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 .
Receipt is acknowledged of Amendments and Remarks filed on 07/31/26 and an IDS filed on 08/21/26. Claims 4 and 22-23 have been amended, new claim 24 has been added and no claims have been cancelled. Accordingly, claims 1, 3-4 and 22-24 are under examination on the merits. Claims 5-6, 8-9, 11-13 and 15-20 remain withdrawn.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Priority
This application, 17158997, filed 01/26/2021 is a continuation of 16601440, filed 10/14/2019 and having 1 RCE-type filing therein; 16601440 is a continuation of 15418388, filed 01/27/2017, now abandoned 15418388 Claims Priority from Provisional Application 62289095, filed 01/29/2016.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
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.
Applicant’s claims:
Claim 1 is directed to an inhalable spray-dried dry powder composition comprising porous microcrystalline particles of fumaryl diketopiperazine and treprostinil, wherein the microcrystalline particles of fumaryl diketopiperazine have a specific trans isomer content of about 45% to 63% and a water content of about 0.4%, and wherein the treprostinil content is about 20% (w/w) of the particles, and wherein the composition is provided in a single-dose disposable inhaler cartridge or capsule in a dose of about 1 mg to about 15 mg of the composition for delivery of the single dose in a single breath, and further wherein up to about 92% of the microcrystalline particles have a volumetric median geometric diameter of less than or equal to 5.8 pm and wherein said porous microcrystalline particles have an average pore size from about 23.8 nm to 26.2 nm, an average pore volume of about 0.43 cm3/g, and a specific surface area (SSA) of about 71 m2/g, and wherein said dry powder produces a 50% to 70% delivery efficiency and an rf/fill greater than 50% upon discharge from a single use breath-powered dry powder inhaler. Claims 22 and 23 recite a dose of 5 mg or 10 mg of the composition.
Claims 1, 3-4 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Baker et al (WO 2009152160) in view of Wilson et al (WO 2014144895), Smutney et al (US 20130104887 A1), Leonard et al (US 20040092470) and Tarara et al (US 20100272823).
Baker et al teach phenylphosphonate prodrugs comprising one or more prostacyclins for the treatment of pulmonary arterial hypertension, and for delivery by aerosolization or dry powder (See abstract).
Disclosed is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a liquid or solid dosage form suitable for nebulization, pressurized metered dose inhalation or dry powder delivery (See Summary and claim 33).
An example of the compounds of formula I is treprostinil (See Page 65, Example 17).
A compound of Formula I or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The said compounds are administered endobronchially as a dry powder formulation to efficaciously deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers. For delivery by DPI, the compound of Formula I is processed into particles with, predominantly, MMAD between about 1 μm and about 5 μm by milling spray. A typically used excipient is lactose (See page 36, 2nd para to Page 37, 2nd para).
Baker et al disclose a compound of Formula I, or a pharmaceutically acceptable salt thereof, is dosed in a therapeutically effective amount ranging from about 10 to about 5000 μg (i.e. 5 mg). The dose will be determined by the host treated and the severity of the disease as determined by those physicians skilled in the art. Preferably, the drug will be administered four, three, two, or most preferably once a day. In another aspect of the invention, a combination of an aerosol formulation of a compound of Formula I and a device significantly enhances the efficiency and speed of drug administration (See Page 37, last para and claims 35-36).
Disclosed is a compound of Formula I or a pharmaceutically acceptable salt thereof, delivered as a dry inhalable powder administered endobronchially as a dry powder formulation to efficaciously deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers (See Page 36, lines 11-18).
Baker et al lack a disclosure on the addition of porous microcrystalline particles of FDKP, the pore size, pore volume, trans isomer content, specific surface area, the water content and specifics of a dry powder inhaler. These are known in the art as taught by Wilson et al, Smutney et al, Leonard et al and Tarara et al.
Wilson et al teach DKP microcrystals made by an improved method where they do not irreversibly self-assemble into microparticles. The microcrystals can be dispersed by atomization and re-formed by spray drying into particles having spherical shell morphology, reading on the “microcrystalline” and “spray dried” features claimed. Active agents and excipients can be incorporated into the particles by spray drying a solution containing the components to be incorporated into microcrystalline diketopiperazine particles. In particular, the microcrystalline particle compositions are suitable for pulmonary drug delivery of one or more peptides, proteins, nucleic acids and/or small organic molecules (see Abstract).
Disclosed are powders comprising a plurality of substantially uniform, microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell and comprise crystallites of a diketopiperazine that do not self-assemble (see [0007]- [0008], [0058]). The particles of Wilson have higher capacity for carrying and delivering drug content to the patient [0059]. Powders made with the microcrystalline particles of Wilson can deliver increased drug content in lesser amounts of powder dose, which can facilitate drug delivery to a patient [0006]. Wilson teaches FDKP microparticle powders with acceptable aerodynamic performance ([0076], [0080]). Wilson discloses a particular embodiment wherein, up to about 92% of the microcrystalline particles have a volumetric median geometric diameter of < 5.8 um [0009]. Wilson teaches high respirable fraction of 62.8%, which the Examiner interprets to encompass delivery efficiency in the absence of a definition in the disclosure (Example 2; Table 4).
The said particle's shell is constructed from interlocking diketopiperazine crystals having one or more drugs adsorbed on their surfaces. In some embodiments, the particles can entrap the drug in their interior void volume and/or combinations of the drug adsorbed to the crystallites' surface and drug entrapped in the interior void volume of the spheres (See [0009]).
In one aspect the diketopiperazine comprises a trans isomer content ranging from about 45% to 65% (See [0010], [0019], [0023] and [0042]).
The drug content to be delivered on microcrystalline particles formed from FDKP can typically be greater than 0.01 % (w/w), such as from about 0.01 % (w/w) to about 75 % (w/w) (See [0084)).
The stability of the particle can be enhanced by small amounts of a surfactant, such as polysorbate-80, in the DKP solution from which the particles are precipitated (See [0071] and claim 15).
Wilson discloses drug delivery systems comprising an inhaler with or without a cartridge, wherein the cartridge is a unit dose dry powder medicament container comprising the particles disclosed herein and an active agent (See [0039]). Wilson discloses an embodiment wherein the flow rates range from about 7 to 70 liters per minute which results in greater than 75% of the container or the cartridge contents dispensed in fill masses between 1 and 50 mg [0039]; the inhalers can discharge greater than 85% of a powder medicament contained in a single inhalation [0041], thereby reading on the feature of Claims 1 and 22-23.
Wilson does not expressly recite “a single use” breath-powered dry powder inhaler as in Claim 1. However, the instant Claim 1’s recitation of “wherein said dry powder produces a 50% to 70% delivery efficiency and an rf/fill greater than 50% upon discharge from a single use breath- powered dry powder inhaler” is rendered obvious by Wilson with its teaching of embodiments wherein the inhalers can discharge greater than 85% of a powder medicament contained in a single inhalation [0041]. Furthermore, Wilson teaches embodiments wherein the inhalation system is configured to provide a single dose by discharging powder from the inhaler as a continuous flow, or one or more pulses [0039]. As such, with dispensing >85% of medicament in a single dose, there would be no need to reuse the inhaler, rendering obvious its singular use.
Smutney is in the same field of study and supports Wilson. Smutney discloses a pulmonary drug delivery system including a breath-powered, dry powder inhaler, and a cartridge for delivering a dry powder formulation. Smutney teaches that the inhaler and cartridge can be provided with a drug delivery formulation comprising DKP and an active ingredient (Abstract). As such, Smutney is compatible with Wilson. Smutney teaches single use, disposable inhalers, as well as reusable inhalers; inexpensive to manufacture ([0008], [0012], [0084]).
Smutney et al teach that the said microparticles having a diameter of between about 0.5 and about 10 microns can reach the lungs, successfully passing most of the natural barriers. The said microparticles with a specific surface area (SSA) of between about 35 and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption (See [0164]). Disclosed are also FDKP microparticles having a specific trans isomer ratio of about 45% to about 65%, the microparticles providing improved flyability (See [0148] and [0165]).
Leonard et al teach a dry powder formulation consisting essentially of an oligo of particle size about 0.1μ to about 100μ micron in diameter for treatment of numerous diseases and conditions by administration into the respiratory tract (See abstract, [0011] and claim 1). The said formulation is delivered via a suitable delivery device including dry powder inhalers (DPI) and metered dose inhaler (MDI) (See [0014]).
Leonard et al further teach that the term “dry” means that the formulation has a moisture content such that the particles are readily dispersible in a dry powder inhalation device to form an aerosol or spray. This moisture content is generally less than about 1% w/w, or less than about 0.5% w/w (See [0040]).
Regarding claims 3-4 and 24, Leonard et al teach that the said dry powder formulation may further comprise one or more surfactant(s), including surfactant protein A, surfactant protein B, C, D or E, phospholipids, etc, (See [0058]).
Tarara et al teach a pulmonary delivery medicament comprising a plurality of particulates, the particulates comprising a structural matrix such as a phospholipid and a water insoluble and/or crystalline active agent. The said pulmonary delivery of bioactive agents is to selected physiological target sites using perforated microstructure powders (See abstract and [0014]).
Tarara et al disclose “By way of contrast, the present invention uses methods and compositions that yield powder formulations having extraordinarily low bulk density, thereby reducing the minimal filling weight that is commercially feasible for use in dry powder inhalation devices. That is, most unit dose containers designed for DPIs are filled using fixed volume or gravimetric techniques (See [0052]).
Tarare et also disclose that “DPIs generally rely entirely on the patient's inspiratory efforts to introduce a medicament in a dry powder form to the lungs” (See [0004]).
It is further disclosed that most devices are manually actuated, but some devices exist which are breath actuated. Breath actuated devices work by releasing aerosol when the device senses the patient inhaling through a circuit (See [0170]).
The said structural matrix defining the perforated microstructure may comprise cyclodextrins, polyacrylates, methylcellulose, polyanhydrides, etc, (See [0064]).
Regarding claims 3-4 and 24, Tarara et al teach that the said particulate formulations may comprise additives including carriers and surfactants including phospholipids, poloxamer, lactose, sucrose, sodium chloride, sodium citrate, mannitol, polyoxyethylene (20) sorbitan monolaurate, etc, (See [0017], [0058]-[0066]).
Tarara et al teach that the said perforated microstructure defined by the structural matrix comprises a spray dried hollow porous microsphere incorporating at least one surfactant. It will further be appreciated that, by altering the matrix components, the density of the structural matrix may be adjusted. The said perforated microstructures preferably comprise at least one active or bioactive agent (See [0054]).
Tarara et al disclose that the mean porosity (i.e. the percentage of the particle surface area that is open to the interior and/or a central void) of the perforated microstructures may range from about 0.5% to about 80%. As to the pores themselves, they typically range in size from about 5 nm to about 400 nm with mean pore sizes preferably in the range of from about 20 nm to about 200 nm. It is significantly advantageous that the pore size and porosity may be closely controlled by careful selection of the incorporated components and production parameters (See [0115]).
Regarding claims 1 and 22-23, Tarara et al teach that currently, the range of dry powder that can be filled into a unit dose container is in the range of 5 to 15 mg which corresponds to drug loading in the range of 25 to 500 μg per dose (See [0133]).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Wilson et al, Smutney et al, Leonard et al and Tarara et al with that of Baker et al to arrive at the instant invention.
It would have been obvious to do so because Baker et al teach dry powder formulations comprising a compound of formula I, such as treprostinil, wherein the administered effective dose by inhalation can be from 1 to 5000 µg (i.e. 5 mg). The inhaler may be a DPI, dry powder inhaler, and the said dry powder may contain an excipient such as lactose. The claims recite a treprostinil content of 20% in the composition which is delivered at a dose of from about 1 mg to about 15 mg, such as 5 mg or 10 mg. It is noted that 20% of 1 mg is 200 µg and 20% of 15 mg is 3 mg.
Regarding the amount and dosage of treprostinil, Baker et al teach an amount/dose of from 1 to 5000 µg, which fully renders the claimed 1 to 15 mg, including 5 and 10 mg obvious.
Wilson et al teach dry powder formulations comprising microcrystalline particles of FDKP, an active agent and at least additives. It is disclosed that the said microcrystalline particles exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance [0062]. This is a situation where elements of references are combined in a predictable manner so that the elements retain their function. As such, the artisan would enjoy a reasonable expectation of success. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed with no change in their respective functions of the compositions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
One with ordinary skill in the art would also have applied the known technique of incorporating active agent treprostinil into the particles by spray drying a solution containing the components to be incorporated into microcrystalline diketopiperazine particles. Applying a known technique to a known method ready for improvement to yield predictable results is the rationale supporting obviousness. See MPEP § 2143 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Regarding the single dose disposable inhaler cartridge or capsule in Claim 1, Wilson has taught the cartridge for the inhaler, and that powder medicament contained can be dispensed in a single inhalation at a dose between 1-50 mg. 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. As recited, the cartridge is not a patentable feature, and is also rendered obvious by the teachings of Wilson and Leonard et al.
Similarly, in the instant Claim 1 recitation of “wherein said dry powder produces a 50% to 70% delivery efficiency and an rf/fill greater than 50% upon discharge from a single use breath- powered dry powder inhaler”, the “from a single use...inhaler” is not given patentable weight. Nevertheless, it is rendered obvious by Wilson because Wilson teaches dispensing >85% of medicament in a single dose, therefore it would be obvious to one skilled in the art that there would be no need to reuse the inhaler, rendering obvious the singular use.
Also singular use powder inhalers are known in the field and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine Smutney with Wilson and Baker et al, and use an inhaler that is single use or reusable because Smutney has disclosed pulmonary drug delivery systems comprising DKP and an active ingredient, and therefore compatible with Wilson, disclosing that these single use, disposable inhalers, as well as reusable inhalers can be manufactured with ease and at low cost. This is a situation where elements of references are combined in a predictable manner so that the elements retain their function. As such, the artisan would enjoy a reasonable expectation of success. Therefore, all of 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 would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding the SSA of the particles, Smutney et al teach that an SSA of up to about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption. Additionally, the disclosed range of about 67 m2/g meets the claimed about 71 m2/g.
Regarding the limitation of trans isomer content, both Wilson and Smutney teach FDK microparticles with a trans isomer content of about 45%, meeting the claimed range.
Regarding the elected buffer feature in Claim 4, Wilson teaches excipients, therefore rendering Claims 3 and 4 obvious. Leonard et al and Tarar et al also teach the addition of excipients including a surfactant such as phospholipids to the said dry powder formulation. Therefore, 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 would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding the limitation of water content less than about 0.4%, Leonard et al teach that a dry powder composition for inhalation generally has low moisture content preferably less than 0.5%.
Tarara et al is also in the same field of endeavor and provide guidance on the pore size and pore volume of a particle for inhalation by a breath actuated inhaler and suitable excipients including lactose and mannitol.
All references teach dry powder formulations comprising an active agent and suitable excipients/carriers. Porous microcrystalline FDKP particles carrying an active agent are disclosed. Treprostinil is a known active agent suitable for treating disorders such as pulmonary hypertension and is known to be in its crystalline form. It is also known in the art to incorporate diketopiperazine for better absorption of an active agent. It is further known in the art that suitable pore size and pore volume of a perforated microstructure are effective in drug delivery to the pulmonary system. Other additives and particle characteristics such as surface area and geometric diameter are also well known in the art as shown.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations. That is one of ordinary skill in the art is more than motivated to incorporate compounds and characteristics that are well known and disclosed for their advantages in the art to the compositions comprising treprostinil with a reasonable expectation of success.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,421,729 in view of Baker et al (WO 2009152160), Smutney et al (US 20130104887) and Tarara et al (US 20100272823). An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims in view of Baker et al, Smutney et al and Tarara et al.
The examined claim 1 is directed to an Claim 1 is directed to an inhalable spray-dried dry powder composition comprising porous microcrystalline particles of fumaryl diketopiperazine and treprostinil, wherein the treprostinil content is about 20% (w/w) of the particles, and wherein the composition is provided in a single-dose disposable inhaler cartridge or capsule in a dose of about 1 mg to about 15 mg of the composition for delivery of the single dose in a single breath, and further wherein up to about 92% of the microcrystalline particles have a volumetric median geometric diameter of less than or equal to 5.8 um and wherein said porous microcrystalline particles have an average pore size from about 23.8 nm to 26.2 nm, an average pore volume of about 0.43 cm3/g, and a specific surface area (SSA) of between 59 m2/g and 63 m2/g, and wherein said dry powder produces a 50% to 70% delivery efficiency and an rf/fill greater than 50% upon discharge from a single use breath-powered dry powder inhaler.
Reference claim 1 is directed to a crystalline diketopiperazine composition comprising a plurality of microcrystalline particles comprising an active agent, said microcrystalline particles being substantially uniform in size and having a volumetric median geometric diameter less than 5 µm, and further having hollow spherical structures; each of said hollow spherical structures comprising a core and a shell, wherein said shell is porous and comprises crystallites of the diketopiperazine, ….. .
The differences are that the reference claim 1 does not expressly disclose treprostinil as the active agent and does not require the pore size. However, the scope of reference claim 1 being drawn to any active agent encompasses treprostinil and as taught by Baker et al Treprostinil is a suitable drug for administration into the lungs by inhalation of a dry power. Smutney et al teach breath-powered inhalers using a single dose cartridge and wherein the SSA is about 67 m2/g. Also as taught by Tarara et al, a pore size of from about 20 nm to about 200 nm and a high porosity are suggested for drug delivery to the pulmonary system.
Accordingly, examined claim 1 and reference claim 1 are so close that they are not patentably distinct.
Claims 1, 3-4 and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 5-6 of U.S. Patent No. 10,772,883 in view of Baker et al (WO 2009152160) and Tarara et al (US 20100272823). An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims in view of Baker et al and Trarara et al.
The examined claim 1 is recited above.
Reference claims are directed to a dry powder pharmaceutical composition comprising inhalable 3,6-di(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine microparticles; wherein each of the microparticles has a specific surface area of 35 m2/g to about 67 m2/g and comprises an active agent and the active agent is present at about 0.1 to about 20% by weight of the microparticles.
The differences are that the reference claims do not expressly disclose the active agent being treprostinil, the amount of it, microparticles comprising porous microcrystalline particles or the pore size or specific surface area. However, the missing limitations are obvious to one of ordinary skill in the art as taught by Baker et al and Tarara et al. Baker et al teach compositions comprising trepsostinil and its single dose for inhalation and Tarara et al teach porous microcrystalline celluolse, a pore size of from about 20 nm to about 200 nm and a high porosity which are suggested for drug delivery to the pulmonary system.
Accordingly, examined claims and reference claims in view of Baker et al and Tarara et al are so close that they are not patentably distinct.
Claims 1, 3-4 and 22-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7, 19 and 24 of copending Application No. 16/434,938 (US 20190321290) in view of Grant et al (US 20140271888) and Baker et al (WO 2009152160). An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims in view of Grant et al and Baker et al.
The examined claim 1 is recited above.
Reference claim 1 is directed to a drug delivery system comprising a dry powder inhaler and an inhalable pharmaceutical dry powder composition for breath-powered pulmonary delivery comprising spray-dried, hollow, porous microcrystalline particles that do not self-assemble, said microcrystalline particles comprising fumaryl diketopiperazine or a salt thereof, and from about 1% to about 5% (w/w) treprostinil or a pharmaceutically acceptable salt thereof, wherein the porous microcrystalline particles have a specific surface area ranging from about 59 m2/g to about 63 m2/g, and wherein the porous microcrystalline particles have a pore size ranging from about 23 nm to about 30 nm, the porous microcrystalline particles have an average pore volume of about 0.43 cm3/g, and up to about 92% of the microcrystalline particles have a volumetric median geometric diameter of less than or equal to 5.8 um and further wherein the inhalable pharmaceutical dry powder composition is provided in a disposable cartridge or capsule in a dose of 150 ug, 720 ug, or 200 ug of the treprostinil or a pharmaceutically acceptable salt thereof for a single inhalation, wherein said dry powder produces a 50% to 70% delivery efficiency and an rf/fill greater than 50% upon discharge from the dry powder inhaler.
The differences are that the reference claims disclose the dose in % while the examined claims disclose in µg. Additionally, the instant claims do not recite the specific surface area. However, the differences are obvious to one of ordinary skill in the art as taught by Grant et al and Baker et al. Grant et al teach compositions comprising porous microcrystalline particles of diketopiperazine and wherein the specific surface area is disclosed as less than 67 m2/g and a high porosity are suggested for drug delivery to the pulmonary system. Baker et al disclose the administered dose of treprostinil in both percentage and microgram and teach that it could be from 1 to 5000 µg.
Accordingly, examined claims and reference claims in view of Grant et al and Baker et al are so close that they are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4 and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13 of US patent No. 12,832,552 (previously rejected under 18/106,948 (US 20230181573)) in view of Baker et al (WO 2009152160) and Tarara et al (US 20100272823). An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims in view of Baker et al and Trarara et al.
The examined claim 1 is recited above.
Reference claim is directed to an inhalation system comprising a dry powder inhaler and dry powder formulation comprising crystalline microparticles of fumaryl diketopiperazine having a specific surface area of between about 35 m2/g and about 67 m2/g, and a prostaglandin in an amount of about 0.01% to about 20% by weight of the microparticles adsorbed to the microparticles, wherein the inhaler has a flow path passing through an area of powder containment and a flow path bypassing the area of powder containment, wherein in use 10-70% of the total flow exiting the inhaler passes through the area of powder containment and 90-30% of the total flow exiting the inhaler bypasses the area of powder containment.
The differences are that the reference claims do not expressly disclose the active agent being treprostinil, the amount of it, microparticles comprising porous microcrystalline particles or the pore size or specific surface area. However, the missing limitations are obvious to one of ordinary skill in the art as taught by Baker et al and Tarara et al. Baker et al teach compositions comprising trepsostinil and its single dose for inhalation and Tarara et al teach porous microcrystalline celluolse, a pore size of from about 20 nm to about 200 nm and a high porosity which are suggested for drug delivery to the pulmonary system.
Accordingly, examined claims and reference claims in view of Baker et al and Tarara et al are so close that they are not patentably distinct.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kinsey et al (WO 2017132601).
Kinsey et al teach a dry powder inhaler including replaceable cartridges containing a dry powder for delivery through the pulmonary tract and lungs, the inhalable dry powders, including medicament formulations comprising active agents for the treatment of diseases such as, pulmonary hypertension, etc, (See abstract).
Disclosed is a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and a drug (See [0013] and [0027]).
In some embodiments, the active ingredient comprises treprostinil (See [0015]).
Pulmonary delivery of powders includes carriers and excipients. An exemplary embodiment is fumaryl diketopiperazine, also known as FDKP. DKP crystalline microparticles with a specific surface area (SSA) of between about 35 m2/g and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption (See [0081]).
Kinsey et al disclose a dry powder for inhalation comprising a plurality of substantially uniform, microcrystalline particles, wherein the microcrystalline particles can be substantially hollow spherical and substantially solid particles comprising crystallites of the diketopiperazine depending on the drug and/or drug content provided and other factors in the process of making the powders. The said microcrystalline particles comprise particles that are relatively porous, having average pore size ranging from about 23 nm to about 30 nm (See [0095]).
In one embodiment, wherein treprostinil is used as the active agent, the dry powder compositions comprise microcrystalline particles of fumaryl diketopiperazine, wherein the treprostinil is adsorbed to the particles and wherein the content of the treprostinil in the composition comprises up to about 20% (w/w) and ranges from about 0.5% to about 10% (w/w), preferably from about 1% to about 5% (w/w) of the dry powder. The said treprostinil composition can be used in the prevention and treatment of pulmonary hypertension by self-administering an effective dose comprising about 1 mg to 15 mg of a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and treprostinil in a single inhalation (See [00108]).
Kinsey et al also disclose that the pharmaceutically acceptable carrier for making dry powders can comprise any carriers or excipients useful for making dry powders and which are suitable for pulmonary delivery. Example of suitable carriers and excipients include, sugars, including saccharides and polysaccharides, such as lactose, mannose, sucrose, mannitol, trehalose; citrates, amino acids such as glycine, L-leucine, isoleucine, trileucine, tartrates, zinc citrate, trisodium citrate, polysorbate 80, and the like (See [00110]).
Smutney et al (US 20090308392 or 8,424,518).
Smutney et al teach a breath-powered, dry powder inhaler, a cartridge, and a pulmonary drug delivery system. The inhaler and/or cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient (See abstract).
It is disclosed that microparticles having a diameter of between about 0.5 and about 10 microns can reach the lungs, successfully passing most of the natural barriers. DKP microparticles with a specific surface area (SSA) of between about 35 and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption (See [0202]).
Grant et al (US 20140271888).
Grant et al teach diketopiperazine microparticles having a specific surface area of less than about 67 m2/g. The diketopiperazine microparticle can be fumaryl diketopiperazine and can comprise a drug. The said microparticles and methods that allow for improved delivery of drugs to the lungs. Embodiments disclosed herein achieve improved delivery by providing diketopiperazine (DKP) microparticles having a specific surface area (SSA) of between about 35 m2/g and about 62 m2/g. DKP microparticles having a specific surface area in this range exhibit characteristics beneficial to delivery to the lungs such as improved aerodynamic performance and improved drug adsorption (See abstract and [0007]-[0010]).
As specific surface area also affects drug loading/content capacity, various embodiments require specific surface areas greater than or equal to 45 m2/g for improved drug adsorption capacity (See [0048]).
Grant et al disclose a preferred embodiment, in which an inhaler system flow rates ranging from about 7 to 70 liters per minute result in greater than 75% of the container powder content or the cartridge powder content dispensed in fill masses between 1 and 30 mg. The said inhalation system can emit a respirable fraction/fill of a powder dose at greater than 40% in a single inhalation, greater than 50%, greater than 60%, or greater than 70% (See [0012]). In an exemplary embodiment, a respirable fraction on fill can be up to about 80%, wherein about 80% of the fill is emitted with particle sizes <5.8 μm (See [0036]).
It is disclosed that the volumetric median geometric diameter (VMGD) of the particles is measured to assess performance of the inhalation system. For example, in various embodiments cartridge emptying of ≧80%, 85%, or 90% and a VMGD of the emitted particles of ≦7.0 μm, or ≦4.8 μm can indicate progressively better aerodynamic performance (See [0035] and Table 4).
Grant et al disclose that the specific surface area of DKP microparticles is a measure of average crystal size and can be used to gauge the relative contributions of crystal nucleation and growth to microparticle characteristics (See [0046]-[0048]).
It is further stated that the combination of a drug and a diketopiperazine can impart improved drug stability and/or absorption characteristics. These microparticles can be administered by various routes of administration. As dry powders, these microparticles can be delivered by inhalation to specific areas of the respiratory system, including the lungs (See [0042]).
Such microparticles are self-assembled microparticles and are comprised of aggregated crystalline plates. The stability of the particle can be enhanced by small amounts of a surfactant, such as polysorbate-80 (See [0043]).
Grant et al disclose that “active agent”, used interchangeably with “drug”, refers to pharmaceutical substances, including small molecule pharmaceuticals, macromolecules, biologicals and bioactive agents, including proteins, polypeptides, peptides, vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antiviral agents, antigens, infectious agents, inflammatory mediators, hormones, etc, (See [0067]).
Response to Arguments
Applicant's arguments filed 07/31/26 have been fully considered but they are not persuasive.
Applicant’s main argument is regarding the residual water content as recited in claim 1 and the applicability of Leonard et al’s teachings. Applicant first argus that “Leonard does not teach or suggest the dryness of any particular component of the formulation, just that the entire formulation meet the standard of having less than 15% water by weight. The present claims are concerned with the residual water content of FDKP, and not the dryness of the ultimate FDKP/treprostinil formulation. Furthermore, Leonard does not recite, teach or suggest any diketopiperazine, let alone FDKP in any dry powder formulation. Thus, Leonard cannot teach or suggest FDKP microcrystalline particles having a water content of 0.4%” (See Remarks, page 7).
The argument is not persuasive. Contrary to Applicant’s statement, the Specification does not teach that the water content of FDKP, but that of the dry powder. Specifically, Specification states:
Dry powders (A, B, C and D) comprising microcrystalline particles made by the methods described above were tested for various characteristics, including surface area, water content and porosity measurements. Four different powders were used in this experiments. All powders tested had a residual water content of 0.4%. Table 2a demonstrates data obtained from the experiments. (See [0117] of published Spec).
Additionally, the claims are directed to “a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and treprostinil,…. “.
Applicants arguments that Leonard et al does not teach FDKP/Treprostinil is also not persuasive. The recitation is a general definition for all dry powders for inhalation and not limited to any particular active agent. The reference is not required to teach a powder comprising FDKP and Treprostinil to render this limitation obvious.
Applicants remark that -none of Leonard’s examples explain how dry the formulations actually are-, is also unconvincing. The recitation is a general definition for all dry powders for inhalation. The reference is not required to show this limitation in an example to render it obvious.
Applicant also argues that “Furthermore, a skilled artisan would not be motivated to adapt the teachings of Leonard to modify Baker. Formulations consisting essentially of oligonucleotides are physiochemically distinct from FDKP particle formulations. Oligonucleotides are hydrophilic and known to be hygroscopic due to their charged phosphate backbones and hydrogen bonding sites. …..” (See Remarks, page 8).
The above argument has been fully considered but found unconvincing. Again, Leonard et al teaches that a dry power formulation should have a moisture content of less than 0.5%. The water uptake of oligonucleotides is a fact that would be recognized by one of ordinary skill in the art and would be adjusted for as needed.
It is further noted that Baker et al teach dry powder formulations comprising Treprostinil and delivered to the pulmonary system via dry powder inhaler. While, Baker et al does not expressly disclose a water content for the said dry powder, it would necessarily have a low water content based on the definition of Leonard et al for a dry powder.
Furthermore, it is noted that Wilson, Smutney and Tarar et al all teach dry powder formulations for inhalation vi a dry powder inhaler. A dry powder disclosed by any and all of the said references would necessarily have allow moisture content.
Next argument is that “Controlling water content to 0.4% in spray-dried porous FDKP microcrystalline particles is non-trivial and no reference suggests it can be reproducibly achieved or that it is beneficial. As shown in Example 1 of the present disclosure, all tested powders of microcrystalline FDKP particles have about 0.4% water content” (See Remarks, page 8).
This argument is not persuasive as stated above. Firstly, the disclosure does not recite the water content of spray-dried FDKP microcrystalline particles, but rather the dry powder comprising FDKP. Secondly, as Leonard et al teach, for a dry powder formulation to be effectively inhaled via a dry powder inhaler, it needs to be sufficiently dry and moisture free. Thus, the skilled artisan would be motivated to make sure the claimed dry powder is indeed sufficiently dry, such as having a moisture content of less than 0.5%.
Applicant further argue that “The Office relies upon various miscellaneous disclosures of pulmonary delivery. The Office relies upon Baker for treprostinil pulmonary delivery and provides separate disclosures allegedly providing for the characteristics of the microcrystalline particles, including FDKP particles (Wilson), FDKP particles with an SSA of between about 35 and 67 m²/g (Smutney), porous particles with a mean porosity of about 20 nm to 200 nm (Tarara), and powders with a water content of less than about 0.5% (Leonard). However, the references provide no teaching, suggestion, or motivation to combine the references in the specific manner claimed” (See Remarks, page 9).
This argument is similarly unpersuasive. The combination of references shows that each and every element of the instant claims has been taught by prior art and that one of ordinary skill in the art would have been motivated to combine them to arrive at the claimed invention.
In this regard the courts have held that “[w]hen an application simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious”. KSR v. Teleflex, 127 S,Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent application claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Consistent with this reasoning, it would have been obvious to have selected various combinations of various disclosed limitations and properties from within prior art disclosure, to arrive at a product / process “yielding no more than one would expect from such an arrangement”.
In this case, the active agent and its use in a dry powder formulation for inhalation, and its dosage amount are known as disclosed by Baker et al. Baker et al lack a disclosure on the addition of porous microcrystalline particles of FDKP, the pore size, pore volume, trans isomer content, specific surface area, the water content and specifics of a dry powder inhaler. These are known in the art as taught by Wilson et al, Smutney et al, Leonard et al and Tarara et al.
For example, Wilson et al teach that powders made with the microcrystalline particles of Wilson can deliver increased drug content in lesser amounts of powder dose, which can facilitate drug delivery to a patient [0006]. Wilson teaches FDKP microparticle powders with acceptable aerodynamic performance, and Smutney teaches a cartridge comprising a drug delivery formulation comprising DKP and an active ingredient and wherein microparticles with a specific surface area (SSA) of between about 35 and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption. The FDKP microparticles having a specific trans isomer ratio of about 45% to about 65%, show improved flyability. Tarra et al teach dry powder formulations wherein the particles preferably have porous structure and provide guidance on the pore size and volume for better delivery of active agents to the pulmonary system. Leonard et al provide a definition of dry powder formulation with its moisture content levels.
Thus, from the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The rejection clearly shows that there is no evidence of an inventive step. Thus, the rejection is maintained.
Applicant made no argument regarding the rejection of claims under obviousness type double patenting over the copending patents and Applications and as such the rejections are maintained.
Claims 1, 3-4 and 22-24 are rejected. Claims 5-6, 8-9, 11-13 and 15-20 remain withdrawn.
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.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
Prosecution Insights