223, col. 2 (emphasis added) (citations omitted); see also, Wu at page 2225, col. 2 (under “2.2. The basic protocol of temperature cycling during crystallization”). See also, Wu at pages 2225-2226 “2.2. The basic protocol of temperature cycling during crystallization” and “3. Application of the temperature cycling technique in crystallization”.
Further, the case of obviousness is very strong because the cited art specifically suggests that ketones as a class, in particular, methyl isobutyl ketone, are suitable solvents from which vilanterol acid addition salts crystallize. Dammalapati at page 13, lines 11-35 (referencing US 7,361,787 at col. 69, lines 40-50)); see also, Box at col. 69, line 64 – col. 70 line 20; Vogel at page 137. Here, Applicant’s limited showing is insufficient to overcome the strong showing of obviousness in this case. Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. MPEP § 716.01(d) (citing Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988)). See also, Pfizer, 480 F.3d at 1372 ("[W]e hold that even if Pfizer showed that amlodipine besylate exhibits unexpectedly superior results, this secondary consideration does not overcome the strong showing of obviousness in this case. Although secondary considerations must be taken into account, they do not necessarily control the obviousness conclusion.").
Applicant’ Additional Arguments
Applicant argues that none of the cited references teaches or suggests applying Ostwald ripening to vilanterol trifenatate crystallization in MIK/MEK under the specific combination of parameters now claimed, nor do they provide any reasonable expectation that such conditions would result in the particular crystal morphology achieved by the present invention. Reply at page 6.
This argument is not persuasive for the following reasons. While Wu teaches temperature cycling generally (what Applicant refers to as Ostwald ripening), it is true that the cited art does not teach, per claim 1 step (e), the specifically claimed cycling number, time per cycle or temperature ranges. However, one of ordinary skill is motivated to optimize (or develop workable ranges) regarding these result-effective variables (for example, to within the parameters of claim 1) as directly taught by Wu. MPEP § 2144.05(II)(B); see footnote 1. Claim 1 steps (a)-(g)) represent a standard temperature cycling protocol as discussed in detail above. Wu teaches that through such successive cycles of dissolution and recrystallization, the characteristics of crystal quality become more desirable. Wu at page 2224, col. 2 – 2225, col. 1. Further one of ordinary skill would expect, based on Wu, that crystallization of vilanterol trifenatate under a temperature-cycling protocol, would produce larger more manageable particles. Wu at page 2225, col. 2 (“Thus, the remaining crystals in suspension grow larger or extra nuclei are generated to deplete the supersaturation, resulting in an increase in size and number of crystals at the end of this ‘recrystallization’ process”).
Applicant further argues that in rejecting a claim under 35 U.S.C. § 103, the USPTO must support its rejection by "substantial evidence" within the record, and by "clear and particular" evidence of a suggestion, teaching, or motivation to combine the teachings of different references. Reply at 9. Applicant argues that there is no substantial evidence, nor clear and particular evidence, within the record of motivation for modifying Dammalapati to arrive at the claimed invention. Id. Without such motivation and absent improper hindsight reconstruction, a person of ordinary skill in the art would not be motivated to perform the proposed modification. Id.
This argument is not persuasive for the following reasons. First, an examiner is reviewed by the board under a preponderance of the evidence standard, under which standard the Examiner must show nonpatentability before the Patent and Trademark Office in order to reject the claims of a patent application. Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1423 (1988). The substantial evidence standard applies to appellate review of the board’s holding. In re Gartside, 203 F3d 1305, 53 USPQ2d 1769 (Fed. Cir. 2000). Here, the motivation to combine Dammalapati with Wu is simply to produce improved, larger, more manageable particles of vilanterol trifenatate under a temperature-cycling protocol as taught by Wu. A motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents; any need or problem known in the field of endeavor at the time of invention and addressed by the patent; and the background knowledge, creativity, and common sense of the person of ordinary skill. MPEP § 2143.01 (citing Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018)).
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 One of ordinary skill in the art is motivated to develop workable or optimum ranges for result-effective parameters, 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). Generally, with respect to optimization of result-effective variables, changes to the prior art involving degree are not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions. MPEP § 2144.05(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929). For example, 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 (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. Id. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. Id. There are several ways by which the applicant may rebut that presumption, for example, a modification of a process parameter may be patentable if it produces a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. MPEP § 2144.05 (III)(A) (citing E. I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018); see also MPEP § 716.02(c) (to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range (citing In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)).