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 01/21/26 and Remarks filed on 07/23/25. Claims 1 and 12 have been amended, claims 2, 7-8, 21 and 33 have been canceled and new claim 35 has been added. Accordingly, claims 1, 9-18, and 34-35 are pending and under examination on the merits.
The Specification has also been amended to include a recitation from original claims.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 is indefinite for depending on a canceled claim. Claim 9 depends on claim 8 which has been canceled.
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.
Applicant claims:
Claim 1 is directed to a pressurized canister comprising a formulation, the formulation comprising an active pharmaceutical ingredient comprising umeclidinium bromide, and vilanterol trifenatate, one or more propellants, wherein the propellant comprises HFC-227, HFC-152a, HFC- 134a, or any combination thereof, and poly(ethylene glycol) having a number average molecular weight of 100 to 500, the poly(ethylene glycol) being 0.0075% to 0.02% by weight of the formulation; wherein an interior of the pressurized canister is coated with a coating comprising a copolymer of a C2-C4 fluoroalkylene and a C3-C6 fluoroalkylene.
Claims 1, 9-18, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Malhotra et al (US 20170119744) in combination with Baker et al (US 20120309725) and Zhu et al (US 20180071231).
Malhotra et al teach a pharmaceutical composition comprising one or more bronchodilators, or one or more pharmaceutically acceptable derivatives thereof, and one or more pharmaceutically acceptable excipients. Preferably, the one or more bronchodilators comprise one or more anticholinergic agents and one or more β2-agonists. Preferably, the one or more anticholinergic agents comprise umeclidinium and the long acting β2-agonists (LABAs) include salmeterol, abediterol, formoterol, vilanterol, etc, (See Abstract, claim 1, [0011], [0037] and [0045]).
The said pharmaceutical compositions are formulated for inhalation and may therefore be administered by any suitable methods used for delivery of the drugs to the respiratory tract, such as an aerosol composition, administered by a metered dose inhaler (MDI), dry powder inhaler (DPI) or nebulizer (See [0070]).
The said one or more pharmaceutically acceptable excipients includes propellants such as HFC/HFA propellants, co-solvents, etc, (See [0072]). The said HFC/HFA propellants are suitable to enable the medicament to be administered via a pressurized MDI and may comprise, one or more of 1,1,1,2-tetrafluoroethane (HFA-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), etc, (See [0073]-[0074]).
Malhotra et al teach that “Suitable surfactants which may be employed in an aerosol composition of the present invention include those which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose inhaler” (See [0077]).
The said co-solvent may comprise glycols such as propylene glycol, polyethylene glycols, etc, (See [0076]).
In Example 3, Malhotra et al disclose a formulation comprising umeclidinium bromide, PEG 400 and HFA 134 or 227.
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It is shown that umeclidinium bromide is delivered at a dose per spray of 62.5 mcg, and the amount of PEG is 0.3% of the formulation. The amount of PVP is 0.001%, and no alcohol or water is present. The formulation comprises a β2 agonist and is in suspension form. The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans (See [0115]-[116]).
Malhotra et al further teach that the formulation is in the form of an aerosol composition for administration using an MDI, packed in plain aluminum cans or SS (stainless steel) cans wherein, such cans may be suitably treated to avoid any adherence of the active on the walls thereof using techniques known in the art, for example coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) (See [0096] and [0077]).
Evidence
The Instant Specification states that “Most commonly, the copolymer is a copolymer of hexafluropropylene and tetrafluoroethylene. Such copolymers are sometimes referred to in the art as FEP” (See [0025] of published spec).
Malhotra et al do not expressly disclose the amount of polyethylene glycol as recited in amended claim 1, or an embodiment wherein the formulation contains both umeclidinium bromide and vilanterol trifenatate or the amount, as recited in amended claim 1 or claim 34. These would have been obvious from the combination of references, including Baker et al and Zhu et al.
Baker et al teach a composition for inhalation comprising umeclidinium bromide (Compound I) and vilanterol (Compound II) wherein umeclidinium bromide (Compound I) is present in an amount of 62.5 mcg/dose and vilanterol (Compound II) is present in an amount of 1 to 100 mcg/dose (See [0045], [0047], and claims 30-31).
Baker et al disclose that Compound (I) and Compound (II), and the combination thereof, are considered to have potential in the treatment of inflammatory or respiratory tract diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis, small airways disease, bronchiectasis and cystic fibrosis (See [0039]).
It is also disclosed that the said spray compositions for inhalation may be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant (See [0092] and claim 36).
It is disclosed that the said combination of active agents is further combined with a surface-active agent and/or a co-solvent and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof (See [0093]).
Zhu et al teach compositions containing albuterol, ipratropium, and a propellant as well as aerosol canisters and inhalers, such as metered dose inhalers, containing such compositions (See abstract).
Disclosed is a composition comprising particulate albuterol or a pharmaceutically acceptable salt or solvate thereof; particulate ipratropium or a pharmaceutically acceptable salt or solvate thereof; and at least one of 1,1,1,2,3,3,3-heptafluoropropane (also known as HFA-227) and 1,1,1,2-tetrafluoroethane (also known as HFA-134a) (See [0003] and [0021]).
Zhu et al disclose that additional components including ethanol and a surfactant may be added. When ethanol is used, it is typically employed in relatively low concentrations. One or more surfactant can also be used to facilitate suspension of the particles in the formulation. Typical surfactants include oleic acid, polyethylene glycol, polyvinylpyrrolidone, or combinations thereof. When polyethylene glycol is employed, it can be any suitable grade. PEG 100 and PEG 300 are most commonly employed. The surfactant is typically present, on a weight percent basis, in an amount no less than 0.0001, no less than 0.01, no less than 0.05, no less than 0.11, no less than 0.12, no less than 0.29, no less than 0.5, or no less than 1, such as 0.001 wt. % to 0.1 wt. %. Particular applications use 0.01 wt. % (See [0025]-[0027]).
Typical metered dose inhalers for the pharmaceutical formulations described herein contain an aerosol canister fitted with a valve. The container and valve typically include an actuator. Most actuators have a patient port, which is typically a mouthpiece, for delivering the formulation contained in the canister (See [0033]-[0035]).
It is disclosed that when the valve stem is released, the pharmaceutical formulation enters the valve, typically to the pre-metering chamber, through an annular space and then travels to the metering chamber (See [0036]).
Upon actuation, typical inhalers, such as metered dose inhalers, that are filled with one of said formulations can produce a fine particle mass of ipratropium, particularly ipratropium bromide or ipratropium bromide monohydrate that is from 3 µg to 20 µg per actuation and a fine particle mass of albuterol, particularly albuterol sulfate, that is from 16 µg to 1116 µg per actuation (See [0039]).
At least one of the various internal components of an inhaler, such as a metered dose inhaler, such as one or more of the canister, valve, gaskets, seals and the like, can be coated with one or more coatings. If the coating solvent is an hydrofluoroether, it is preferred if the coating solvent comprises a C4 to C10 hydrofluoroether. Examples of suitable hydrofluoroethers include those selected from the group consisting of methyl heptafluoropropylether, ethyl heptafluoropropylether, methyl nonafluorobutylether, ethyl nonafluorobutylether and mixtures thereof (See [0049] and [0058]-[0063]).
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 Malhotra et al, Baker et al and Zhu et al to arrive at the instant invention.
One of ordinary skill in the art would have been motivated to do so because Malhotra et al teach a method of making an aerosol composition for administration via an MDI comprising one or more active agents including umeclidinium bromide and vilanterol trifenatate, a polyethylene glycol and an HFA propellant and coat the interior surface of the canister including the valve and the actuator with a suitable polymer coating material including FEP. Malhotra et al teach that such formulation would be effective in treating respiratory conditions and exhibit improved delivery because the interior surface of the canister is suitably coated. Malhotra et al teach that MDIs are an effective device for such delivery and comprise of surfaces such as walls, valves, etc.
Baker et al teach the combination of umeclidinium bromide and vilanterol trifenatate and their dose amounts. Thus, it would have been obvious to one of ordinary skill in the art to have taken the specific combination of Baker et al into the compositions of Malhotra et al with a reasonable expectation of success, particularly in treating diseases mediated via the M3 muscarinic acetylcholine receptor and/or the beta-2 adrenoreceptor, for example in the prophylaxis and treatment of inflammatory or respiratory tract diseases.
Zhu et al is also directed to a pressurized formulation for inhalation vi a metered dose inhaler comprising two active agents including a bronchodilator and a cholinergic agent, a propellant and excipients including suitable surfactants and solvents. Zhu et al disclose that suitable surfactants include polyethylene glycol preferably PEG 100 or PEG 300 which is present in the formulation at concentrations including 0.01 to 1% such as 0.001 wt. % to 0.1 wt. % and particularly 0.01 wt. %. Zhu et al further suggest coating the interior surfaces of the said inhaler with a suitable coating agent to provide formulation stability.
As such one of ordinary skill in the art having possession of all references would have been motivated to have incorporated the teachings of Malhotra et al, Baker et al and Zhu et al because all three teachings are obvious variations of one another. Malhotra et al teach combination of agents suitable for treating respiratory conditions the active agents including umeclidinum bromide and abediterol. Baker et al teach the specific combination of umeclidinum bromide and vilanterol trifenatate are specifically beneficial in treating respiratory conditions. Additionally, one of ordinary skill in the art would have realized that one cholinergic agent can be substituted by another in the same formulation for the same purpose. Malhotra et al teach that polyethylene glycol is a suitable excipient, and while they use PEG 400 in one example at 0.3%, the broadest reasonable interpretation is that it may be any molecular weight. Zhu et al states that preferred are PEG 100 and PEG 300 and disclose lower amounts including 0.01% is sufficient tom impart its benefits to the formulation. Thus, it would have been obvious to one of ordinary skill in the art that PEG 300 can be chosen as the polyethylene glycol of Malhotra et al at 0.01% with a reasonable expectation of success. Zhu et al also provide guidance on the concentration range of agents including surfactant.
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 concentration range of PEG in the formulation, MPEP 2144.05 states: “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Claims 1, 9-18, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Malhotra et al (US 20170119744) in combination with Zhu et al (US 20180071231) and Malhotra et al (WO 2012110770).
Teachings of Malhotra et al ‘744 and Zhu et al are delineated above and incorporated herein.
Malhotra et al ‘744 teach a composition comprising one or more bronchodilators including an anticholinergic such as umeclidinium bromide and a β2 agonist such as abediterol or vilanterol.
The combined references do not expressly disclose a combination of umeclidinium bromide and vilanterol trifenatate, as in amended claim 1, or the amount of vilanterol as claimed in claim 34. This would have been obvious in view of Malhotra et al ‘770.
Malhotra et al ‘770 teach pharmaceutical compositions for inhalation comprising glycopyrrolate (an anticholinergic) and a beta2-agonist (See Abstract, and claim 1). In one embodiment the composition comprises glycopyrrolate and vilanterol (See Page 6, lines 1-2; page 8 and page 10, lines 1-2 and claim 6).
A particularly preferred pharmaceutically acceptable salt of vilanterol is vilanterol trifenatate, which may be present in an amount of from about 3 µg to about 50 µg (See paragraph bridging pages 13-14).
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 Malhotra et al ‘770 with the combination of Malhotra et al ‘744 and Zhu et al to arrive at the instant invention. The reasons for combining Malhotra et al ‘744 and Zhu et al are delineated above and incorporated herein, as they read on claim 1.
It further would have been obvious to one of ordinary skill in the art to have combined the teachings of Malhotra et al ‘770 with that of Malhotra et al ‘744 and Zhu et al because Malhotra et al ‘744 teach the therapeutic advantage of combining two or more bronchodilators including anticholinergics and β2 agonists and lists abediterol and vilanterol as effective β2 agonists. Malhotra et al ‘770 also teach a combination of glycopyrrolate (an anticholinergic) and vilanterol.
Malhotra et al ‘744 teach a method of making an MDI comprising one or more active agents including umeclidinium bromide and/or vilanterol trifenatate, a polyethylene glycol and an HFA propellant and coat the interior surface of the canister including the valve and the actuator with a suitable polymer coating material including FEP. Malhotra et al teach that such formulation would be effective in treating respiratory conditions and exhibit improved delivery because the interior surface of the canister is suitably coated. Malhotra et al ‘744 exemplifies a composition comprising umeclidinium bromide and abediterol. Malhotra et al ‘770 teach combining an anticholinergic (glycopyyronium) and a β2 agonist including vilanterol trifenatate and provide guidance on the amount of it.
Thus, it would have been obvious to substitute Malhotra et al ‘744’s β2 agonist, abediterol with Malhotra et al ‘770’s vilanterol trifenatate and arrive at the claimed invention with a reasonable expectation of success, as Malhotra et al ‘770 disclose the compound and provides guidance on the dosage amount.
It is generally considered to be prima facie obvious to substitute components which are taught by the prior art to be well known and useful for the same purpose in order to form a composition that is to be used for an identical purpose. The motivation for substituting them flows from their having been used in the prior art, and from their being recognized in the prior art as useful for the same purpose. As shown by the recited teachings, instant claims are no more than the substituting conventional components of β2 agonists. It therefore follows that the instant claims define prima facie obvious subject matter. Cf. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958).
Regarding the concentration range of PEG in the formulation, MPEP 2144.05 states: “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
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, 9-18, and 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-8, 13-20, 36-37 of copending Application No. 17/620,325 (US 20220241524) in view of Malhotra et al (US 20170119744). The Obviousness Double Patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims and would have been obvious over the reference claims in view of Malhotra et al ‘744.
Specifically, the examined claims are directed to a pressurized canister comprising a formulation, the formulation comprising an active pharmaceutical ingredient comprising umeclidinium or a salt thereof, vilanterol or a salt thereof, or a combination of two or more of the foregoing; one or more propellants, and poly(ethylene glycol) having a number average molecular weight of 375 or less; the wherein an interior of the poly(ethylene glycol) being 0.001% to 0.11% by weight of the formulation; wherein an interior of the pressurized canister is coated with a poly(fluoroalkylene) polymer or a copolymer of poly(fluoralkylenes). Claims 33 and 34 are directed to the formulation of claim 1 wherein umeclidinium or a salt thereof and vilanterol or a salt thereof are present.
Reference claims are directed to a pressurized canister comprising a formulation, the formulation comprising umeclidinium or a pharmaceutically acceptable salt thereof and vilanterol or a pharmaceutically acceptable salt thereof, HFC-152a; and 0.005% to 0.05% PVP by weight of the formulation; wherein the interior of the pressurized canister is coated with a poly(fluoroalkylene) polymer or a copolymer of poly(fluoralkylenes).
The examined claims differ from the reference claims in that examined claims require PEG 375 or less and one or more propellants, while reference claims require PVP and HFC 152. The difference however, are obvious, especially in view of the teachings of Malhotra et al.
Malhotra et al teaches formulations comprising umeclidinium and vilanterol which exhibit significant bronchodilation effect (See [0016]) and a HFC/HFA propellants including (HFA-134(a)), (HFA-227), or HFC-152a (See [0074]). Malhotra et al also teach that the formulation may comprise one or more excipients including polyvinylpyrrolidone or polyethylene glycol and provide suggestion on their suitable amounts. PVP may be added at for example, 0.001% of the formulation.
Thus, it would have been obvious to one of ordinary skill in the art to have selected PEG, PVP or a combination of them for the said formulations, based on the teachings of Malhotra et al. Therefore, examined claims are an obvious variation of reference claims and 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.
Van Oort et al (WO 2013153146).
Van Oort et al teach a composition for inhalation comprising umeclidinium bromide and vilanterol trifenatate at a ratio of from 10:1 to 1:1, particularly 5:1 (See page 6, lines 25-36).
Lewis (Metered dose inhalers: old and new).
Lewis reviews the metered dose inhalers (MDI), their parts and function and discloses that MDIs inherently contain a metering valve and an actuator and that the actuation of the actuator releases medicine from the canister.
It is disclosed that “On actuation of the MDI (Figure 1B), the MDI’s metering chamber becomes closed to the formulation reservoir and opens to the atmosphere, resulting in the expansion of the propellant-based formulation and atomisation through the actuator orifice” (See Introduction, 2nd para).
Further it is disclosed that “The additional support provided by the modified actuator was introduced to prevent accidental opening of the valve as a result of unintentional axial movement of the valve stem. The updated design remains an important feature of present actuators” (See 2.1, 1st para).
Slowey et al (US 20190054010)
Slowey et al teach compositions containing tiotropium or a pharmaceutically acceptable salt or solvate thereof, citric acid or a salt thereof, glycerol, ethanol, and a propellant, as well as aerosol canisters and inhalers containing the same (See abstract).
The said propellant is one or both of the two common propellants for aerosol formulations: HFA 134a and HFA-227 (See [0024]).
The said compositions comprise suitable surfactants including glycerol or polyethylene glycol, preferably PEG 100 or PEG 300. It is present at a concentration range of no more than 2%, no more than 1% or no more than 0.75% (See [0028]-[0029]).
Slowey et al also disclose that the container and valve typically include an actuator. Most actuators have a patient port, which is typically a mouthpiece, for delivering the formulation contained in the canister. The patient port can be configured in a variety of ways depending on the intended destination of the formulation (See [0037]).
Further disclosed is that the total dose of tiotropium, such as tiotropium bromide delivered in a single actuation can be any suitable dose depending on the nature of the condition and patient population that the inhaler is designed to treat (See [0042]).
Slowey et al teach that at least one of the various internal components of an inhaler, such as a metered dose inhaler, such as one or more of the canister, valve, gaskets, seals, and the like, can be coated with one or more coatings. The coating solvent usually comprises an alcohol or a hydrofluoroether. Polymers, such as polyethersulphones, fluoropolymers such as PTFE, FEP, or PFA, can also be included (See [0051], [0063] and [0079]).
Jinks et al (US 20170152396).
Jinks et al teach that methods of making components for a medicinal delivery device in which a primer composition comprising a silane having two or more reactive silane groups separated by an organic linker group is applied to a surface of a component, then a coating composition comprising an at least partially fluorinated compound is applied to the primed surface (See abstract).
Jinks et al also teach methods of making metal components in which a coating composition comprising an at least partially fluorinated compound is applied to a surface cleaned with a solvent. The method ccomprising a) providing a component of a medicinal delivery device, b) providing a coating composition comprising an at least partially fluorinated compound (See [0039]-[0041]).
Jinks et al further disclose that the medicament may comprise a medicament that may be a drug, vaccine, DNA fragment, etc. Suitable drugs include those for the treatment of respiratory disorders, e.g., umeclidinium, glycopyrrolate, salmeterol, fluticasone, vilanterol, abediterol, etc, a salt thereof or mixtures of them (See [0070]).
It is disclosed that the medicinal delivery device is preferably a metered dose inhaler or a dry powder inhaler. Thus, preferably, the component (preferably comprising metal) is a component of a metered dose inhaler selected from the group consisting of an actuator, an aerosol container, a ferrule, a valve body (that defines a metering chamber), a bottle emptier, a valve stem and a compression spring (See [0071]).
An aerosol formulation used in a metered dose inhaler typically comprises a medicament and liquefied propellant including HFA 134a, HFA 227 or mixtures thereof. Pressurized metered dose inhalers including aerosol containers (in particular metal aerosol containers) whose interior surfaces are coated are particularly advantageous for containing and delivering medicinal aerosol formulations comprising a medicament that is dispersed in said formulation (See [0072] and [0075]).
Jinks et al disclose an embodiment wherein the said medicinal aerosol formulation contains low amounts of ethanol (less than 5 wt % with respect to the formulation), or is substantially free (less than 0.1 wt % with respect to the formulation) or free of ethanol (See [0076]).
Jinks et al state that the coated test valves and control valves were incorporated into metered dose inhaler and used to deliver a formulation of micronised salbutamol sulphate suspended in HFA134a. The target dose of the product was 100ug per actuation and the cold filling technique was employed for the filling process (See [0249]).
Response to Arguments
Applicant's arguments filed 01/21/26 have been fully considered but they are not persuasive.
Applicant’s amendments to the claims have necessitated modified grounds of rejections. Applicant’s arguments so far as they pertain to the maintained references and rejections are discussed below.
Applicant’s first statement is that “At the time of filing, the only inhaler form for delivering umeclidinium bromide and vilanterol trifenatate was a dry powder inhaler, which is not suitable for all patients because it depends on inspiratory effort and many patients cannot inhale deeply enough to receive an effective dose” (See Remarks, page 8).
This statement is not sufficient to place the claims in condition for allowance. While the only inhaler form of the combination available in the market may have been the dry powder, the suspension and solution of it was disclosed in the prior art well before the filing of this Application. For example, Baker et al published in 2012, clearly discloses that suspension or solution can be prepared and provides guidance on the additives required to make this suspension. Baker et al teach:
Spray compositions for inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the pharmaceutical product and a suitable propellant such as …. 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid derivative” (See [0092]-[0094]).
Therefore, a pressurized pack (canister) comprising a suspension comprising umeclidinium, vilanterol, an HFA propellant and a surfactant has been disclosed.
Next statement is that Applicants have discovered a problem, identified a source of the problem and discovered a solution to the problem. Applicant argues that the problem was deposition of the umeclidinium and vilanterol on the canister interior even when the canister is coated and the solution is incorporating PEG 100-500 at 0.0075 to 0.02 wt% of the formulation. Applicant points to Example 1, Comparative example 1 and data provided in Tables 1-3 (See Remarks, page 9).
The Specification discloses that they compared a formulation according to Example 1, with the Comparative formulation 1. Formulation 1 is said to have the bottle, components and valves “coated with a fluoropolymer coating according to the general process described in Example 2 of U.S. Patent Application Publication 2017/0152396 A1, Jinks et al. The formulation used was umeclidinium bromide (1.237 mg/mL), vilanterol trifenatate (0.667 mg/mL), and PEG 300 (0.01 weight percent) in HFC-227 propellant” (See [0040] of published Spec).
The Specifications then states that “Comparative Example A. MDIs were prepared using the same method as described in Example 1 with the exception that the PEG 300 was not included in the formulation” (See [0044] of the published Spec).
Thus, the data compares two similar formulations one with 0.01 wt% PEG 300 and one without. That is, the advantage in percent recovery of the medicaments (i.e. umeclidinium and vilanterol) is due to the addition of PEG. The Specification does not compare formulations comprising other active agents such as those recited by Zhu et al, or other amounts of PEG as disclosed by Malhotra et al to persuasively argue that they discovered a benefit from PEG 100-500 at 0.0075 to 0.02 wt%. Both Malhotra et al and Zhu et al teach making inhalable suspensions comprising active agents and a surfactant including a PEG such as PEG 300 and Baker et al teach the same formulations comprising a surfactant. Therefore, not only the combination of prior art references would have led one of ordi8nary skill in the art to the same formulations, the solution to the problem was disclosed by the prior art. For example, Malhotra et al, specifically, teach that surfactants improve the performance of valve systems of the metered dose inhaler.
Regarding the rejection of claims over Malhotra et al ‘744 and Zhu et al, Applicant’s argument is that 1- A person of ordinary skill in the art would not have been motivated to substitute the amount of PEG disclosed in Zhu for the PEG 400 in the umeclidinium-containing formulation of Example 3 of Malhotra' 744 let alone have a reasonable expectation of success in doing so. And 2- Malhotra' 744 and Zhu are directed to formulations with different active ingredients. Zhu teaches a formulation that includes ipratropium, an anticholinergic agent, whereas Example 3 of Malhotra' 744 (as relied upon by the Examiner) includes umeclidinium, a different anticholinergic agent. Even though ipratropium and umeclidinium fall within the same general compound class, compounds within a class can have materially different physicochemical properties that can affect formulation behavior, and therefore are not necessarily interchangeable in the same formulation. Moreover, in view of Malhotra'744 and Zhu, a person of ordinary skill in the art would not have reasonably expected that including PEG in the claimed amount of 0.00750o to 0.0200 by weight of the formulation would yield a desirable formulation (See Remarks, pages 10-12).
The above arguments are not persuasive. Malhotra et al teach an aerosol composition comprising one or more bronchodilators, propellants and surfactants. It is stated:
“According to an aspect of the present invention, there is provided a pharmaceutical composition comprising one or more bronchodilators. Preferably, the one or more bronchodilators comprise one or more anticholinergic agents and one or more β2-agonists. Preferably, the one or more anticholinergic agents comprise umeclidinium or darotropium. Preferably, the one or more β2-agonists comprise abediterol” (See [0037]), and that
“Suitable surfactants which may be employed in an aerosol composition of the present invention include those which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose inhaler” (See [0077]).
While PEG is only exemplified in one formulation comprising umeclidinium and abediterol, Malhotra et al’s disclosure teaches formulations that can contain any two or three bronchodilators and surfactant. Malhotra et al also teaches the reason for adding a surfactant. Zhu et al also discloses suspensions comprising two bronchodilators, and teach that typical surfactants are included, such as oleic acid, polyethylene glycol, and that preferably PEG 100 and PEG 300 are employed. Zhu et al also provide guidance on the concentration of PEG including ranges that are claimed and tested.
Therefore, Zhu et al’s teachings would have motivated one of ordinary skill in the art to incorporate their concentration ranges of PEG into the formulations of Malhotra et al with a reasonable expectation of success. There is nothing disclosed in Malhotra et al or Zhu et al that would suggest their recommendations on adding a suitable surfactant are effective in the specific disclosures provided.
For example, regarding the modifications on the concentration range of PEG, MPEP 2144.05 states: “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Thus, the normal desire of scientists or artisans to improve upon what is already generally known, here is that Zhu et al teach that PEG can be added to an aerosol suspension at concentration ranges from 0.001 to 1% by weight. They prefer smaller ranges such as 0.01% or 0.1%. This teaching provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. It is further noted that generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. The specification does not support any criticality of the claimed range.
Then Applicant argues that “The Examiner asserts that, "one of ordinary skill in the art would have realized that one cholinergic agent can be substituted by another in the same formulation for the same purpose." See Office Action, page 10, 2. As explained in MPEP §2144.03(A), Official Notice is permissible only for facts capable of instant and unquestionable demonstration as being well- known. A reasonable expectation of success that one cholinergic agent may be substituted for another in the same formulation is not such a fact. …. Accordingly, if the Examiner maintains that compounds of the same class are interchangeable in the same formulation, Applicant respectfully requests that the Examiner identify specific documentary support for that assertion” (See Remarks, page 12).
The argument is neither convincing nor sufficient to overcome the rejections. The statement that it would have been obvious to modify… is a rational for obviousness not an Office Notice, as stated. As stated in MPE, “RATIONALE MAY BE IN A REFERENCE, OR REASONED FROM COMMON KNOWLEDGE IN THE ART, SCIENTIFIC PRINCIPLES, ART-RECOGNIZED EQUIVALENTS, OR LEGAL PRECEDENT”. Any rejection under USC 103, requires a rational for obviousness. However, documentary support for this rational is in the many references of record. As stated above Malhotra et al ‘744 teach suspension formulations that can comprise any two or three bronchodilators, including a β2-agonists (LABAs) including salmeterol, formoterol, indacaterol, olodaterol, carmoterol, milvetrol, abediterol and vilanterol and LAMA's such as indacaterol, aclidinium and formoterol, aclidinium and glycopyrrolate, tiotropium, olodaterol and umeclidinium. Specific examples include umeclidinium bromide and abediterol, Baker et al teach suspension formulations comprising umeclidinium bromide and vilanterol trifenatate, Malhotra et al ‘770 teach suspension formulations comprising glycopyrrolate and a beta2 agonist selected from vilanterol, olodaterol, formoterol and indacaterol, Zhu et al teach suspension formulations comprising albuterol and ipratropium bromide, Jinks et al teach, bronchodilators, such as albuterol, terbutaline, ipratropium, oxitropium, tiotropium, aclidinium, umeclidinium, glycopyrrolate, salmeterol, formoterol, procaterol, indacaterol, milveterol, olodaterol, vilanterol, abediterol, etc.
Regarding the rejection of claims over Malhotra et al ‘744, Zhu et al and Malhotra et al ‘770 argues that “a reasonable expectation of success in substituting a medicament of one class with a different medicament of the same class is not given. The mere fact that compounds fall within the same general class does not instantly and unquestionably demonstrate to a person of ordinary skill in the art that substitution would yield a successful formulation” (See Remarks, Page 3).
The above argument is also not persuasive. As stated above the combination of Malhotra et al ‘744, Zhu et al and Malhotra et al, would have led one of ordinary skill in the art to the same compositions as claimed. Malhotra et al ‘744 teach a suspension composition that may comprise umeclidinium and vilanterol as well as a propellant and a surfactant. They provide guidance on the dose of umeclidinium bromide. Malhotra et al ‘770 teach similar compositions and provide dose of vilanterol trifenatate. It would have been obvious to one of ordinary skill in the art to take guidance from Malhotra et al’770 on the safe and effective dose range of vilanterol with a reasonable expectation of success.
Applicant made no argument regarding the rejection of claims under obviousness type double patenting over reference claims of copending Application 17/620,325 in view of Malhotra et al.
Claims 1, 9-18, and 34-35 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616