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 .
Claims 36-55 have been presented for examination on the merits.
Priority
This Application is a continuation of Application No. 17/281,399 filed on 03/30/2021 which is a 371 of PCT/IB2019/058295 filed on 09/30/2019 which claims benefit to two provisional Applications filed on 10/01/2018.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41-44, 47, 49 and 52-53 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 is rejected as being indefinite for reciting “albuterol sulfate or a pharmaceutically acceptable salt thereof”. This is indefinite because “sulfate” is the salt of albuterol. Therefore, it is not clear what the claim is drawn to.
Claims 42-44 are rejected as being indefinite for reciting mL in the range without indicating what the said unit of mL is referring to. Is it the propellant, total volume of the composition or something else? Claim 1 does not recite a liquid formulation.
Claims 47 and 49 are indefinite for reciting concentration ranges in percentages without indicating what the said percentage is based on. Are they based on the total weight of the composition, the propellant, part of it or something else?
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 47 recites the broad recitation from 0.0001 wt% to 1 wt%, and the claim also recites optionally 0.001 wt% to 0.1 wt% and optionally 0.1 wt% which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 52-53 recite the limitation "particle size" in the composition of claim 36. There is insufficient antecedent basis for this limitation in the claim. Claim 36 does not support this limitation. There is no recitation of particles in claim 36.
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.
Claims 36-39, 41, 45-47 and 50-55 are rejected under 35 U.S.C. 103 as being unpatentable over Lulla et al (US 20130160761).
Lulla et al teach a pharmaceutical aerosol composition comprising at least one hydrofluoroalkane propellant; at least one active agent complexed with an adjuvant; and, optionally, at least one pharmaceutically acceptable excipient (See abstract). The said active agent may be in amorphous, crystalline, monohydrate or anhydrous form (See [0067]). It is further disclosed that the active agent in the composition may be ipratropium bromide anhydrous- PVP complex or monohydrate and HFA 227(See [0105], composition 4).
Regarding claims 36, 39 and 41, Lulla et al exemplify a composition comprising salbutamol sulphate-PVP, Ipratropium-PVP complex, lactose and HFA-227 (See composition 15). It is disclosed that the active agent used in the process of preparing the complex with an adjuvant may be in amorphous, crystalline, monohydrate or anhydrous form (See [0067]).
Lulla et al disclose that preferably, the said pharmaceutical aerosol composition comprises bronchodilators such as tiotropium (e.g., as the bromide salt), salbutamol (i.e. albuterol) (e.g., as the sulphate salt), etc (See 0051]).
It is disclosed that suitable HFA propellants for the said compositions include 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227). The said HFA propellants may be used alone or in a mixture of HFA propellant and another miscible adjuvant (see [0072] and [0073]).
Regarding claims 37-38 and 44-47, Lulla et al teach that the said pharmaceutical aerosol composition comprises at least one pharmaceutical active agent complexed with an adjuvant, at least one hydrofluoroalkane (HFA) propellant and optionally other suitable excipients (See [0034]). In a particularly advantageous embodiment, the adjuvant is a polymer, preferably a polyvinylpyrrolidone (PVP), which when complexed with drugs, they yield good quality pharmaceutical aerosol suspensions (See [0035]). The amount of the said adjuvant in the drug-adjuvant complex are 0.5%, 1%, 2%, etc, by weight of the drug (See [0039]-[0040]).
As for the homogeneity of the suspension, Lulla et al disclose that an object of the said composition is to provide a pharmaceutical aerosol composition with dose uniformity throughout the life of the can, and that it was surprisingly found that when the drug was complexed with an adjuvant such as PVP, aggregation of fine drug particles was reduced significantly and hence keeping the composition stable during the storage period. It was also found that the composition continued to exhibit uniform delivered dose characteristics throughout the life of the MDI (See [0025] and [0033]).
Regarding claims 52-53, Lulla et al teach that the said drug-adjuvant is in particulate (micronised form). At least 95% by weight of the particles have a diameter of from 0.5 to 10 micrometers, and most preferably from 0.5 to 5 micrometers (See [0040]). Preferred drugs include ipratropium bromide and tiotropium bromide (See [0043], [0047] and claim 13).
Regarding claims 36 and 54-55, Lulla et al exemplify an aerosol composition comprising ipratropium bromide anhydrous-PVP complex and HFA-227, placed in a canister of a metered dose inhaler (See [0101]-[0104]).
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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 followed the teachings of Lulla et al to arrive at the instant invention.
One of ordinary skill in the art would have been motivated to follow Lulla et al’s teachings on making a formulation comprising anhydrous ipratropium bromide because Lulla et al teach a composition comprising ipratropium bromide anhydrous- PVP complex and HFA 227 and states that the anticholinergic agent can be present in anhydrous or monohydrate form. Lulla et al meet the remaining claimed limitation as they teach and motivate adding a surfactant and second active agent including albuterol (salbutamol). Lulla et al further provide guidance on the suitable particle size range of the active agent and astable homogenous suspension. The formulations are placed in and dispensed from a metered dose inhaler.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claims 36-39 and 41-55 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al (WO 2016164508) in view of Shur et al (Influence of crystal form of ipratropium bromide on micronisation and aerosolization behavior in dry powder inhaler formulations) or CN 107033140.
Zhu et al teach 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 (HFA-227) and 1, 1,1,2-tetrafluoroethane (HFA-134a) (See Summary).
Regarding claims 36, 41 and 51, Zhu et al disclose that when the concentration of albuterol is discussed, it refers to albuterol sulfate, and when the concentration of ipratropium is discussed, it refers to ipratropium bromide monohydrate. It should therefore be understood that if another form, hydrate, or salt of ipratropium is used, the concentration of that other form or salt should be calculated on a basis relative to ipratropium bromide monohydrate. A person of ordinary skill in the relevant arts can easily perform this calculation by comparing the molecular weight of the form, hydrate, or salt of ipratropium that is used to the molecular weight of ipratropium bromide monohydrate (See page 2, lines 7-20).
Regarding claims 41-42 and 52-53, Zhu et al disclose that the said albuterol sulfate, is in particulate form. The canister size of the particles of albuterol sulfate, can be from 1 micrometer to 5 micrometers, and the concentration of albuterol is expressed in terms of mg/mL, can be no greater than 1, and no greater than 11, etc. such as a concentration of 4.13 mg/mL or 5.28 mg/mL (See page 2, lines 25-33). Similarly, ipratropium, particularly ipratropium bromide is in particulate form, and is present at a particle size of from 1 micrometer to 5 micrometers (See page 4, lines 6-16).
Regarding claims 43-44, Zhu et al teach that the concentration of ipratropium can be no greater than 2.0, no greater than 1.5, or no greater than 0.5. Common concentrations are from 0.5 mg/mL to 2 mg/mL (See Page 4. Lines 26-36).
Regarding claim 39, Zhu et al teach that the propellant is typically 1, 1, 1,2,3,3,3,-heptafluoropropane, 1, 1, 1,2-tetrafluoroethane, or a combination thereof. The propellant typically also serves as a dispersant for the particles of albuterol sulfate and ipratropium bromide (See page 5, lines 1-4).
Regarding claims 37-38, Zhu et al teach that the particles of albuterol sulfate and ipratropium bromide are suspended in the propellant (See page 5, lines 5-8).
Regarding claims 37-38, 45-49, Zhu et al teach that in order to facilitate this suspension, additional components can be added to the formulation, including ethanol and surfactants. Ethanol is typically employed in relatively low concentrations, such as no greater than 5%, no greater than 2.8, etc. Typical ranges of ethanol concentration are from 0.1 wt.% to 5 wt.%, including 1 wt.% (See page 5, lines 9-33). The said one or more surfactant facilitating suspension of the particles in the formulation include oleic acid, sorbitan monooleate, sorbitan trioleate, soya lecithin, polyethylene glycol, polyvinylpyrrolidone, or combinations thereof. Concentration ranges of surfactants can be from 0.0001 wt.% to 1 wt. %, such as 0.001 wt.% to 0.1 wt.%, or 0.01 wt.% (See page 5, line 34 to page 6, line 27).
Regarding claims 54-55, Zhu et al state that the said formulations can be used with any type of inhaler. Metered dose inhalers are most common. Typical metered dose inhalers for the pharmaceutical formulations contain an aerosol canister fitted with a valve (See page 7, lines 27-35).
The said composition is stable after six months of storage inside an aerosol canister at a temperature of 40° C and a relative humidity of 75% (See claim 39).
Zhu et al teach each and every limitation of the claims and teach any form or hydrate of ipratropium bromide can be incorporated in the said formulations. However, Zhu et al lack a specific disclosure on ipratropium bromide anhydrous. This is taught by Shur et al or CN ‘140.
Regarding claims 50-51, Shur et al disclose a study aimed to investigate the relationship between the mechanical properties of anhydrous and monohydrate ipratropium bromide (IB) crystals, their processing behavior upon air-jet micronisation and aerosolisation performance in dry powder inhaler (DPI) formulations (See Abstract, Objective).
It is concluded that monohydrate and anhydrous crystals of IB exhibited similar mechanical properties and interfacial properties upon secondary processing. As a result, the performance of the DPI formulations were similar (See Abstract, Conclusion and page 1334).
Regarding claims 50-51, CN ‘140 teach a preparation method of ipratropium bromide, by preparing ipratropium bromide anhydride, then preparing ipratropium bromide. This method is simple to operate, and safe, cost is low, is more suitable for industrialized production (See abstract).
It is disclosed that ipratropium bromide anhydride is prepared with the reducing agent reducing compounds such as potassium borohydride or sodium borohydride (See Page 3 of the translation, lines 7-8).
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 Shur et al or CN ‘140 with that of Zhu et al to arrive at the instant invention. It would have been obvious to do so because Zhu et al teach pharmaceutical compositions comprising a combination of albuterol sulfate and ipratropium bromide or ipratropium bromide monohydrate. While Zhu et al specifically discloses that the said formulations can be made by any form, hydrate or salt of ipratropium bromide, it does not expressly teach ipratropium bromide anhydrous. Shur et al compare the monohydrate and anhydrous forms of ipratropium bromide and concludes that they have the same performance and properties. CN ‘140 also teach preparation of ipratropium bromide and ipratropium bromide anhydrate and discloses that the said method is simple to operate, safe, cost is low, and is more suitable for industrialized production. As such one of ordinary skill in the art having possession of the references would have easily been motivated to prepare the said formulations with anhydrous form of ipratropium bromide with a reasonable expectation of success.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claims 36-55 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al (6,585,958) in combination with Zhu et al (WO 2016164508) and Shur et al (Influence of crystal form of ipratropium bromide on micronisation and aerosolization behavior in dry powder inhaler formulations) or CN 107033140.
Keller et al teach a pressure-liquefied propellant mixture for aerosols, in particular 1,1,1,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoropropane and one or more pharmaceutically active agent in suspension or solution aerosols (See Abstract and claim 1).
Regarding claims 36, 41 and 51, Keller et al teach a composition comprising an HFA propellant and an active agent selected from ipratropium bromide and salbutamol (interpreting claim 41 to be drawn to albuterol or a salt thereof) (See Col. 8, lines 3-34).
Regarding claims 37-38, Keller et al teach the active compound(s) is/are suspended in the propellant and the formulation are homogenized (See Col. 3, lines 20-23 and Col. 11, lines 10-15).
Regarding claims 39-40, Keller et al teach that examples of suitable hydrofluoroalkanes which can be used in the propellant mixtures and aerosol formulations include 1,1,2,2,-tetrafluoroethane (HFA 134), 1,1-difluoro-ethane (HFA 152a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) (See Col. 7, lines 33-42).
Regarding claims 45-47, Keller et al teach that the use of a surface-active agent is frequently indicated, in particular in the case of suspension formulations, but can also be advantageous in solution formulations, e.g. for valve lubrication. Customary surface-active agents are suitable, such as oleic acid, lecithin, sorbitan trioleate,) sorbitan monooleate, etc. The proportion of surface-active agent, can be from 0.0001 to 1% by weight, in particular from 0.001 to 0.1% by weight, based on the total formulation (See Col. 10, lines 50-67).
Regarding claims 48-49, Keller et al teach that the said formulations may comprise a co-solvent preferably ethanol which an be present at from 0.01% to 15% by weight of the total formulation (See Col. 10, lines 25-37).
Regarding claims 52-53, Keller et al teach that the particles of active agents are micronized and have particle size range of less than 6 micron and preferably from 2 to 4 microns (See Col.4, lines 50-55 and Col. 9, lines 54-60).
Regarding claims 54-55, Keller et al teach that the said formulations are administered by a metered dose inhaler, which comprise a container (See Col. 5, lines 48-52, Col. 6, lines 40-48 and claims 47 and 51).
Keller et al disclose an example wherein 2 g of micronized ipratropium bromide are weighed into a pressure addition vessel. After sealing and evacuation thereof, 6.0 kg of a mixture of HFA 227 and HFA 134a are added. After homogenizing this mixture, the suspension obtained is dispensed by means of the pressure-filling technique into containers which are equipped with a metered-dose valve (See Example 2).
Keller et al lack a specific disclosure on the ipratropium bromide being monohydrate or anhydrous. This is well known in the art as taught by Shur et al or CN ‘140. Keller et al also does not disclose the salt of salbutamol. This is known as taught by Zhu et al.
The teachings of Zhu et al, Shur et al and CN ‘140 are delineated above and incorporated herein.
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 CN ‘140 or Shue et al and Zhu et al with that of Keller et al to arrive at the instant invention. It would have been obvious to do so because Keller et al teach pharmaceutical compositions comprising ipratropium bromide, salbutamol, an HFA propellant, surfactants and ethanol in a suspension form delivered to a subject in a metered dose inhaler. Keller et al does not teach whether the said ipratropium bromide is in monohydrate or anhydrous form. However, Shur et al and CN ‘140 teach composition’s comprising ipratropium bromide anhydrous or a method of safely and economically preparing ipratropium bromide and ipratropium bromide anhydrate. As such one of ordinary skill in the art having possession of both references would have been motivated to incorporate Shu et al and/or CN ‘140’s suggestion on ipratropium bromide anhydrous into the formulations of Keller et al with a reasonable expectation of success, as references teach that both active agents are suitable for inhalation and treating bronchial conditions.
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 one anticholinergic for another. 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).
It further would have been obvious to have incorporated Zhu et al’s disclosure on the commonly used sulfate salt of salbutamol in the formulations of Keller et al with a reasonable expectation of success.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pfrengle et al (US 20050143410)
Pfrengle et al teach a new crystalline anhydrate of tiotropium bromide, processes for preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly COPD and asthma (See Abstract and [0013]).
It is disclosed that anhydrous tiotropium bromide is particularly characterised by slightly hygroscopic characteristics, which ensure a high degree of stability of the crystal modification and particularly well suited to the preparation of pharmaceutical formulations for administration by inhalation (See [0012]).
The said pharmaceutical formulations comprising crystalline tiotropium bromide anhydrate are for administration by inhalation such as inhalable powders or for example propellant-containing aerosol formulations, particularly inhalable powders and propellant-containing aerosol suspensions (See [0024]).
It is disclosed that the suspensions contain as propellent gas only HFA 227, a
mixture of HFA 227 and HFA 134a or only HFA 134a (See [0068]-[0069]). The propellant-containing inhalable aerosols or suspension formulations may also contain other constituents such as surface-active agents (surfactants), adjuvants, antioxidants.
The surface-active agents (surfactants) present in the suspensions are preferably selected from the group consisting of Polysorbate 20, oleic acid, propyleneglycol, polyethyleneglycol, glyceryl trioleate, ethanol and isopropanol. The suspensions contain surfactants preferably in an amount of 0.0005-1%, particularly preferably 0.005-0.5% (See [0075]- [0076]).
It is disclosed that the said crystalline tiotropium bromide anhydrate is obtained in finely divided form, i.e. micronized. Preferably after micronising the active substance has a mean particle size of 0.5 to 10 μm, preferably 1 to 6 μm. Preferably at least 90% of the particles of active substance have a particle size which is within the said size ranges (See [0081]).
The constituents of the formulation are mixed with the propellent gas or gases (optionally at low temperatures) and filled into suitable containers. The said propellant-containing suspensions may be administered using inhalers known in the art such as pMDIs (pressurized metered dose inhalers) (See [0083]-[0084]).
Claims 36-55 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616