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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/27/26 has been entered.
Receipt is acknowledged of Amendments and Remarks filed on 05/27/26. Claims 1 and 8 have been amended, new claims 14-23 have been added and no claims have been cancelled. Accordingly, claims 1, 3, 8-9, 13 and 15-23 are pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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.
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 a method for treating pulmonary hypertension, the method comprising: administering by oral inhalation a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine (FDKP) and treprostinil, wherein the microcrystalline particles of fumaryl diketopiperazine have a specific trans isomer content of about 45% to 63%, wherein the treprostinil content is about 1% (w/w) to about 10% (w/w) based on total weight of the dry powder composition, wherein the dry powder composition is provided in a single-dose disposable inhaler cartridge or capsule in a dose of about 1 mg to about 15 mg, thereby treating the pulmonary hypertension, wherein the FDKP particles are porous, substantially solid, have a residual water content of 0.4%, and comprise pores having average pore volumes of about 0.43 cm3/g and average pore size from about 23.8 nm to 26.2 nm as determined by BJH adsorption, wherein the dry powder inhaler includes a housing and a body, wherein the body comprises a mounting area for a cartridge that includes the dry powder composition, and the body and the housing are movable relative to one another linearly and are operably configured to engage one another to effectuate the cartridge to be reconfigured to attain an airflow pathway for discharging the powder dose upon an single inhalation, and wherein the cartridge is replaceable and for single use and comprises a lid and a cup which are movable relative to one another in a translational motion.
Claims 1, 3, 8-9, 13 and 15-23 are rejected under 35 U.S.C. 103 as being unpatentable over Baker et al (WO 2009152160) in view of Olschwski et al (US 20080200449) Wilson et al (WO 2014144895), Tarara et al (US 20100272823), Smutney et al (US 20090308391) and/or Steiner et al (US 20040182387) and Leonard et al (US 20040092470).
Baker et al teach inhaled 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. 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).
Olschewski et al teach treprostinil can be administered using a metered dose inhaler (See abstract).
Disclosed is a method for treating pulmonary hypertension comprising administering to a subject in need thereof treprostinil or its derivative, or a pharmaceutically acceptable salt thereof using a metered dose inhaler (See [0010] and [0029]).
Olschewski et al further teach that treprostinil, or 9-deoxy-2′,9-alpha-methano-3-oxa-4,5,6-trinor-3,7-(1′,3′-interphenylene)-13,14-dihydro-prostaglandin F1, is a prostacyclin analogue (See [0031]).
It is disclosed that a metered dose inhaler in the present context means a device capable of delivering a metered or bolus dose of respiratory drug, such as treprostinil, to the lungs. The said inhalation device can be a pressurized metered dose inhaler or a dry powder inhaler (See [0040]-[0041] and claims 3 and 21).
Olschewski et al further teach that a dose of the treprostinil administered during a single event ranges from about 15 μg to about 100 μg of the Treprostinil (See [0044] and claim 26). Treprostinil can be administered a single time per day or several times per day (See [0047]).
Baker et al and Olschewski et al lack a disclosure on the trans isomer content, addition of porous microcrystalline particles of FDKP, the pore size, residual water content and the specifics of a dry powder inhaler. These are known in the art as taught by Wilson et al, Tarara et al and Leonard et al.
References also lack disclosure on the specifics of the inhaler as shown in claims 1 and 14. This would have been obvious in view of the teachings of the art including Smutney et al and Steiner 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. 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]).
Wilson et al disclose a method of making dry powders comprising microcrystalline particles suitable for pulmonary administration wherein diketopiperazine comprises a trans isomer content ranging from about 45% to 65%. Formulations of FDKP particles having a defined specific surface area less than 67 m2/g also provide dry powders for inhalation with acceptable aerodynamic properties, as stated in Patent No. 8,551,528 (See [0010], [0019], [0023], [0041]-[0042] and [0078]).
Disclosed is a diketopiperazine composition comprising a plurality of substantially uniformly formed, microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that do not self-assemble (See [0010] and [0012]).
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 et al state that the said inhalation system has a resistance value of, for example, approximately 0.065 to about 0.200 (VkPa)/liter per minute (See [0039]).
As evidenced:
Patent No. 8,551,528 (Grant et al) teaches diketopiperazine microparticles having a specific surface area of less than about 67 m2/g. (See abstract, Col. 1, line 59 to Col. 2, line 37, claims 1 and 9).
Tarara et al teach a pulmonary delivery medicament comprising a plurality of particulates, the particulates comprising a structural matrix 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]).
The said particulate formulations may comprise additives including carriers and surfactants such as lactose, sucrose, sodium chloride, sodium citrate, mannitol, polyoxyethylene (20) sorbitan monolaurate, etc, (See [0059]-[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]).
Smutney et al also teach a breath-powered, dry powder inhaler, a cartridge, and a pulmonary drug delivery system, the dry powder inhaler having a unit dose cartridge and a drug delivery formulation comprising a diketopiperazine and an active ingredient, and comprises a housing, a mouthpiece, a cartridge placement area, and a mechanism for opening and closing the medicament cartridge (See Abstract).
Disclosed is a dry powder inhaler comprising a gear mechanism configured to effectuate movement of the cartridge; wherein the mouthpiece and the housing are moveably attached by the hinge (See [0018]).
Smutney et al teach that in the said inhaler, the container is movable from the containment configuration to the dosing configuration and vice versa, and in the dosing configuration, the second raised area of the mouthpiece undersurface and the container form or define an air inlet passageway to allow ambient air to enter the internal volume of the container or expose the interior of the container to ambient air (See [0014]).
Additionally, it is disclosed that the said inhaler comprises “a mouthpiece 330 comprising the top portion of body 305 of the inhaler and having an aperture 355 relatively centrally located in the body and surrounded by flange 358; mouthpiece oral placement section 312 is configured to extend from the inhaler body and has an air outlet for placing in the oral cavity of a patient at dosing. The inhaler further comprises housing 320 which is engageably attached to mouthpiece 330 by a geared mechanism. In this embodiment, the geared mechanism is, for example, a rack and pinion 363 (see also FIG. 15A) which allows for an angular movement of the mouthpiece relative to the housing. Rack mechanism 363 is engaged to sled 317 to effectuate movement of container 351 of cartridge 350 to move slideably under the cartridge top and under the cartridge boss 326 when the inhaler is in the closed position (See [0139] and Fig. 14).
In one embodiment, the cartridge comprises a container and a lid or cover, wherein the container can be adapted to a surface of the lid and can be movable relative to the lid or the lid can be movable on the container and can attain various configurations depending on its position, for example, a containment configuration, a dosing configuration or after use configuration (See [0019]).
Smutney et al teach a cartridge holder 115 in the shape of a cup (See [0126]) and that “FIG. 35-38B further illustrate cartridge 150 comprising top or lid 156 and container 151 defining an interior space or volume”. In an embodiment container 151 or lid 156 can be movable, for example, by translational movement upon top 156, or top 156 can be movable relative to the container 151. In one embodiment, container 151 can be movable by sliding on flanges 153 on lid 156 when lid or top 156 is stationary, or lid 156 can be movable by sliding on a stationary container 151 depending on the inhaler configuration (See [0158]).
Steiner et al ‘387 disclose a dry powder inhaler comprising in general, a housing having an air intake, an air flow-control/check-valve, a mixing section and a mouthpiece, which operates effectively over a broad inhalation tidal volume range of human breath. A cartridge loaded with a single dose of medicament can be installed in the mixing section. Disclosure is also to a medicament-containing inhaler cartridge which will supply medicament for complete air entrainment and proper dispersion into the air stream. The cartridge contains a medicament powder, and it can be installed in and removed from the mixing chamber (See entire document, especially the abstract, [0010], [0014], [0015] and [0053)).
Steiner et al disclose that “In general, the mixing section 30 is provided with shapes on its interior surface to encourage air flow acceleration so as to suspend medicament particles in the air-flow and to de-agglomerate them. Within the cup 32 a medicament-containing cartridge 301 can be mounted. As more fully described below, the cartridge 301 is provided with air inlet and outlet holes (FIGS. 5-9), the cup 32 is sized and shaped so as to direct air into the cartridge through the lower inlet hole. The air then generally flows up through the cartridge in an upward direction while producing a dual counter-rotating helical motion, and out of the cartridge and down the mouthpiece as particularly suggested in FIG. 19. As suggested in FIG. 18, excess volume of air can flow around the outside of the cartridge but within the mixing chamber to again mate with the emerging medicament-laden air discharged from the cartridge and flowing into the mouthpiece. Thus, air flowing into the mixing chamber feeds the cartridge inlet holes, helps to extract air flowing out from the cartridge discharge holes, dilutes the medicament-laden air flow, and provide controlled, even concentrations of medicament particles into the mouthpiece air flow. The particle entrainment and dilution in the mouthpiece are provided primarily by the cartridge bypass air” (See [0063)).
Steiner et al also claim an inhaler wherein the inhaler includes a venturi for the regulation of proper volumetric aerosolizing air-flow through the cartridge and bypass-air-flow around the cartridge (See Claim 46).
Steiner et al disclose that the inhaler mixing section holds a cartridge containing a dry powder medicament. The cartridge has two telescopically assembled halves, and each half has an air inlet hole or orifice-port and an air outlet hole or orifice-port. When the halves are twisted so as to align the air holes, the air stream from the check valve enters the cartridge and then picks up, fluidizes and de-agglomerates the medicament powder in the cartridge. The airflow entraining the particles then exits the cartridge and flows through the mouthpiece to the inhaler user (See [0019]).
It is disclosed that the said inhaler includes a cartridge adapted to contain a medicament; adapted to be mounted within the housing mixing cavity; and adapted to be altered in configuration between an open medicament-dispensing configuration and a closed medicament-retaining configuration (See at least claims 2 and 44).
Steiner et al also disclose that “These airstream flows and the sub-stream flows thus result in complete air entrainment of all medicament particles in the cartridge, and delivery of a complete, closely metered medicament dose to the patient” and that the inhaler comprises a check value mechanism adapted to assist that flow of air to the mixing chamber only when there is sufficient inhalation by the patient to deliver a full dose of medicament to the patient (See [0075] and claim 47).
Leonard et al teach a dry powder formulation consisting essentially of an oligo of particle size about 1µ to about 100 µ 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]).
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 Smutney et al, Steiner et al, Wilson et al, Tarara et al and Leonard et al with that of Baker et al and Olschewski 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.
Regarding the amount and dosage of treprostinil, Baker et al teach an amount/dose of from 1 to 5000 µg, which fully meets the claimed 200 µg.
It is further noted that as taught by Olschewski et al, it is well known and commonly practiced method of treating PH with treprostinil delivered by inhalation with a dry powder inhaler. Olschewski et al also provide guidance on the dosage amount and disclose that treprostinil is a prostacyclin analogue. Baker et al teach inhaled prostacyclins including treprostinil for the treatment of pulmonary arterial hypertension for delivery as a dry powder.
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.
Additionally, Wilson et al provides specifics of a suitable inhaler and Smutney et al and Steiner et al provide more details on an efficient device. One with ordinary skill in the art would be motivated to incorporate the details and specifics of Smutney et al and Steiner et al’s device into the instant claimed method and in combination with the teachings of Wilson et al to arrive at a more efficient delivery system. 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).
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.
Regarding the porous particles, Wilson et al teach that the diketopiperazine crystals have interior voids that entrap the drug and disclose the void volume. Tarara et al is also in the same field of endeavor and provide guidance on the porosity and pore size of a particle for inhalation by a breath actuated inhaler and suitable excipients including lactose and mannitol. It would be expected that there is direct correlation between pore size and pore volume. Thus, one of ordinary kill in the art is more than capable of determining the pore volume from pore size and porosity.
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.
Regarding the limitation of residual water content of 0.4%, Leonard et al teach that a dry powder composition for inhalation generally has low moisture content preferably less than 0.5%.
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 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, 3, 8-9, 13 and 15-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-15 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 claims are drawn to a method for treating pulmonary hypertension, the method comprising: administering by oral inhalation a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine (FDKP) and treprostinil, wherein the microcrystalline particles of fumaryl diketopiperazine have a specific trans isomer content of about 45% to 63%, and wherein the treprostinil content is about 20% (w/w) based on total weight of the composition, 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, thereby treating the pulmonary hypertension, and further wherein the FDKP particles are porous, substantially solid, have a specific surface area of about 71 m2/g, and comprise pores having average pore volumes of about 0.43 cm3/g and average pore size from about 23.8 nm to 26.2 nm as determined by BJH adsorption, wherein the dry powder inhaler includes a housing and a body, wherein the body comprises a mounting area for a cartridge that includes the dry powder composition, and the body and the housing are movable relative to one another linearly and are operably configured to engage one another to effectuate the cartridge to be reconfigured to attain an airflow pathway for discharging the powder dose upon an single inhalation, and wherein the cartridge is replaceable and for single use and comprises a lid and a cup which are movable relative to one another in a translational motion.
Reference claims 1-15 are directed to a method of treating pulmonary arterial hypertension comprising administering to a patient in need of treatment by oral inhalation using a dry powder inhaler comprising a dry powder composition comprising up to 200 µg of treprostinil or a pharmaceutically acceptable salt thereof, and/or one or more pharmaceutically acceptable carriers and/or excipients.in claims 12-15 are drawn to an excipient being fumaryl diketopiperazine.
The differences are that the examined claims disclose the dose in % while the reference claims disclose the dose in µg. Additionally, the reference claims do not recite the specific surface area, the trans isomer content or specifics of the inhaler. 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 (i.e. pore volume) are suggested for drug delivery to the pulmonary system. Grant et al also disclose a trans isomer content of about 45% demonstrated improved performance and the particles have a specific surface area of up to about 67m2/g. Baker et al disclose the administered dose of treprostinil in both percentage and microgram and where 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, 8-9, 13 and 15-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13, 15-19 of copending Application No. 17/158,997 (US 20210146071) in view of Grant et al (US 20140271888). 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.
The examined claims are delineated above.
Reference claims 1 is directed to a method for treating pulmonary hypertension, the method comprising: administering a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and treprostinil, wherein the treprostinil content is up to about 20% (w/w) in the composition, and treating the pulmonary hypertension. Claim 16 is drawn to the method of claim 11, wherein the administering provides a dose of about 1 mg to about 15 mg of the dry powder composition. Claim 19 recites the parts and specifics of the inhaler.
The differences are that the reference claims do not recite the specific surface area, the trans isomer content or specifics of the inhaler. However, the differences are obvious to one of ordinary skill in the art as taught by Grant 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 (i.e. pore volume) are suggested for drug delivery to the pulmonary system. Grant et al also disclose a trans isomer content of about 45% demonstrated improved performance.
Accordingly, examined claims and reference claims in view of Grant et al are so close that they are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
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 05/07/26 have been fully considered but they are not persuasive.
Applicant’s first argument is that “amended claim 1 recites about 10 µg to about 750 µg of treprostinil in dose of a dry powder composition. This is a narrow, fully supported, pharmacologically meaningful range of treprostinil that is not taught or suggested by any of the cited references” (See Remarks, page 6, 1st para).
The argument is not persuasive because Olschewski et al teach inhalation of a dose of Treprostinil comprising from 15 to about 100 µg, meeting the amended dose. Baker et al also provide guidance on the dose which can be determined by one of ordinary skill in the art from 10 to 5000 µg, which encompasses 100 and 200 µg. It is also noted that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Applicant’s next argument is that “the Office's reliance on Baker as the primary reference is misplaced. Baker only refers to treprostinil in the background section and solely as an example of existing therapies. The actual disclosure and claimed invention of Baker is prodrug forms of prostacyclin, and Baker does not teach or suggest the use of treprostinil itself” (See Remarks, page 6, 2nd para).
The above argument is not convincing. Baker et al teach inhaled prostacyclins including treprostinil for the treatment of pulmonary arterial hypertension for delivery as a dry powder. While Baker et al disclose compositions comprising other active agents, i.e. other pristacyclines, it does not take away from its teahcings of trperostinil. Baker et al disclose examples of formulations and Example 17 is specifically to treprostinil. Also as evidenced by Olschewski et al, treprostinil is a prostacyclin analogue. Olschewski et al also disclose that it is well known and commonly practiced method of treating PH with treprostinil delivered by inhalation with a dry powder inhaler.
Next argument is that “Claim 1 is further amended to recite that the microcrystalline particles of fumaryl diketopiperazine comprise a residual water content of about 0.4%. Support for this limitation is found at paragraph [0117] of the present disclosure. The Office alleges Wilson, as evidenced by Grant (US Patent No. 8,551,528), render the diketopiperazine microparticles of the present claims obvious. Applicant respectfully submits that none of the cited references teach or suggest the residual water content of the present claims” (See Remarks, page 7, 2nd para).
This argument is also not convincing. The added limitation of water content was taught by Leonard et al, which teach that dry powders should have a water content of less than 0.5%.
The other argument is that “the process used to produce the FDKP particles of the present disclosure is unique. The present application demonstrates that the recited residual water content arises from a specific and tightly controlled preparation process. …… While Wilson and Grant each disclose a FDKP preparation, neither is identical to the present disclosure. The Office acknowledges that Wilson (at [0098]) and Grant (at column 11, lines 62-66) form the FDKP precipitate at 16°C ± 2°C. This temperature range does not overlap with the 25°C ± 5°C of the present disclosure. This distinction is dispositive because residual water content is inherently dependent on formation conditions and a person of ordinary skill would not reasonably expect identical residual moisture from non-overlapping process conditions” (See Remarks, page 7, 3rd and 4th para).
The above argument is similarly found unconvincing. Firstly, it is noted that Grant et al disclose a temperature of about 16°C. ± about 2°C. That is about 16+ about 2 includes 18-20. The instant Specification discloses about 25° C.±5°C which includes 19-20. Thus, the ranges both overlap and are very close. Secondly, the prior art teach that a dry powder formulation should have a water content that is less than 0.5%. Thus, one of ordinary skill in the art would have made all attempts to make the powder as dry as needed. This includes the powders disclosed by Grant et al and Wilson et al. Thirdly, the only recitation in the Specification is 4 samples that all had a water content of 0.4%. It has not been compared with any other ranges to show the difference in outcomes.
Applicant further argues that “the claimed residual water content is not an arbitrary optimization parameter but is important to achieving consistent particle morphology and aerodynamic performance. This is demonstrated in the specification where powders with 0.4% moisture exhibit controlled surface area (59-63 m²/g), pore size (23-26 nm) and pore volume (about 0.43 cm³/g). The combination of all of these elements is not taught or suggested in the cited art. Lastly, controlling water content to 0.4% in spray-dried porous particles is non-trivial and no reference suggests it can be reproducibly achieved or beneficial” (See Remarks, pages 7-8).
The argument has been given full consideration and found unconvincing. The references as stated above teach each and every element of the claimed method and it would have been obvious to combine them to arrive at the claimed invention. As stated above, the water content of less than 0.5% is taught by Leonard et al and would have been more than obvious to one of ordinary skill in the art to make sure the dry powder is indeed as dry as possible. Baker et al and Olschewski et al clearly teach inhalation, by a dry powder of a composition comprising treprostinil for treating PH and Wilson et al, Steiner et al, Tarara et al, Leonard et al and as evidenced by Grant et al teach all the limitations of the particles, and device.
Applicant made no argument regarding the rejection of claims under provisional obviousness type double patenting over Application No. 16/434,938. This rejection is maintained.
Applicant’s arguments regarding the rejection of claims under provisional obviousness type double patenting over Application No. 17/158,997 are unpersuasive. While there was a restriction in Application No. ‘997, withdrawn claims 11-13 and 15-19 are drawn to the method of treating PH, which are the same as instant claims. Thus, the rejection is minatianed.
Claims 1, 3, 8-9, 13 and 15-23 are rejected.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
Prosecution Insights