DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/08/2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/30/2026 has been considered by the examiner.
Status of the Claims
The response filed 05/08/2026 is acknowledged.
Claims 1-2, 4-6, 8-17, 19-21, and 23-26 are pending.
Applicant’s election of Group I, claims 1-8, in the reply filed on 07/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 9-17 and 19-26 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/29/2025.
Claims 1-2, 4-6, and 8 are treated on the merits in this action.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Withdrawn
The rejection of claims 4-5 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends has been withdrawn due to amendment.
Response to Arguments
Applicant's arguments filed 05/08/2026 have been fully considered but they are not persuasive.
Applicant argues Codina teaches away from the claims as provided herein and does not remedy this deficiency of Kangas. Applicant argues Codina explicitly states that "it is recommended to use crystalline paclitaxel with a small crystal size because this can minimize the risk of losses. Preferably the crystal size is [in] the range of nanometers." (Emphasis added) See lines 30-32 on page 8 of Codina. Applicant argues one skilled in the art reading Codina understands that markedly smaller crystal sizes (nanometers) are superior to larger crystal sizes of 1 µm and 10 µm as recited in the amended claims of the present application.
This argument is unpersuasive.
There is nothing in Codina which specifically disparages particle sizes of 1 µm or greater or 10 µm or greater, e.g., examples showing sizes in the claimed range resulted in such low adhesion that no crystals were present after navigating to a target tissue site. Codina actually teaches the particles should be small, and offers a preference for crystal sizes in the range of nanometers. However, preferred embodiments do not constitute a teaching away from Codina’s broader teaching of small particle sizes. See MPEP 2123, II. Further, Kangas clearly teaches the seed nucleating microcrystals my range up to about 20 µm (Kangas, e.g., 0053). The skilled artisan would have understood Kangas, e.g., ¶ 0053, as teaching a broader range of nucleating particle sizes which may be present in a suspension for coating the device surface with a microcrystalline drug. Since Kangas expressly teaches applying a crystalline drug having a particle size of about 10 µm or less or about 20 µm or less to the outer surface of a device (Kangas, e.g., 0011 and 0053), and wherein the device is a balloon (Kangas, e.g., 0028), any fears the skilled artisan, reading Codina, may have harbored about drug particle sizes larger than nanometer size are explicitly resolved by the teachings of Kangas.
The claimed particle size range of having a crystal size of at least 1 µm and wherein at least 90% of the at least one taxane active agent is in the form of microcrystals having a crystal size of 10 µm are clearly within and overlapping with the range of 10 µm or less or 20 µm or less suggested by Kangas. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
It is additionally noted that the same paragraph in Codina goes on to explain the benefits of crystalline taxanes, including the fact that the crystalline forms offer high transfer to tissue, excellent drug retention in tissue, a means to achieve an extended effect, and offers high biological effectiveness with less probable restenosis (Codina, e.g., 0026). Thus, Codina suggests there are benefits to be derived from crystalline drug in a coating on a medical device which is applied in combination with a triacylglycerol within the scope of the claimed invention, e.g., trioctanoylglycerol, aka, tricaprylin (Codina, e.g., 0053).
Applicant argues Codina provides that the preferable amorphous/crystalline paclitaxel ratio in weight is 10/90 to 50/50 so that it achieves the synergistic effect of the immediate effect of amorphous paclitaxel and long-lasting effects of crystalline paclitaxel. See lines 17-28 on page 9 of Codina. Applicant argues that based on this disclosure of Codina, one skilled in the art is taught away from having a high concentration of crystalline drug, such as at "wherein the at least one tri-O-acylglycerol and the at least one limus active agent are present in a mass ratio of 10% - 30% tri-O-acylglycerol to 90% - 70% limus active agent", because the aforementioned synergistic effect would not be achieved due to the too high concentration of crystalline drug.
This argument is unpersuasive.
It is not clear what relevance the amorphous/crystalline ratio of the drug in Codina’s coating has to the percent of microcrystals having a size of at least 10 µm in the coating suspension, particularly since Kangas teaches crystalline drug is applied from a suspension distinct from the amorphous drug coating composition. The crystal size is not a measure of the amount of drug in the coating suspension which is crystalline.
With respect to the limitation of wherein the at least one tri-O-acylglycerol and the at least one limus active agent are present in a mass ratio of 10% - 30% tri-O-acylglycerol to 90% - 70% limus active agent, it is noted that Codina teaches a drug to trioctanoylglycerol, aka, tricaprylin ratio of 75/25 to 85/15, preferably 80/20 to balance coating integrity and losses during navigation with optimal drug concentration and transfer to the tissue to be treated. (Codina, e.g., 0023). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
Applicant argues Kangas teaches away from the amended claims as provided herewith, in particular wherein at least 90% of the at least one limus agent is in the form of microcrystals having a crystal size of at least 10 µm. Applicant argues in paragraph [0011] of Kangas, the maximum particle size of the crystalline form of the drug in Kangas' seed layer is about 10 µm or less. Applicant argues in paragraph [0055] of Kangas, the microparticulate drug crystals have a mean particle size of less than 10 µm. Applicant argues the examples of Kangas use seed crystals that are -1 µm ("Average particle size is about 1 pm"). See Example 1 of paragraph [0081]. Applicant argues the SEM images and examples of Kangas show that the crystals are less than 10 µm. Applicant argues one skilled in the art reading Kangas as a whole, including paragraphs [0011] and [0055] and the examples, understands that crystal sizes of the drug of less than 10 µm are highly preferred and are what was prepared.
This argument is unpersuasive.
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. Kangas clearly teaches the seed nucleating microcrystals my range up to about 20 µm (Kangas, e.g., 0053). The skilled artisan would have understood Kangas, e.g., ¶ 0053, as teaching a broader range of nucleating particle sizes which may be present in a suspension for coating the device surface with a seed microcrystalline layer.
Based on Applicant’s remarks, it appears there is agreement that Kangas teaches applying microcrystals with a particle size of 10 µm or less. This teaching would have led the skilled artisan to modify Codina’s compositions comprising paclitaxel and trioctanoylglycerol (Codina, e.g., 0053) for coating a device with small crystals of paclitaxel on the surface (Codina, e.g., 0026), by preparing a suspension of paclitaxel microcrystals having a particle size of 10 µm or less and trioctanoylglycerol. Further, Kangas suggests particle size may vary and the size of the particle is a result effective parameter the skilled artisan would have optimized to retain the particles on the device surface (Kangas, e.g., 0070 too large size makes it easy to dislodge).
The claimed particle size range of at least 1 µm and wherein at least 90% of the at least one taxane is in the form of microcrystals having a crystal size of at least 10 µm is clearly within and overlapping with the range of about 10 µm or less or about 20 µm or less suggested by Kangas. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
To the extent that Applicant is arguing Kangas is not enabled to prepare a suspension having particle sizes of paclitaxel in the claimed range, it is noted that the claimed range is explicitly within and overlapping with a particle size of about 10 µm or less suggested by Kangas (Kangas, e.g., 0011), and Kangas clearly teaches known techniques for optimizing particle sizes over the range of from about 20 µm to about 10 nm as desired (Kangas, 0055-0058).
Additionally, it is noted that Kangas, e.g., Fig. 2, teaches devices comprising a surface having a drug particle size, e.g., length, within which the claimed range resides. See Kangas, e.g., 0032, teaching crystals having a length of about 5-10 µm on the device.
Applicant has argued a prima facie case of obviousness can be rebutted by showing that a range is critical. See MPEP #2144.05(III)(A). Applicant argues that as provided by the present application, the size of the microcrystals of the at least one taxane active agent is critical. Applicant argues the crystals of the taxane active agent should have a size of at least 1 µm. Applicant argues that in preparing the suspension of the present invention, it has been found that stable suspensions can be obtained only when the at least one taxane active agent has substantially no crystals with a crystal size of less than 1 µm. Applicant argues the specific recited tri-O-acylglycerols enabled the formation of stable suspensions of microcrystalline taxane active agents (as demonstrated by the examples in the present application) with the microcrystalline taxane active agent that has at least 1 µm and wherein at least 90% of the at least one taxane active agent has microcrystalline taxane active agent of at least 10 µm. Applicant has argued that as provided in the present application, a problem with crystalline taxane active agents is that "suspensions of particles larger than 1 - 5 µm tend to sediment rapidly, which subsequently makes uniform coating with microcrystalline taxane active agent from suspensions much more difficult." Applicant argues that unexpectedly, the claimed suspensions with the recited specific tri-O-acylglycerols and crystalline sizes of the at least one taxane active agent ("at least one taxane active agent in the form of microcrystals having a size of at least 1 µm " and "wherein at least 90% of the at least one taxane active agent is in the form of microcrystals having a crystal size of at least 10 µm " (Emphasis added)) exhibited no sedimentation of the microcrystals, even over extended periods (>100 hours), no dissolution of the microcrystals, uniform distribution of the microcrystals in the suspension ("floating" behavior), and preservation of original crystal morphology and size distribution. Applicant argues the experimental data in the examples of the present application clearly demonstrate that other tri-O-acylglycerols, such as those with shorter or longer chain lengths, failed to provide stable suspensions, and even minor structural variations resulted in either dissolution or sedimentation of the taxane active agent microcrystals. Applicant argues that Table 9, Examples 2 and 3, triacetin (Example 2), trihexanoylglycerol (Example 2), triheptanoylglycerol (Example 3), tridodecanoylglycerol (Example 2) and tritetradecanoylglycerol (Example 2) resulted in dissolution and/or led to sedimentation and instability.
This argument is unpersuasive.
Codina teaches excipients having formula 1 (Codina, e.g., claim 1) such as trioctanoylglycerol, aka, tricaprylin (Codina, e.g., 0053) offer uniform coatings of crystalline paclitaxel on devices (Codina, e.g., 0027) with excellent adhesion such that losses during navigation are very low (Codina, e.g., 0042). Thus, there was clear motivation to select the recited trioctanoylglycerol as the adhesion coating excipient.
The claimed invention does not require that the suspension contains no crystals with a size of less than 1 µm in the suspension. It is noted that that the suspension requires at least one taxane active agent in the form of microcrystals having a crystal size of at least 1 µm. However, the claim does not exclude additional actives or additional particle populations having a size of less than 1 micron.
In response to Applicant’s argument that one skilled in the art understands from the present application, that if the crystal size is less than 1 µm, the taxane active agent dissolves too quickly and the suspension is unstable: it is noted that while this may have been shown in the examples for suspensions containing paclitaxel, specific amount of a particular tri-O-acylglycerol, and a specific volume of a particular solvent combination, i.e., 100 mL of solvent containing 1.56 mL ethyl acetate and 84.4 mL heptane (Spec, example 2, and example 3), the claims are not limited to these specific compositions containing particular amounts of specific taxane actives and amounts, tri-O-acylglycerol amounts, and solvent combination and volume.
More importantly, it is unclear where the particle sizes of the exemplified suspensions are disclosed. Therefore, the criticality of the particle size cannot be compared with the claimed invention to determine if the proffered data is commensurate in scope.
There is insufficient data to establish criticality over the full scope of suspension compositions reading on, e.g., any taxane active in any amount, particle size range including an unbound upper limit on particle size, and variable solvent systems encompassed by the invention as presently claimed. Regarding solvents, for example, since heptane is a non-solvent (Spec., e.g., pg. 35:11-21), the skilled artisan would expect less solubility of 1 µm sized crystals if the solvent system contains a different solvent system, e.g., more heptane, e.g., 100% heptane or a greater volume of heptane.
Objective evidence of unexpected results must be commensurate in scope with the claimed invention. See MPEP 716.02(d). As explained above, the proffered evidence in Examples 2 and 3 showing suspension stability over 100 hours has been shown for suspensions containing paclitaxel in specific amounts (1% and 3%), specific amount of a particular tri-O-acylglycerol, and a specific volume of a particular solvent combination, i.e., 100 mL of solvent containing 1.56 mL ethyl acetate and 84.4 mL heptane (Spec, example 2, and example 3). The claimed invention reads on any taxane active or combination thereof in any amount, trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, or triundecanoylglycerol in any amount, a broad particle size range including an unbound upper limit on particle size, and variable solvent systems which deviate significantly from the proffered evidence shown. The data does not support the size ranges encompassed by claim 1, or the ranges recited in claim 4 or 5 in combination with the limited requirements of claim 1. It is unclear what the particle size distribution is in the disclosed test suspensions, therefore the criticality of the particle size cannot be assessed even if the claimed composition was commensurate in scope with the proffered evidence. Since even minor structural variations may result in either dissolution or sedimentation (Remarks, e.g., pg. 10), the evidence of record cannot be extrapolated over the full scope of the claimed invention.
Rejections Addressing Applicant’s Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-6 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 includes the limitation of at least one taxane active agent in the form of microcrystals having a crystal size of at least 1 µm, and wherein at least 90% of the at least one taxane active agent is in the form of microcrystals having a crystal size of at least 10 µm.
It is not clear if the combination of limitations was intended to require two distinct microcrystal particle populations or if the combination of limitations was intended to require a single microcrystal particle population with two size requirements. In each case “the at least one taxane active agent” would be interpreted to mean the taxane active agent is the same.
In the former case the claim would require two separate microcrystal particle size populations of the same taxane active agent and the particle size limitations define two distinct particle populations which differ by size, i.e., one particle population at least 1 µm in size and the second particle population defined by at least 90% being a size of at least 10 µm.
In the latter case the claim would require a single microcrystal particle population of the same taxane active agent and the microcrystal particle size limitations would refer to the same microcrystal particle population, e.g., a lower bound of 1 µm and at least 90% of the microcrystals having a size of at least 10 µm.
It is important that a person of ordinary skill in the art be able to interpret the metes and bounds of the claims so as to understand how to avoid infringement of the patent that ultimately issues from the application being examined. See 2173.02, II.
Dependent claims do not clarify this issue.
Claims 4 and 5 do not indicate which microcrystal size range of claim 1 is intended to be further limited and may refer to separate particle populations, e.g., claim 4 applies to the population having a size of at least 1µm, while claim 5 refers to the particle size population having a size of at least 10 µm.
Clarification is required.
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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Codina, WO 2016015874 A1 and Kangas, US 20150250772 (cited previously).
Codina teaches a composition for coating a medical device comprising paclitaxel and a lipophilic excipient, e.g., caprylic acid triglyceride, i.e., trioctanoylglycerol (Codina, e.g., claim 6). Codina teaches the composition further comprising a solvent (Codina, e.g., claim 15). Codina teaches the form of the taxane may be crystalline and the form of the taxane may be controlled by selection of the solvent used in the preparation of the formulation for coating (Codina, e.g., 0024). Crystalline form of the taxane is desired for sustained dosing and longer effect to achieve better therapeutic results with less probable restenosis (Codina, e.g., 0026). Codina teaches the taxane having a small crystal size, e.g., in the range of nanometers (Codina, e.g., 0026).
Codina does not expressly teach a composition for coating the medical device containing a solvent in which the crystals of the taxane do not dissolve. Thus, Codina does not expressly teach the composition in the form of a suspension.
However, Kangas teaches microparticulate crystalline drug may be applied to medical devices as a coating when the coating formulation contains microcrystalline drug in a suspension (Kangas, e.g., 0052). Selecting excipients in which the drug is substantially undissolved enables the drug to be applied while remaining in the crystalline form (Kangas, e.g., 0043). Applying the drug in microcrystalline form in a suspension may be done to form coatings on the device with drug in crystalline form (Kangas, e.g., 0050-0055).
Like Codina, Kangas teaches coatings on medical devices containing paclitaxel in crystalline form facilitates longer tissue drug residence times (Kangas, e.g., 0028).
Kangas teaches non-polymeric excipients, such as oils (triglycerides) may be included in the coating to facilitate adhesion of the drug to the device (Kangas, e.g., 0040-0043). This teaching is congruent with Codina teaching the lipophilic excipient, e.g., caprylic acid triglyceride, i.e., trioctanoylglycerol (Codina, e.g., claim 6) is effective to retain crystalline paclitaxel on the device while also promoting paclitaxel transfer to tissue at the treatment site (Codina, e.g., 0030-0035).
Kangas clearly teaches the coating formulation may be in the form of a microcrystalline drug suspension (Kangas, e.g., 0052) which contains a vehicle in which the microcrystalline drug does not dissolve (Kangas, e.g., 0056: non-solvent for the drug such as water or heptane). Crystallization inducing solvents are listed in Kangas, e.g., 0065. Kangas exemplifies the choice of coating formulation non-solvent may be the same non-solvent used during crystallization and crystal sizing through grinding (Kangas, e.g., 0081-0083).
Kangas teaches applying drugs to the stent using a formulation in which the drug is dissolved may be undesirable because it results in uncontrolled crystal morphology, poor control over drug crystal location on the surface of the device, and poor adherence to the device surface (Kangas, e.g., 0070).
Thus, Kangas provides motivation for the skilled artisan to have modified coating formulations containing paclitaxel and a lipophilic excipient, e.g., caprylic acid triglyceride, i.e., trioctanoylglycerol as known from Codina by using a non-solvent for paclitaxel for a number of benefits including increased control over crystalline paclitaxel form and particle size, improved control over the location of crystalline drug on the device surface, and improved adherence of the crystalline drug particles to the device surface.
Regarding the limitation of microcrystals having a size of at least 1 µm and wherein at least 90% of the at least one limus active agent is in the form of microcrystals having a crystal size of at least 10 µm:
Kangas teaches applying microcrystals with a particle size of 10 µm or less or 20 µm or less (Kangas, e.g., 0053). This teaching would have led the skilled artisan to modify Codina’s compositions comprising paclitaxel and trioctanoylglycerol (Codina, e.g., 0053) for coating a device with small crystals of paclitaxel on the surface (Codina, e.g., 0026), by preparing a suspension of paclitaxel microcrystals having a particle size of 10 µm or less or 20 µm or less and trioctanoylglycerol. Further, Kangas suggests particle size may vary and the size of the particle is a result effective parameter the skilled artisan would have optimized to retain the particles on the device surface and obtain a uniform coating (Kangas, e.g., 0070 too large size makes it easy to dislodge).
The claimed particle size range of microcrystals having a size of at least 1 µm and wherein at least 90% of the at least one taxane is in the form of microcrystals having a crystal size of at least 10 µm is clearly within and overlapping with the range of 10 µm or less or 20 µm or less suggested by Kangas. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05.
Regarding the limitation of wherein the at least one tri-O-acylglycerol and the at least one limus active agent are present in a mass ratio of 10% - 30% tri-O-acylglycerol to 90% - 70% limus active agent: Codina teaches a coating formulation having mass ratio of 20 tricaprylin to 80 drug (Codina, e.g., 0053 and 0023). This is an example in the claimed ranges. The skilled artisan would have been motivated to start optimization using these amounts since Codina exemplifies these amounts as effective to achieve the reported improvements of drug adhesion and surface retention.
Regarding the limitation of wherein the solvent is a non-solvent having a dielectric constant er at 20°C of < 2.0 or the solvent mixture contains at least 50% by volume of a non-solvent having a dielectric constant er at 20°C of < 2.0: Kangas clearly names heptane as a non-solvent so that the drug is substantially undissolved (Kangas, e.g., 0056-0057). Heptane has properties consistent with those claimed as evidenced by the specification, e.g., pp. 44-45 table 2. This clear teaching in Kangas would have prompted the skilled artisan to use heptane as a non-solvent vehicle to modify coating formulations suggested by Codina as a suspension for the benefits reported in Kangas.
As evidenced by the specification, trioctanoylglycerol is soluble in heptane (Spec, e.g., pg. 42:15-19).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention to modify compositions comprising a taxane and caprylic acid triglyceride by formulating the coating as a suspension containing a solvent system in which the drug does not dissolve and having a crystal size of about 10 µm or less or about 20 µm or less so that the drug remains in desired crystalline form as suggested by Kangas with a reasonable expectation of success. The skilled artisan would have seen this modification as the use of known solvent selection techniques to improve Codina’s coating compositions in the same way. The skilled artisan would have been motivated to formulate Codina’s taxane coating compositions in the form of a suspension using a solvent in which taxane microcrystals having a crystal size of about 10 µm or less or about 20 µm or less do not dissolve as suggested by Kangas to produce a coating containing crystalline forms of taxane thereby achieving the sustained dosing and longer taxane effect to achieve better therapeutic results with less probable restenosis desired by Codina while also enjoying a number of benefits including increased control over crystalline paclitaxel form and particle size, improved control over the location of crystalline drug on the device surface, and improved adherence of the crystalline drug particles to the device surface.
The skilled artisan would have had a reasonable expectation of success because Kanga expressly teaches suspensions of microcrystalline drug may be formulated with non-solvents for the drug to enable drug coatings containing crystalline drug forms having improved properties.
Applicable to claim 2: Codina teaches paclitaxel (Codina, entire document, e.g., 0053 and claims).
Applicable to claim 3: Codina teaches a coating formulation having mass ratio of 20 tricaprylin to 80 paclitaxel (Codina, e.g., 0053). This is an example in the claimed ranges.
Applicable to claims 4-5: Kangas teaches micron sized drug crystals (Kangas, e.g., 0051-0052), e.g., having a size in the claimed ranges, e.g., preferably having a mean particle size of less than 20 microns, e.g., less than about 10 microns (Kangas, e.g., 0053-0055). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05. Further particle size may vary and the size of the particle is a result effective parameter the skilled artisan would have optimized to retain the particles on the device surface (Kangas, e.g., 0070 too large size makes it easy to dislodge).
Applicable to claim 6: Kangas teaches wherein the drug has a crystallinity in the claimed range, e.g., about 100% (Kangas, e.g., 0073 and 0077). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Claim 8 is included in this rejection as further limiting an optional solvent mixture limitation of claim 1.
Accordingly, the subject matter of claims 1-2, 4-6, and 8 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claim(s) 1-2, 4-6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Codina, WO 2016015874 A1 and Kangas, US 20150250772 (cited previously) as applied to claims 1-2, 4-6, and 8 above, and further in view of Bui-Khac, US 5759539.
The combined teachings of Codina and Kangas teach a suspension according to claim 1 as enumerated above. The combined teachings of Codina and Kangas do not expressly teach the paclitaxel suspension having a solvent mixture of at least one polar organic solvent and at least one nonpolar organic solvent as set forth in claim 8. To the extent that claim 8 is limiting, solvent mixtures having the characteristics set forth in claim 8 were known and used to induce crystallization of paclitaxel and were known for maintaining desired crystalline nature of paclitaxel in suspension as evidenced by the teachings of Bui-Khac.
For example, Bui-Khac teaches the solvent mixture of ethyl acetate and hexane was known to induce crystallization of paclitaxel and allow manipulation of the crystalline suspension, e.g., filtration (Bui-Khac, e.g., c8:5-32).
Kangas teaches vehicle which may be effective to induce crystallization of the drug includes similar mixed solvents such as heptane/ethyl acetate (Kangas, e.g., 0065).
It would have been obvious before the effective filing date of the presently claimed invention to modify compositions for coating comprising a taxane and caprylic acid triglyceride by formulating the coating composition as a suspension containing a solvent system in which the taxane does not dissolve so that the drug remains in desired crystalline form as suggested by Kangas with a reasonable expectation of success. The skilled artisan would have seen this modification as the use of known solvent selection techniques to improve Codina’s coating compositions in the same way. The skilled artisan would have been motivated to formulate Codina’s taxane coating compositions in the form of a suspension using a solvent in which taxane microcrystals do not dissolve as suggested by Kangas to produce a coating containing crystalline forms of taxane thereby achieving the sustained dosing and longer taxane effect to achieve better therapeutic results with less probable restenosis desired by Codina while also enjoying a number of benefits including increased control over crystalline paclitaxel form and particle size, improved control over the location of crystalline drug on the device surface, and improved adherence of the crystalline drug particles to the device surface. The skilled artisan would have been motivated to formulate the taxane microcrystal coating suspension suggested by the combined teachings of Codina and Kangas using known solvent systems effective to induce and maintain crystallization of paclitaxel such as ethyl acetate and hexane as reported by Bui-Khac to maintain the paclitaxel crystalline form and particle size as recommended by Kangas. The skilled artisan would have had a reasonable expectation of success because Kangas suggests similar solvents and solvent mixtures, e.g., heptane and ethyl acetate as effective to suspend the drug.
Accordingly, the subject matter of claims 1-2, 4-6, and 8 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-6, and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, and 8 of U.S. Ap. No. 18036664 in view of Kangas, US 20150250772.
The claims in this case and the copending case have been amended to recite substantially similar suspension formulations which differ only by the active agent. The particle size ranges, solvent, and tri-O-acylglycerol identity and ratio with the active are now the same.
The claims of the reference application teach a suspension for coating of a medical device selected from a catheter balloon, a balloon catheter, a stent, or a cannula, the suspension containing: a) at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, and triundecanoylglycerol, b) at least one limus active agent in the form of microcrystals having a crystal size of at least 1 µm, and c) a solvent or a solvent mixture in which the at least one tri-O-acylglycerol dissolves and in which the microcrystals of the at least one limus active agent do not dissolve, wherein at least 90% of the at least one limus active agent is in the form of microcrystals having a crystal size of at least 10 µm; wherein the at least one tri-O-acylglycerol and the at least one limus active agent are present in a mass ratio of 10% - 30% tri-O-acylglycerol to 90% - 70% limus active agent; wherein the solvent is a non-solvent having a dielectric constant er at 20°C of < 2.0 or the solvent mixture contains at least 50% by volume of a non-solvent having a dielectric constant er at 20°C of < 2.0.
The difference between the reference claims (limus) and the present claims (taxane) is the active agent.
Kangas teaches paclitaxel and analogs thereof (taxane) and rapamycin and analogs thereof (limus) were both known water soluble drugs used for inhibiting restenosis when delivered from a medical device surface (Kangas, e.g., 0028-0035).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention to modify coating suspensions of the reference claims by including a taxane with a reasonable expectation of success. The skilled artisan may have seen this as a substitution of one known anti-restenosis drug for another to predictably arrive at a suspension of crystalline drug useful for coating medical devices effective to inhibit restenosis. Alternatively, the skilled artisan may have seen this modification as a combination of two known drugs useful for the same purpose to predictably arrive at a suspension of crystalline drug useful for coating medical devices effective to inhibit restenosis. See MPEP 2144.06. The results would have been predictable since Kangas suggests both drugs were known to form crystalline forms and were known for delivery from medical device surfaces as inhibitors of restenosis.
Accordingly, the subject matter of claims 1-2, 4-6, and 8 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A WAX can be reached on 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
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