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 .
Response to Arguments
Applicant’s response from 6/16/2026 is acknowledged.
Claim Rejections - 35 USC § 103
Applicant’s claim amendments and arguments have been carefully considered, and a new search has been conducted. In view of Applicant’s claim amendment reciting “wherein the composition contains less than 1000 ppm but greater than 0.5 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition”, the rejection under 35 U.S.C. 103 of claims 1-3 and 6-21, is hereby withdrawn, and is similarly not applied to new claim 23. Malhotra does not disclose the benefit of decreasing dissolved oxygen. Further, Mahajan solely pertains to reducing headspace oxygen during packaging, and not to the content of dissolved oxygen in the composition.
Applicant’s arguments over new claim 22 have been considered, but have not been found to be persuasive. The Examiner attempted a phone call on July 16, 2026 to Applicant’s representative Dr. Feng, and she also followed up with a generic email to state that a voice mail was left. She meant to propose an Examiner’s amendment to have claim 22 be cancelled. It appears from the automatic response that Applicant’s representative if out of the office, in vew of which the rejection of claim 22 has been made.
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.
Claim 22 is 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).
New claim 22 is directed to:
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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).
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, but not Applicant’s specifically claimed HFA-152a. However, the art as a whole also provides specific motivation to use HVA-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, aka HFA-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 wherein the propellant component is entirely R-152a, which meets Applicant’s limitation that the R-152a be at least 90%.
The compositions taught by Malhotra do not include any water, absent evidence to the contrary. This alone meets Applicant’s claim limitation of less than 500 ppm water content. Applicant’s claim 22 further recites that 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. Moreover, the prior art OECD SIDS discloses that typical impurities in propellants include a very level in ppm of water.
Specifically, 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.”
Accordingly, based on the disclosure of Malhotra and OECD SIDS it would have been obvious to a person of skill in the art to formulate the composition with no water, but to expect that some very low levels of water (ppm) would be present, such as in view of humidity and impurities, such as documented for HFC-152a. As to their precise amount of ppm, as documenting impurities is a requirement in the pharmaceutical arts, it would have been obvious to determine their precise range/ amount in the composition, such as per Applicant’s claim.
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 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 R-152a, aka HFA-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, to include with no water to minimal water, as water is a known propellant impurity.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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