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 .
Applicant’s arguments, filed 07/25/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5 stand rejected under 35 U.S.C. 103 as being unpatentable over Ticehurst et al (US 20140141247 A1), in view of Halliwell (WO 2017075232), as evidenced by Wilson et al (Powder Tech, 2018, 339, pp 641-650).
Ticehurst et al teach it was known to recrystallize fluticasone propionate with controlled particle size suitable for micronization (abs). In one embodiment, the D(0.9) of the particles was 135.9 microns, the D(0.5) was 55.1 microns, and the D(0.1) was 15.4 microns (table 2 ex 4). The process yields particles that are 5-200 microns in length, with a width of 3-30 microns (¶ 17).
Ticehurst et al do not teach the specific milling process and resulting particle size structure instantly claimed.
Halliwell teaches that recrystallization produces large crystal dimensions, which make it possible to resize (by milling) drug crystals into substantially uniform dimensions (p.7). As evidenced by Wilson, resizing crystal particles via milling breaks particles along the shortest axis, reducing needle length, whilst preserving needle width (into 3rd ¶, graphical abs). Large crystals up to 2000 microns were obtained, and the large crystals were then resized (ex. 1). The particle size distribution of the resized crystals are disclosed (see fig 1b, 1c). Crystals of ropivacaine (crystalline active) can be shortened and sieved before coating (pg. 7). The recrystallized, resized and sieved drug crystals may have at least two dimensions that are substantially the same, providing an aspect ratio of 1:1 (pp. 7-8). The crystals have at least one dimension ranging from 35-500 microns, more typically in the range of 50-200 microns (pg. 8 lines 4-7, figs 1b, 1c).
With regards to claim 1, where Ticehurst et al and Halliwell are directed to crystalline actives with similar crystal sizes that are suitable for size reduction techniques, it would have been obvious to use the milling method of Halliwell in the process of Ticehurst et al, where they are reasonably expected to result in the desired crystal sizes.
Regarding wherein at least 90% by mass of the recrystallized crystals have the shortest dimensions in the range of 50-250 microns of claim 1, where Ticehurst et al and Halliwell are both directed a method of producing larger crystalline active agents that are resized to desired sizes, it would have been obvious for the skilled artisan to adjust the crystal sizes to other sizes that were known to be suitable for resizing, such as up to 2000 microns, as taught by Halliwell, as a matter of routine optimization to achieve desired particle sizes for desired dosage forms, etc. See MPEP 2144.05(II)(A). While Halliwell does not explicitly disclose that 90% by mass have the shortest dimension in the range of 50-250 microns, recrystallized drugs for resizing were known to be up to 2000 microns, which appears to overlap the range instantly claimed. See MPEP 2144.05(I). Further, where an aspect ratio of 1 was known with particle sizes ranging from 35-500 microns, and were resized by shortening (i.e., only segmenting along the lengthwise axis while retaining the transverse plane dimensions), it appears the shortest dimensions of the particle would fall within the particle size ranges made obvious above.
Regarding wherein no more than 10% of the sized crystals are less than 30 microns of claim 1, it would have been obvious to modify the process of Ticehurst et al, by adjusting the size of the sized crystals to other sizes that were known to be suitable for sized crystalline drug forms, such no more than 10% of the sized crystals having a particle size less than 30 microns, as shown in Fig. 1C of Halliwell, in order to optimize the particle size distribution for desired dosage forms, etc. See MPEP 2144.05(II)(A).
Regarding claims 2-5, it is noted that the crystal sizes instantly claimed overlap with those taught by the Halliwell. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). While the specific percentages by weight are not specifically disclosed, it is reasonably expected that the limitations are met where the disclosed sizes are within the range and the disclosed sizes are expected to be the majority of the crystal sizes.
Response to Arguments
First, Applicants assert Ticehurst et al do not disclose a method to generate fluticasone propionate crystals in the claimed size range distribution, particularly with respect to D10. Applicants assert the recrystallization and milling of Ticehurst et al are not the same steps as claimed at least because they do not achieve the claimed particle size distributions. Further, Applicants assert Ticehurst et al is limited to smaller particle size distributions than the claimed crystals and assert these are not suitable for coating.
Second, Applicants assert that the instantly claimed process minimizes small or fine crystals, improves the uniformity of the drug crystals, and asserts that fluid bed coating works most optimally when the drug crystals have a controlled, reproducible particle size distribution.
First, respectfully, this argument is not persuasive. While it does appear that the D10 particle sizes from the working embodiments of Ticehurst et al appear to be smaller than those instantly claimed, Ticehurst et al more broadly teaches a process of resizing recrystallized fluticasone propionate with a controlled particle size to achieve sizing for desired dosage forms. Helliwell et al teach a similar process where particle sizes overlapping those instantly claimed were known, and even teaches the recrystallized larger crystals had a particle size of up to 2000 microns with the resized particles ranging from 35-500 microns with an aspect ratio of 1. Helliwell et al also teach a D10 particle size distribution falling within the claimed ranges were known to be produced by this process, as discussed above. As such, it would have been obvious for the skilled artisan to optimize the process of Ticehurst et al for desired administration forms, for the same reasons discussed above. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, 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. See MPEP 2144(II)(A).
Regarding the recrystallization and milling of Ticehurst et al, Ticehurst et al was used in combination with Helliwell et al, which makes obvious to the claimed recrystallization and resizing methods with particle size distributions falling within or overlapping the instantly claimed ranges, as discussed above.
Applicants assert the particles of Ticehurst et al are not suitable for coating, however, Applicants have not provided evidence to support this assertion and attorney argument does not replace evidence where evidence is necessary. See MPEP 2145(I). There are no teachings or suggestions in the reference that suggest that the particles are unsuitable for coating.
Second, Applicants assert that the instantly claimed process minimizes small or fine crystals, improves the uniformity of the drug crystals, and that fluid bed coating works best with a controlled particles size, however, Applicants have not provided evidence to support this assertion and attorney argument does not replace evidence where evidence is necessary. See MPEP 2145(I). Even so, both Ticehurst et al and Helliwell et al are both directed to resizing crystalline drugs in order to control particle size distribution. Further, it appears that Applicants are asserting supersized particles are not known and that preferential segmentation of the supersized crystals is critical to achieving a particle size distribution as instantly claimed, but large drug crystals appear to be known from Helliwell et al, where they are resized by specifically shortening the drug crystals (i.e., preferential segmentation). Applicants have not provided evidence to support this assertion of criticality. Additionally, the examiner notes that Helliwell et al teach a particle size distribution falling within the instantly claimed ranges, as discussed above.
Claims 6-8, 12, and 13, stand rejected under 35 U.S.C. 103 as being unpatentable over Halliwell (WO 2017075232) and Ticehurst et al (US 20140141247 A1), in view of Malamatari (Pharmaceutical nanocrystals: production by wet milling and applications, Drug Discovery Today, Volume 23, Issue 3, March 2018, pp. 534-547), as evidenced by Turk et al (Pharmaceutics, 2021, 13, 746, pp 1-11).
Halliwell is discussed above and further teaches the particles were resized by milling (example 1). The recrystallized particles may have smaller/finer crystals attached to the surface; to remove these finer crystals, the particles were suspended in a polyvinyl alcohol (PVA) solution and washed with methanol and water (p.21), sieved (p.21), and individually coated with PVA (p.9). The degree of the crystallinity of the PVA coating may be controlled by thermal curing at a certain temperature for a certain period of time (p.10). Halliwell teaches methods of forming polymeric coatings on particles are well known in the art, and include spray coating, air suspension techniques, etc. (pg 12 last ¶ - pg 13 1st ¶).
Halliwell and Ticehurst et al are discussed above but do not specifically teach using a rotor/stator homogenizer to provide shorter crystals, nor the use of fluid bed coating equipment to coat the polymer membrane on the sized crystals.
Malamatari teaches it was known to resize crystalline actives with rotor-stator mills (i.e., homogenizer) (abs, pg 539 2nd col 3rd ¶ and “Rotor-stator mixers/wet mills”). Rotor-stator mills lead to size reduction (“Rotor-stator mixers/wet mills”). Fluticasone propionate is taught as a suitable drug (pg 543 1st col last ¶). Fluidized-bed coating was known technique to be used with crystalline drugs (pg 541 2nd col 2nd ¶). As evidenced by Turk et al, fluidized bed coating is a process used in the pharmaceutical industry to coat drugs with a polymer film (intro 1st ¶).
Regarding claim 6, it would have been obvious to use a known milling method for reducing the particle size of crystalline drugs, such as by using rotor/stator homogenizers, where Halliwell and Malamatari both teach milling as a method for shortening crystalline actives.
Regarding claim 7, a person having ordinary skill in the art following the teachings of Halliwell would have been motivated to use sieving to provide the desired sized particles having substantially uniform dimensions as taught by Halliwell.
Regarding claim 8, it would have been obvious to suspend the particles in PVA and wash with methanol and water, in order to remove finer crystals from the resized crystals, as taught by Halliwell. Further, it appears polyvinyl alcohol reads on a surfactant, therefore, the limitation of the rinsing liquid comprising a surfactant and one or more solvents is met.
Regarding claim 12, it would have been obvious to use known techniques to coat the sized fluticasone propionate crystals made obvious by Halliwell and Ticehurst et al above, such as by using fluid bed coating equipment, as taught by Malamatari.
Regarding claim 13, it would have been obvious to coat the crystals with a polyvinyl alcohol, as taught by Halliwell.
Response to Arguments
Applicants assert Turk et al are relied upon to show the milling step, however, the claimed process requires a “sizing” step that is “segmenting the supersized crystals along the respective lengthwise axes while retaining the dimensions of the transverse plane perpendicular to the lengthwise axis.” Applicants assert this is different from “milling” in micronization, which does not have preferential segmentation.
Respectfully, this argument is not persuasive. Applicants assert that Turk et al was recited for teaching the milling step, however, Turk et al was only cited as an evidentiary reference that defines the process of fluidized bed coating, which is taught by Malamatari. The examiner notes that Malamatari was cited for teaching rotor-stator milling was a known method for resizing crystalline drugs, as discussed above, which appears to be the same resizing method instantly claimed, which recites rotor-stator milling. Segmenting the crystals along the respective lengthwise axes while retaining the dimensions of the transverse plane perpendicular to the lengthwise axis is taught by Helliwell et al and evidenced by Wilson et al, as discussed above.
Claim 9 stand rejected under 35 U.S.C. 103 as being unpatentable over Halliwell (WO 2017075232), Ticehurst et al (US 20140141247 A1), Malamatari (Pharmaceutical nanocrystals: production by wet milling and applications, Drug Discovery Today, Volume 23, Issue 3, March 2018, pp. 534-547), and Chen (CN 101757634 A).
Halliwell, Ticehurst et al, and Malamatari, are discussed above but do not specifically teach polysorbate 80 as the surfactant (description, ¶¶ 2, 33).
Chen discloses a pharmaceutical composition comprising fluticasone propionate, where TWEEN 80 (i.e., polysorbate 80) was known to be used as a surfactant.
It would have been obvious to substitute polysorbate 80 for the PVA used as the rinse of Halliwell, where polysorbate 80 is a surfactant that is known to be suitable for use with fluticasone propionate. See MPEP 2143(I)(B).
Regarding the amounts, a skilled artisan would reasonable be expected to determine the working range of polysorbate 80 to use in the rinsing liquid, such as 0.05-1 wt%. MPEP 2144.05(II).
Response to Arguments
Applicants assert Malamatari and Chen et al do not cure the deficiency of Ticehurst as they are limited to conventional milling processes.
Respectfully, this argument is not persuasive. Regarding claim 9, Malamatari is discussed above, and Chen et al was cited for simply teaching known surfactants used pharmaceutical compositions of fluticasone propionate.
Nonstatutory Double Patenting
Claims 1-9, 12, and 13, stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/753,995 (reference application), hereinafter referred to as ‘995, in view of Halliwell (WO 2017075232), Ticehurst et al (US 20140141247 A1), Malamatari (Pharmaceutical nanocrystals: production by wet milling and applications, Drug Discovery Today, Volume 23, Issue 3, March 2018, pp. 534-547), and Chen (CN 101757634 A). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘995 discloses a dosage form comprising fluticasone propionate crystals coated with a polyvinyl alcohol membrane (claim 1). 90% of the total mass of the particles are no larger than 250 microns, 50% have a mean size in the range of 120-160 microns, 10% are less than 65 microns (claim 7).
‘995 does not disclose a process for providing crystals of fluticasone propionate of desired size and morphology as instantly claimed.
Where the polyvinyl alcohol coated crystal fluticasone propionate particles comprise the same coating as instantly claimed and have overlapping particle size distributions, it would have been obvious to modify the particles of ‘995 by formulating the fluticasone propionate crystals with the method made obvious by Halliwell, Ticehurst et al, Malamatari, and Chen, for the same reasons discussed above as applied to each of the instant claim limitations.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The following are also rejected for the same reasons:
Copending Application No. 17/735,915
Copending Application No. 17/457,248
Response to Arguments
Applicants assert claims 1-10, 12 and 13 are patentably distinct from the reference application because Ticehurst et al do not render the claims obvious, as set forth above.
Respectfully, this argument is not persuasive. Examiner disagrees for the same reasons above and of record. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have not provided argument with respect to copending application nos. 17/735,915 and 17/457,248. Accordingly, the claims stand rejected for the same reasons above and of record.
Claims 1-9, 12, and 13, stand rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,351,124 B2, hereinafter referred to as ‘124, in view of Halliwell (WO 2017075232), Ticehurst et al (US 20140141247 A1), Malamatari (Pharmaceutical nanocrystals: production by wet milling and applications, Drug Discovery Today, Volume 23, Issue 3, March 2018, pp. 534-547), and Chen (CN 101757634 A). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘124 discloses a pharmaceutical composition comprising one or more crystals of local anesthetic agent (crystalline active), and a polyvinyl alcohol coating, wherein each microparticle has at least one dimension in the range of 35-500 microns (claim 1). The local anesthetic agent is ropivacaine (claim 14).
‘124 does not disclose a process for providing crystals of fluticasone propionate of desired size and morphology as instantly claimed.
It would have been obvious to modify ‘124 by formulation the crystals with the method made obvious above by Halliwell, Ticehurst et al, Malamatari, and Chen, for the same reasons discussed above as applied to each of the instant claim limitations.
It would have been obvious to substitute fluticasone propionate for the active of ‘124, for the same reasons discussed above by Halliwell and Ticehurst et al, where both are drawn to crystal drugs that are coated and have an overlapping size range.
The following are also rejected for the same reasons:
U.S. Patent No. 9,987,233 B2
U.S. Patent No. 11,219,604 B2
Response to Arguments
Applicants assert claims 1-10, 12 and 13 are patentably distinct from the reference application because Ticehurst et al do not render the claims obvious, as set forth above.
Respectfully, this argument is not persuasive. Examiner disagrees for the same reasons above and of record. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have not provided argument with respect U.S. Patent Nos. 9,987,233 B2 and 11,219,604 B2. Accordingly, the claims stand rejected for the same reasons above and of record.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/MARIANNE C SEIDEL/Primary Examiner, Art Unit 1600