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 17 June 2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Interpretation
The limitation “solid particles of at least one active pharmaceutical ingredient (API)” has been interpreted as solid particles composed of at least one active pharmaceutical ingredient. Accordingly, additional materials in combination with the API, e.g., silica, that do not appear to exert any therapeutic activity are considered to meet the limitation of solid particles of at least one API.
The limitation “non-active silica particles” has been interpreted as silica particles comprising less than 1% of API, since p. 7, lines 5-10 of the instant Specification discloses wherein “active silica particles” refer to silica particles most preferably comprising from 1-20 weight-% of an API. Thus, absent additional clarification or support in the instant claims, one of ordinary skill in the art would reasonably interpret silica particles having less than 1 weight-% of API as not active.
Claim Rejections - 35 USC § 103 (maintained)
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 15-20, 22-23, 25-26, 28 and 30-37 are rejected under 35 U.S.C. 103 as being unpatentable over Niskanen et al. (US 2018/0311165 A1, 11/01/2018, IDS reference) (hereinafter Niskanen).
Regarding claims 15-17, 25, 26, 28, 30, 32, and 34-36, Niskanen discloses a depot in the form of silica hydrogel composite having at least one encapsulated active pharmaceutical ingredient (API) for sustained-release drug delivery and parenteral administration, comprising silica particles. The particles of the composite body comprise 0.1-80 wt.% of API ([0040]). The term encapsulated describes the way in which API exists within the depot, meaning that at least one molecule of API is confined within a supra molecule of a carrier, e.g., silica hydrogel and products of sol-gel processes ([0034]). The hydrogel composite is obtained by mixing the silica particles with a silica sol ([0041]) wherein the silica sol has a solid content of <5 wt. %. The hydrogel composite comprises up to 85 wt. % of said silica particles, and the hydrogel composite is shear-thinning ([0048]). The particles of the composite body include microparticles having a diameter between 1 and 300 µm ([0055]) and particles having a diameter between 50 and 1000 nm ([0056]). By adjusting the proportion of API that is encapsulated in the hydrogel and adjusting the amount of API that is encapsulated in the silica microparticles, release times and release profiles can be optimized providing a dose of API from the gel before release from the microparticles starts ([0050]). The depot may be administered to a patient as an injectable formula ([0060]).
Accordingly, Niskanen discloses a silica hydrogel composite comprising up to 85 wt. % of silica particles, formed from a mixture comprising a silica sol having a solid content of < 5 wt. %; silica particles having a diameter between 50 and 1000 nm; and an API, wherein at least a portion of the silica particles may surround at least one molecule of an API and may have a diameter between 1 µm and 300 µm. Together these would provide compositions as claimed instantly. The prior art is not anticipatory insofar as this combination must be selected from various lists/locations in the reference. It would have been obvious, however, to make the combination since all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See MPEP § 2143 (I)(A).
Regarding claims 15 and 34 reciting a diameter range of the non-active silica particles (i.e. ≤ 100 µm), the claimed ranges would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art (i.e. diameter between 50 to 1000 nm). Moreover, in any case, as noted by p. 9, line 32 – p. 10, line 1 of the instant Specification, silica sols contain solid silica particles with particle size of typically below 1 µm. Thus, it appears the solid silica particles within the silica sol of Niskanen would be reasonably expected to possess substantially the same particle sizes. As such, the claimed diameters of non-active silica particles (i.e. ≤ 100 µm) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art. See MPEP § 2144.05. Moreover, in any case, the selection of appropriate particle sizes within a silica sol would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed sizes. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claims 15, 17, and 34 reciting a solids content in the silica sol, as discussed above, Niskanen discloses wherein the silica sol has a solid content of < 5 wt. %. Accordingly, the claimed ranges (i.e. less than 3 weight-%, or 0.5 – 3 weight-%, respectively) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art (i.e. < 5 wt. %). 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). Moreover, in any case, the selection of appropriate solids content within a silica sol would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed amounts of solids content. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claims 15 and 26 reciting a diameter of solid particles comprising at least one API, as discussed above, Niskanen discloses silica particles containing an API having diameter of 1-300 µm. Accordingly, the claimed ranges (i.e. 1-300 µm, or 1-200 µm, respectively) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art. 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). Moreover, in any case, the selection of appropriate particle sizes within a silica hydrogel composite would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed sizes in µm. "[W]here 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." See MPEP § 2144.05(II)(A). Claim 34 is rejected based on the same reasons set forth above in rejecting claims 15 and 26.
Regarding claim 15 reciting amounts of non-active silica particles (i.e. up to 75 weight-%), it is noted such recitation does not actually require any amount of non-active silica particles. Regarding claims 25 and 34 reciting amounts of non-active silica particles (i.e. 20-75 weight-%), as discussed above, Niskanen discloses wherein the API may be contained in the hydrogel, in the silica microparticles, or both. Furthermore, Niskanen further discloses wherein the composite may have a solid content of 20-75 wt. % ([0058]). Thus, Niskanen discloses adjusting amounts of the API in the microparticles and the hydrogel to reach the disclosed solid content of the composite. As such, although Niskanen does not explicitly disclose an amount of silica particles, it would have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed ranges of silica particles through routine experimentation based on the general guidance of Niskanen. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claims 15 and 34 reciting wherein the solid particles comprising at least one API comprise at least 90 weight-% of the at least one API, or alternatively, regarding claims 35 and 36 reciting wherein the solid particles comprise at least 99 weight-% of the at least one API, although Niskanen does not explicitly disclose a content of API, Niskanen discloses spray-drying the particles such that that at least one molecule of API is confined within a supra molecule of a carrier, e.g., silica hydrogel and products of sol-gel processes (i.e. surrounded by). As noted by p. 20, ¶ 1 of the instant Specification, the solid particles of API become encapsulated between the silica particles (non-active silica particles and aggregated silica nanoparticles). Accordingly, as Niskanen discloses substantially the same encapsulation, it would appear to have taken no more than the relative skills of one of ordinary skill in the art to have adjusted the spray drying parameters and arrived at spray-dried particles of API that comprises at least 90 weight-%, or alternatively, at least 99 weight-%, of API, through routine experimentation based on the level of API desired in the particles. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claim 18 reciting a diameter range of the non-active silica particles (i.e. 1-100 µm), as noted by p. 9, line 32 – p. 10, line 1 of the instant Specification, silica sol contains solid silica particles with particle size of typically below 1 µm. Thus, it appears the silica sol of Niskanen would be reasonably expected to possess substantially the same particle sizes. As such, the claimed diameters of non-active silica particles (i.e. 1-100 µm) would have been obvious to one of ordinary skill in the art since they overlap with, or alternatively are close to, the ranges of the prior art. See MPEP § 2144.05.
Regarding claim 19, as discussed above, p. 9, line 32 – p. 10, line 1 of the instant Specification notes that typical particle sizes of a silica sol is below 1 µm. Thus, it appears the silica sol of Niskanen would be reasonably expected to possess substantially the same solid particle sizes. As such, the claimed ranges (i.e. ≤ 100 nm) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art. See MPEP § 2144.05(I). Moreover, in any case, the selection of appropriate diameters of silica sol particles would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed range in nm. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claim 20, Niskanen further discloses wherein the composite has a solid content of 20-75 wt. % ([0058]). Accordingly, the claimed ranges (i.e. 20 to 80 weight-%) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art. See MPEP § 2144.05(I). Moreover, in any case, the selection of appropriate solids content of a silica hydrogel composite would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed amounts of solids content. "[W]here 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." See MPEP § 2144.05(II)(A).
Regarding claim 22, Niskanen further discloses wherein the silica sol is made from tetraethyl orthosilicate (TEOS) ([0042], [0090]). As noted by page 19, lines 20-21 of the instant Specification, tetraethoxysilane-derived silica is an alkoxysilane-derived silica. Thus, the TEOS of Niskanen meets the limitation of alkoxysilane-derived silica as claimed.
Regarding claim 23, Niskanen further discloses wherein the particles of the composite body may be spray dried particles, fiber fragments and molded or casted monoliths as such or as crushed ([0047]). Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the particles of the composite body, including those from the silica sol, in an instantly claimed form since these are known and effective forms suitable for particles of silica in a composite body as taught by Niskanen.
Regarding claim 31, as discussed above, Niskanen discloses wherein the depot may be administered to a patient as an injectable formula.
Regarding claim 33, Niskanen further discloses wherein an exemplary API includes meloxicam, which is practically insoluble in water ([0046]).
Regarding claim 37, as discussed above, Niskanen discloses wherein the silica composite comprises up to 85 wt. % of the silica particles, wherein at least a portion of API is encapsulated within the hydrogel, and a portion is encapsulated in the silica microparticles. Accordingly, Niskanen teaches or at least suggests active silica particles comprising at least one active pharmaceutical ingredient that is the same as the active pharmaceutical ingredient of the solid particles. Regarding the claim reciting the active silica particles comprising an amount of API, although Niskanen does not explicitly disclose an amount of API, it would appear to have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed range (i.e. 0.1-70 weight-%) through routine experimentation based on the level of active suitable for the release times and release profiles desired. "[W]here 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." See MPEP § 2144.05(II)(A). Regarding the claim reciting a combined amount of non-active silica particles and active silica particles, as discussed above, Niskanen discloses wherein the silica hydrogel composite comprises up to 85 wt. % silica particles. Accordingly, it would have been obvious to one of ordinary skill in the art to have selected an amount of non-active silica particles and an amount of active silica particles, such that the total amount is within the disclosed range of up to 85 wt. %. Such amounts selected would appear to equate to a total amount that overlaps the claimed range (i.e. up to 75 wt. %), thus making the claimed range obvious. See MPEP § 2144.05(I). Moreover, in any case, the selection of appropriate weight percentages of silica particles appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed weight percentages. "[W]here 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." See MPEP § 2144.05(II)(A).
Response to Arguments
Applicant mainly asserts that Niskanen fails to teach or suggest solid particles comprising at least one active pharmaceutical ingredient (API) having a diameter of 1-300 µm, wherein the solid particles comprise at least 90 weight-% API. The closest disclosure in Niskanen indicates that the particles of the composite body comprise 0.1 to 80 weight-% encapsulated active pharmaceutical ingredient ([0040]). Thus, even in its most API-rich embodiment, Niskanen teaches composite particles in which a substantial fraction (20 weight-%) of the particle is constituted by non-API components, in particular silica. Further, Niskanen discloses that the NSAID is dissolved in an alkali solution and subsequently combined with a silica sol prior to spray drying for the production of NSAID-silica microparticles ([0042]). Niskanen further discloses that the resulting composite particles have a diameter of 50 nm to 300 µm ([0055-0056]). However, this disclosure relates to the composite microparticles as a whole and does not describe or suggest the presence of separate solid API particles having a defined particle size range and comprising at least 90 weight-% API. Accordingly, even though Niskanen discloses spray-dried microparticles within the recited size range, it does not disclose or suggest the claimed solid API particles, nor does it disclose particles meeting the required API purity within the solid particle phase. It is also believed that there would be no motivation for a person of ordinary skill in the art to modify Niskanen such that the particles of the composite body would comprise at least 90 weight-% encapsulated API. Niskanen
The Examiner appreciates Applicant’s clarifying comments and explanation about the formation of the aggregate particles. Unfortunately, Examiner does not find Applicant’s assertions to be persuasive. The embodiment asserted in the Remarks does not appear to be consistent with the claims’ language and the teachings of the Specification. It should be noted the instant claims are directed to a final product (i.e. silica hydrogel composite), and not initial ingredients to form the hydrogel. For example, regarding the term “formed from” in claim 1, it appears p. 20, ¶ 1 of the instant Specification speaks to such embodiment, specifically teaching wherein:
“the silica hydrogel composite is formed at least by i) aggregated silica sol nanoparticles in silica sol (which also comprises the aqueous solution), ii) non-active silica particles, and iii) solid particles of active pharmaceutical ingredients, wherein the solid particles of active pharmaceutical ingredient become encapsulated between the silica particles (non-active silica particles and aggregated silica nanoparticles) and the aqueous solution is homogeneously distributed throughout the whole mass of the hydrogel composite.”
In comparison, instant claim 1 as amended requires only silica particles having a diameter of less or equal to 100 µm. It is not clear to the Examiner how such range differentiates such silica particles from the particles of the silica sol, as “less or equal to 100 µm” would encompass particles having a diameter in nanometer ranges. As such, it would appear to have taken no more than the relative skills of one of ordinary skill in the art to have adjusted, for example, the spray drying conditions of Jus, to obtain solid particles of at least one active that is surrounded by (i.e. encapsulated between) silica particles, where Niskanen discloses the composite particles, comprising the at least one active and silica particles, may have a diameter of between 1 and 300 µm ([0055]), and the silica particles have a diameter of, for example, between 50 and 1000 nm ([0056]).
In addition, it is noted that instant claims 15 and 34 do not actually require any solids content in the silica sol since less than 3 weight-% would encompass 0 weight-%, and it is unclear to the Examiner how the claimed invention is achieved without some solids content in the silica sol.
Moreover, instant claim 15 does not actually require any non-active silica particles, since up to 75 weight-% of non-active silica particles would encompass 0 weight-%.
As such, claim 15 as amended speaks to an embodiment wherein the silica hydrogel composite is formed from a mixture comprising: any amounts, including 0 weight-%, of silica particles having any diameter ≤ 100 µm; a silica sol having any solids content less than 3 weight-% in any diameter range; and solid particles having a diameter of 1-300 µm and comprising at least 90 weight-% of at least one API.
Claim 34 as amended speaks to an embodiment wherein the silica hydrogel composite is formed from a mixture comprising: 20-75 weight-% of silica particles having any diameter ≤ 100 µm; a silica sol having any solids content less than 3 weight-% in any diameter; and solid particles having any diameter ≤ 300 µm and comprising at least 90 weight-% of at least one API.
It is noted that neither embodiments appear to be reasonably representative of the embodiment that appears to be preferred in the Specification. As such, it is unclear to the Examiner which claim scope is sought by the Applicant. Further directions are kindly requested.
Regarding Applicant’s assertion that Niskanen does not teach wherein the solid particles comprise at least 90 weight-% of the at least one API, the Examiner respectfully disagrees. As discussed above, Niskanen teaches wherein the composite particles (i.e. aggregated particles comprising at least one active and silica particles) comprise up to 80 weight-% of the at least one active. Therefore, Niskanen does not disclose wherein the particles of the at least one active itself is limited to 80 weight-%, rather that the composite particles may comprise up to 80 weight-% of API. As such, it would appear to have taken no more than the relative skills of one of ordinary skill in the art to have adjusted, for example, the spray drying conditions of Jus, to obtain particles of the at least one active, that comprises at least 90 weight-% of the at least one API.
It is further noted that pp. 10-11 of the instant Specification notes that micronization is understood to be any method used to produce small solid particles, e.g., solid particles of active pharmaceutical ingredients, and includes wherein the solid particles are produced by spray-drying or by any dissolution-precipitation/crystallization cycle. Accordingly, it would reasonably appear that spray-dried particles are capable of having the instantly claimed particle size ranges. As such, Applicant’s assertions regarding spray dried particle sizes are unpersuasive.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Niskanen et al. (US 2018/0311165 A1, 11/01/2018, IDS reference) (hereinafter Niskanen) in view of Gisslinger et al. (“A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia – the TEAM-ET 2.0 trial”, 03/28/2019) (hereinafter Gisslinger).
The disclosure of Niskanen has been discussed in detail above and differs from the instant claim insofar as not disclosing wherein the active is anagrelide.
However, Gisslinger discloses wherein the use of a prolonged-release formulation of anagrelide improves tolerability without reducing its efficacy (p.698, right col., lines 8-10).
Niskanen discloses a depot suitable for sustained-release drug delivery. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the depot of Niskanen with another active such as anagrelide, since it is a known active that benefits from prolonged-release formulation as taught by Gisslinger.
Response to Arguments
Applicant does not present specific arguments with regard to Niskanen and Gisslinger.
Since the Examiner has discussed Niskanen above, this rejection is maintained.
Examiner’s Note
The Examiner notes the Specification appears to support an embodiment where the silica hydrogel composite comprises: (i) silica sol, comprising: aggregated silica sol nanoparticles and an aqueous solution, wherein the silica sol has a solids content of 0.5 – 3 weight-%, and wherein the silica sol nanoparticles have a diameter of 5 – 100 nm; (ii) non-active silica particles comprising less than 0.1 weight-% active pharmaceutical ingredient (API), wherein the non-active silica particles have a diameter of 1 – 100 µm; and (iii) solid particles comprising at least 90 weight-% of API, wherein the solid particles have a diameter of 1 – 200 µm, wherein the solid particles are encapsulated between a combination of the non-active silica particles and the aggregated silica sol nanoparticles and the aqueous solution is homogeneous distributed throughout the silica hydrogel composite, and wherein the API comprises anagrelide HCl.
It is not yet clear to the Examiner of the demonstrated quantities of: the total amount in % of solid particles in the silica hydrogel composite; the individual amounts of (i), (ii), and (iii) and the significance of such amounts contributing to the formation of the silica hydrogel composite (for example, Example 1 notes specifically that 920 mg of micronized API and 6780 mg of non-active silica particles were suspended in 12.6 ml of R300 silica sol followed by 6.1ml of pH adjuster to a final pH of 5.8). It is similarly not yet clear to the Examiner whether the pH plays a role in the integrity of the silica hydrogel composite, which appears to contribute to its capability as a sustained and/or controlled release formulation.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Leino et al, (US 2018/0311150 A1, 11/01/2018, IDS reference), drawn to a depot formulation comprising a biodegradable silica hydrogel composite incorporating an active pharmaceutical ingredient.
Jokinen et al, (US 2010/0119500 A1, 05/13/2010, IDS reference), drawn to a shear thinning injectable silica composition comprising silica prepared by sol-gel process with a functional agent incorporated into the material.
Jokinen et al. (US 2016/0136088 A1, 05/19/2016), drawn to a silica hydrogel composite obtained by mixing silica particles having a diameter of ≤ 1000 µm and a silica sol with a solid content of ≤ 5 wt. %, said silica hydrogel composite comprises up to 85 wt. % of said silica particles and is shear thinning.
Conclusion
THIS ACTION IS MADE FINAL. 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 LUCY TIEN whose telephone number is (571)272-8267. The examiner can normally be reached Monday - Thursday 8:30 AM - 6:30 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SAHANA KAUP can be reached at (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUCY M TIEN/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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