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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/5/2026 has been entered.
Response to Arguments
Applicant’s response from 1/5/2026 is acknowledged.
Claim Rejections - 35 USC § 103
Applicant’s arguments have been carefully considered, but have not been found to be persuasive. Applicant has amended the claims, and made arguments against the claims as amended. In view of Applicant’s claim amendments, a modified rejection has been made below.
Double patenting
In view of Applicant’s claim amendments, this rejection is hereby withdrawn.
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.
Claims 1-3 and 6-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2012/110770 A2 to Malhotra et al. (“Malhotra”, of record), and further in view of Horita et al., Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan, Int J Chron Obstruct Pulmon Dis. 2015 Apr 21;10:813–822 (“Horita”, of record), WO 2013/054137 A1 to Corr et al. (“Corr”, of record) and OECD SIDS (1,1,Difluoroethane (HFC-152a), SIDS Initial Assessment Report for SIAM 22”, UNEP Publications, June 2006, 81 pages (“OECD SIDS”, of record).
Malhotra teaches pharmaceutical compositions comprising, inter alia, indacaterol or indacaterol maleate and a propellant. It is disclosed that the composition is administered by a metered dose inhaler (MDI). (p. 8, last paragraph; p. 13, 2nd full paragraph; p. 16, 2nd paragraph; and Examples 1 to 12). Malhotra teaches the propellant is one or more of HFA-134a, HFA-227, HFC-32, HFC-143a, HFC-134 and HFC-152a, with HFA-134a and HFA-227 exemplified in the Examples. (p. 16, fourth paragraph). Malhotra is directed to the administration of glycopyrrolate in combination with a beta2-agonist, preferably indacaterol, and optionally an inhaled corticosteroid. It is disclosed that each of the drugs “are formulated for simultaneous, separate or sequential administration”. (p. 8, last paragraph). Additionally, Malhotra also teaches the “active ingredients may be used as separate formulations or as a single combined formulation”. (p. 15, penultimate paragraph). Glycopyrrolate suitable counter ions/ salts, include the bromide salt, etc. (p. 11, third paragraph).
Applicant has currently amended the claims to recite:
1. A pharmaceutical composition comprising:
(i) a drug component consisting of at least one indacaterol compound selected (i) from indacaterol and indacaterol maleate, at least one corticosteroid selected from a group consisting of budesonide, beclomethasone and the pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable salt of glycopyrrolate; and
(ii) a propellant component at least 90 weight % of which is 1,1-difluoroethane (HFA-152a).
Malhotra claims a composition, which is broadly directed to a combination with any corticosteroid.
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There is a further more limiting dependent claim 18 to two specific corticosteroids (fluticasone and mometasone), but this claim does not use the transitional phrase “consisting of” limiting it to just these two corticosteroirds, and is again, a dependent claim on ultimately claim 16, wherein claim 16 is directed to any corticosteroid.
The Specification of Malhotra provides: “Commercially available corticosteroids include beclomethasone, budesonide, fluticasone, mometasone, ciclesonide and triamcinolone.” This explicitly discloses the two corticosteroids claimed by Applicant- beclomethasone and budesonide.
Applicant has pointed to one embodiment in the Specification, specifically noted in Malhotra as “In one embodiment”, and noted that therein the specification uses the transitional phrase “selected from the group consisting of” as to the recited corticosteroid:
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Based on that, Applicant has argued that Malhotra is only limited to the fluticasone and mometasone as corticosteroids.
However, as was noted above, this is not the correct interpretation of Malhotra, because: (i) the claims in Malhotra are broadly directed to any corticosteroid; (ii) even narrower claims of Malhotra do not use the transitional phrase “consisting of” in terms of corticosteroids, and (iii) disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2123.
The compositions taught by Malhotra do not include any water, absent evidence to the contrary (reading on instant claim 2).
Malhotra teaches surfactants may be used to stabilize the solution formulation. Suitable surfactants disclosed by Malhotra include oleic acid, polyvinylpyrrolidone and lecithin, per Applicant’s claim 10. (p. 17, 1st full paragraph, Example 9). Further, the indacaterol solution composition (as required by instant claim 18) of Example 9, for instance, also includes ethanol, per Applicant’s claim 11. The indacaterol suspension formulations (as required by instant claim 16) disclosed in Example 1, are free of surfactant and ethanol, per Applicant’s claim 12
Malhotra teaches that a number of beta2-agonist, among them, indacaterol, can be co-formulated with glycopyrrolate. However, additional art specifically guides towards Applicant’s specification combination of indacaterol and glycopyrrolate.
Horita discloses a pharmaceutical composition and an inhalation device for dispensing it in the treatment of COPD of indacaterol and glycopyrronium bromide, which has already undergone clinical trials and has been approved in more than 40 countries. It further makes comparison to other bronchodilator combinations for treatment of COPD, e.g. of the salmeterol–fluticasone combination. Specifically, it provides: “Once-daily dual-bronchodilator therapy with combined indacaterol and glycopyrronium bromide in one device (Ultibro, Breezhaler), often called QVA149, was first approved in 2013 in Japan and Europe. As of November 2014, more than 40 countries had approved this medication except for the USA. This is the first dual bronchodilator in one device. Now, the Breezhaler is the only device that can provide long-acting muscarinic antagonist (glycopyrronium bromide), long-acting beta agonist (indacaterol), and a combination of the two medications (QVA149). The choice among the three medications allows a patient to use the same inhalation device even when the regimen is changed from single-bronchodilator therapy to dual-bronchodilator therapy. In addition, the quick bronchodilation effect and once-daily administration can improve patient adherence to medical treatment for chronic obstructive pulmonary disease (COPD). To our knowledge, as of November 2014, the safety and the efficacy of QVA149 have been evaluated in 14 randomized controlled trials. The 14 trials generally showed good safety profiles, and there were better or not-inferior bronchodilator effects of QVA149 when compared with placebo, or other inhaled medication. According to the Japanese Respiratory Society guidelines, QVA149 is a combination of the two first-line bronchodilators. Our meta-analysis indicated that QVA149 is superior to the salmeterol–fluticasone combination to treat COPD in respect of the frequency of adverse effects, exacerbation, pneumonia, and improvement of trough forced expiratory volume in 1 second (FEV1). Thus, we believe that QVA149 can be a key medication for COPD treatments.” (Abstract).
As noted above vis-à-vis Malhotra, it discloses a number of possible propellants, to include Applicant’s claimed HFC-152a. However, the art as a whole also provides specific motivation to use HVC-152a as the specific propellant as well. As noted in Horita, the actual clinical trials and choice of products on the market in inhalation device drug combinations for COPD is amongst three specific medications, one of which employs indacaterol and glycopyrronium bromide, and another one, which employs salmeterol–fluticasone.
Corr discloses and claims a pharmaceutical composition that is free of polar excipients, said composition comprising: (a) a propellant component consisting essentially of 1 ,1-difluoroethane (R-152a), (b) a surfactant component comprising oleic acid; and (c) a drug component consisting of salbutamol sulphate. (claim 1). The composition is suitable for delivering the salbutamol sulphate from a pressurised aerosol container using a metered dose inhaler (MDI).
Corr discloses a number of concerns vis-a-vis other propellants, such as, inter alia, the following. “Although R-134a and R-227ea have low ozone depletion potentials (ODPs), they have global warming potentials (GWPs), 1430 and 3220 respectively, that are now considered to be too high by some regulatory bodies, especially for dispersive uses when they are released into the atmosphere.” (p. 2, ll. 20-24). “There are also other problems with R-134a and R-227ea. Most pharmaceutical actives for treating respiratory disorders, such as asthma, tend not to dissolve well in either R-134a or R-227ea and have to be handled as suspensions in the propellant. Drug suspensions give rise to a number of problems, such as nozzle blockage, agglomeration and sedimentation, the latter problem making it essential to shake the MDI thoroughly before use to ensure that the drug is evenly distributed in the propellant. Furthermore, if the pharmaceutical active settles quickly following re-suspension in the propellant, as is often the case, then the propellant/drug composition must be delivered from the MDI shortly after shaking in order to ensure that the dose that is delivered contains an effective concentration of the pharmaceutical active.” (p. 3, ll. 4-14). In view of these, Corr concludes: “There is a need for a MDI aerosol formulation that has a reduced GWP in comparison with R-134a and R-227ea, that has acceptable flammability and toxicity performance, which forms stable suspensions and that has reduced irritancy,” and that accordingly it is an object of the invention to provide a pharmaceutical composition that consists essentially of R-152a, oleic acid as a surfactant, and salbutamol sulfate as a drug. (p. 4, ll. 1-14). This teaches the limitation of Applicant’s claim 8, wherein the propellant component is entirely R-152a. To the extent that some of Applicant’s claims require that the R-152a be at least 90%, 95%, etc., as was noted above Malhotra teaches that the propellant can be one or more the specifically named ones.
Instant claim 2 is drawn the pharmaceutical composition of claim 1, wherein the composition contains less than 500 ppm of water based on the total weight of the pharmaceutical composition. As was noted above, Malhotra does not disclose water, so this meets this limitation. Instant claim 3 is drawn the pharmaceutical composition of claim 2, wherein the composition contains greater than 0.5 ppm of water based on the total weight of the pharmaceutical composition. Whereas 0.5 ppm (i.e., 0.00005%) is exceedingly small and Malhotra does not disclose the removal of trace amounts of water from the disclosed compositions, and the need for a desiccant and special preparation conditions to remove atmospheric humidity, it would be expected that there would be greater than 0.5 ppm of water in the disclosed compositions.
Instant claim 9 recites wherein the propellant component contains from 0.5 to 10 ppm of unsaturated impurities. OECD SIDS discloses HFC-152a purity of greater than 99.9% and that “[t]ypical impurities in HFC-152a include low level (ppm) water, [and] low level (ppb) residual HCl and/or HF acids.” The presence of unsaturated impurities is not disclosed.
Instant claim 21 is drawn to a metered dose inhaler (MDI) fitted with a sealed and pressurized aerosol container containing a pharmaceutical composition as claimed in claim 1. This claim limitation is disclosed by Malhotra at, for example, page 21, 1st paragraph and Examples 1-9.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Malhotra, Horita, Corr and OECD SIDS in order to prepare a pharmaceutical composition and an MDI with it according to Applicant’s claims with a reasonable expectation of success. The skilled artisan would have been motivated to do so since: Malhotra discloses a composition and an MDI with all of Applicant’s claimed ingredients; Horita specifically discloses a clinically approved product with Applicant’s claimed active ingredients in combination as just one of three available MDIs for treatment of COPD, of which one other one is with sambuterol, and; Corr specifically discloses formulating this sambuterol with HVF-152a with a number of specific advantages recited over other propellants. Thus, the art as a whole discloses some very well-established leading products and ingredients, and their formulating with well established and preferred inactive ingredient propellants with advantageous properties for dispersing the composition as an MDI for the treatment of COPD.
Instant claim 13 is drawn to the pharmaceutical composition of claim 1, wherein the composition after storage in uncoated aluminum containers at 40°C and 75 % relative humidity for 1 month will produce less than 0.15% by weight of impurities from the degradation of the at least one indacaterol compound based on the total weight of the at least one indacaterol compound and the impurities. Instant claim 14 is drawn to the pharmaceutical composition of claim 1, wherein the composition after storage in uncoated aluminum containers at 40°C and 75 % relative humidity for 3 month will produce less than 0.3% by weight of impurities from the degradation of the at least one indacaterol compound based on the total weight of the at least one indacaterol compound and the impurities. Claim 15 is drawn to the pharmaceutical composition of claim 1, wherein at least 98.0 % by weight of the at least one indacaterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminum containers at 40°C and 75 % relative humidity for 3 months. Claim 19 is directed to the pharmaceutical composition of claim 1, wherein the composition when delivered from a metered dose inhaler yields a fine particle fraction of the at least one indacaterol compound which is at least 40 weight % of the emitted dose of the at least one indacaterol compound. Claim 20 is directed to the pharmaceutical composition of claim 1, wherein the composition when delivered from a metered dose inhaler yields a fine particle fraction of the at least one indacatero! compound which is at least 30 weight % of the emitted dose of the at least one indacaterol compound even after storage of the pharmaceutical composition at 40°C and 75 % relative humidity for 3 months.
Example 2 of the instant specification demonstrates that the claimed chemical stability of the indacaterol formulation of claim 1 occurs as a result of formulating indacaterol with HFA-152 in uncoated aluminum cans. In particular, see Table 5 at page 34.
The aerosol formulations of both Malhotra and Corr are taught to be contained in uncoated aluminum containers. See Malhotra, page 21, 1st sentence, and Examples 1-9. See Corr, page 10, Example 1. Since the formulation of instant claim 1 has been rendered obvious, including the packaging of said formulation in uncoated aluminum cans, by the above cited art, the claimed stability of indacaterol (claims 20-21) would naturally result.
Instant claim 17 is drawn to the pharmaceutical composition of claim 24, wherein the drug particles in the suspension take at least 1.5 minutes to settle following complete dispersion of the drug particles in the suspension.
The specification at page 22, lines 10 – 15 recites: “It has been found that the use of propellants comprising 1, 1-difluoroethane (HFA-152a) in pharmaceutical compositions containing an indacaterol compound that is dispersed or suspended in the propellant can unexpectedly increase the time it takes for the particulate drug to settle following thorough dispersion in the propellant compared to the settling times that are observed when either HFA-134a or HFA-227ea is used as the propellant.”
Therefore, especially in view of the above teaching by the specification, since the formulation of instant claim 1 (i.e., a composition comprising indacaterol, glycopyrrolate and a HFA-152a propellant) has been rendered obvious by the above cited art, the claimed settling time of indacaterol recited by claim 25 would naturally result.
Instant claim 19 is drawn to the pharmaceutical composition of claim 1, wherein the composition when delivered from a metered dose inhaler yields a fine particle fraction of the at least one indacaterol compound which is at least 40 weight % of the emitted dose of the at least one indacaterol compound. Instant claim 20 is drawn to the pharmaceutical composition of claim 1, wherein the composition when delivered from a metered dose inhaler yields a fine particle fraction of the at least one indacaterol compound which is at least 30 weight % of the emitted dose of the at least one indacaterol compound even after storage of the pharmaceutical composition at 40°C and 75 % relative humidity for 3 months.
The specification at page 26, lines 5 – 15 recites: “It has also been found that the use of a propellant comprising 1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containing an indacaterol compound, such as indacaterol or indacaterol maleate, and the propellant that are designed to be delivered using a metered dose inhaler can unexpectedly improve the aerosolization performance of the pharmaceutical composition after storage when that composition is delivered from the metered dose inhaler compared to the performance that is observed when either HFA-134a or HFA-227ea is used as the propellant. In particular, the fine particle fraction of the indacaterol compound in the emitted dose after storage of the pharmaceutical composition at 40°C and 75% relative humidity for 3 months days is at least 30 weight % and preferably at least 35 weight % of the emitted dose of the indacaterol compound.”
Therefore, especially in view of the above teaching by the specification, since the formulation of instant claim 1 (i.e., a composition comprising indacaterol, glycopyrrolate and a HFA-152a propellant) has been rendered obvious by the above cited art, the limitations of claims 19 and 20 would naturally result.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht, 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode, 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2012/110770 A2 to Malhotra et al. (“Malhotra”), and further in view of Horita et al., Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan, Int J Chron Obstruct Pulmon Dis. 2015 Apr 21;10:813–822 (“Horita”), WO 2013/054137 A1 to Corr et al. (“Corr”) and OECD SIDS (1,1,Difluoroethane (HFC-152a), SIDS Initial Assessment Report for SIAM 22”, UNEP Publications, June 2006, 81 pages (“OECD SIDS”), as applied to claims 1-3 and 6-21 in the 35 U.S.C. 103 rejection above, and further in view of Mahajan et al., The Effect of Inert Atmospheric Packaging on Oxidative Degradation in Formulated Granules”, Pharmaceutical Research, Vol. 22(1), pp. 128-140, 1/2005 (“Mahajan”).
The teachings of Malhotra, Horita, Corr and OECD SIDS are discussed in the 35 U.S.C. 103 rejection above.
Instant claim 4 is drawn to the pharmaceutical composition of claim 1, wherein the composition contains less than 1000 ppm [i.e., 0.1%] oxygen based on the total weight of the composition. Instant claim 5 is drawn to the pharmaceutical composition of claim 4, wherein the composition contains greater than 0.5 ppm oxygen based on the total weight of the composition.
Oxidative drug degradation caused by drug contact with molecular oxygen is well known by one of ordinary skill in the pharmaceutical arts. For example, Mahajan teaches that “[o]xidative degradation of drug substances in pharmaceutical products is well documented and is thought to occur in many cases via autoxidative processes involving headspace molecular oxygen in the primary package. Reducing the headspace oxygen concentration inside a package could thus be an option for reducing oxidative degradation in pharmaceutical products.” (Abstract). The study presented by Mahajan demonstrates increased drug degradation with increasing headspace oxygen concentration. (Results section, pages 133-138). One of ordinary skill would have been motivated by this knowledge to minimize potential degradation of the indacaterol aerosol formulations rendered obvious by the teachings of Malhotra, Horita, Corr and OECD SIDS, supra, by the removal of atmospheric oxygen present in the formulation.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. In re Opprecht, 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode, 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627