DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/02/2026 has been entered.
Response to Amendment
Applicant’s response of 01/02/2026 has been received and entered into the application file. Claims 1-4,7,9,11,14-16,174-176,178-179,182, 183,187,192,195,198,202-203 and 231 are pending in this application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 7, 9, 11, 14-16, 231 are rejected under 35 U.S.C. 103 as being unpatentable over Surber et al. (WO 2020/041631 A1), Highland et al. (Efficacy and Safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate, 01/08/2021), Weers (WO 2012/106575 A1), Lee et al. (Synergistic combination dry powders for inhaled antimicrobial therapy: Formulation, characterization and in vitro evaluation, European Journal of Pharmaceutics and Biopharmaceutics, 2013) and Jones et al. (An Overview of Dry Powder Inhalation for Systemic Drug Delivery, ONdrugDeliveryMegazine, Nov 2017).
Surber et al. teach formulations of nintedanib and salts thereof, indolinone derivative compounds and salts thereof for aerosolization and use of such formulations for the prevention or treatment of various fibrotic diseases (Abstract). The specially formulated nintedanib solutions for aerosol administration are used in methods of treatment of lung disease such as pulmonary fibrosis, idiopathic pulmonary fibrosis and may other conditions ([0049]). The formulations can permit mist or liquid nebulized, or dry powder inhaled aerosol administration ([0094]). Surber et al. teach that the embodiments can include sugar, saccharin, sweetener ([0113]). A method for treating or preventing progression of pulmonary disease comprises administration of nintedanib with pirfenidone ([0050]). Furthermore, pirfenidone further increase nintedanib composition stability, increases aqueous solubility, and reduces viscosity that otherwise exists at high nintedanib composition concentrations ([0006]). In some embodiments, the compositions further comprise a second anti-fibrotic or anti-inflammatory agent suitable for pulmonary delivery ([0107]).
Surber et al. do not specifically mention mycophenolate or mycophenolic acid.
Highland et al. teach efficacy and safety of nintedanib and mycophenolate for the treatment of interstitial lung disease (Title). The numerical reduction in the rate of decline in forced vital capacity (FVC) provided by nintedanib and mycophenolate suggests that combining immunosuppression with nintedanib might provide additional benefits in reducing the progression of interstitial lung disease (page 10, left col, last paragraph). Furthermore, the annual rate of decline in FVC in participants taking mycophenolate who were treated with nintedanib was close to the annual rate of decline in FVC observed in healthy adults (page 10, right col, 1st paragraph).
Surber does not explicitly mention nintedanib and pirfenidone within a single dry powder particle.
Weers teaches dry powder formulations of particles that contain two or more active ingredients for treating airway diseases. Each particle has a core of a first active ingredient that is coated with a layer of a second active ingredient (Abstract). The active ingredients can be any active pharmaceutical ingredients that are useful for treating airway diseases ([0015]).
Above references do not explicitly mention homogenous mixture.
Lee discloses combination antimicrobial therapy that is synergistic. Lee developed a novel synergistic dry powder inhaler (DPI) formulation via the pulmonary route. Binary (ciprofloxacin and gatifloxacin) and even ternary combinations were prepared via spray-drying (Abstract). Lee discloses that the co-spray-dried formulation was homogeneous, with minimal molecular segregation during the spray-drying process (page 282).
Jones et al. disclose the use of specific excipients in dry powder inhalation formulations. Manufacturing protein pharmaceuticals requires processes that will not damage them. For example, spray drying in its various forms has been employed and results in products with a low moisture content, helping to improve their stability. Excipients (e.g., sugars and polyols such as lactose, mannitol and cyclodextrin) need to be added to the formulations to produce particles with the correct aerodynamic properties and are used to reduce particle aggregation (pg 2, Excipients In Inhaled Formulations section).
Surber et al. teach pharmaceutical compositions comprising nintedanib, pirfenidone, and/or anti-inflammatory agent. Highland et al. teach that the combination of nintedanib and mycophenolic acid have advantages in the treatment of interstitial lung disease. Weers teaches dry powder formulations of particles that contain two or more active ingredients. Lee teaches that a DPI formulation can comprise two active ingredients that are homogenous in nature. Jones et al. disclose that a careful selection of excipients is crucial in formulating inhalers. One of ordinary skill in the art would be motivated to create a homogenous dry powder formulation comprising two or more active ingredients in a single particle as taught by references above.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined nintedanib, pirfenidone and/or mycophenolic acid into a dry powder formulation for potential treatment of lung diseases. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, administration via inhalation is taught above.
Regarding claim 3, nintedanib and pirfenidone in a composition is discussed above.
Regarding claim 4, nintedanib and mycophenolic acid in a composition is taught above.
Regarding claim 7, Surber et al. teach that the embodiments can include sugar, saccharin, sweetener ([0113]).
Regarding claim 9, Surber et al. teach that the composition can further comprise lactose, sucrose, dextrose ([0118]).
Regarding claim 11, Surber et al. teach that the composition can further comprise mannitol ([0131]).
Regarding claims 14-15, Surber et al. teach that the compositions can comprise amino acids such as arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, lysine and proline ([0153]).
Regarding claim 16, Surber et al. teach that in another embodiment, a composition comprises isoleucine, leucine ([0114]).
Regarding claim 231, Highland et al. teach a combination therapy of nintedanib and mycophenolic acid and Surber et al. teach a therapy comprising nintedanib and pirfenidone. One of ordinary skill in the art would immediately envisage the composition comprising pirfenidone and mycophenolic acid as a potential treatment option for lung disease. And it would have been obvious to do so in this instant application.
Claims 174-176,182-183,187,192,195, 198,202-203 are rejected under 35 U.S.C. 103 as being unpatentable over Surber et al. (WO 2020/041631 A1), Highland et al. (Efficacy and Safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate, 01/08/2021), Weers (WO 2012/106575 A1), Lee et al. (Synergistic combination dry powders for inhaled antimicrobial therapy: Formulation, characterization and in vitro evaluation, European Journal of Pharmaceutics and Biopharmaceutics, 2013) and Jones et al. (An Overview of Dry Powder Inhalation for Systemic Drug Delivery, ONdrugDeliveryMegazine, Nov 2017) as applied to claims 1-4, 7, 9, 11, 14-16, 231 above, and further in view of Overhoff et al. (Use of thin film freezing to enable drug delivery: a review. J. Drug Del. Sci. Tech. 2009).
Teachings of Surber et al. and Highland et al. are discussed above. Furthermore, Surber et al. teach that the dry powder formulation may be prepared by precipitation techniques such as spray drying, solvent extraction, lyophilization ([0151]).
Overhoff et al. teach thin film freezing to produce pharmaceutical powders. The process comprises impingement and solidification of liquefied droplets onto a cold solid surface. This technique improves the bioavailability of poorly water-soluble compounds and biopharmaceuticals. Various combinations of 1,3-dioxolane (solubility enhancer) in tert-butanol (ideal freezing and spreading characteristics) have been used to manufacture itraconazole thin film freezing particles while acetonitrile in water has been used to increase the properties of a feed solution containing tacrolimus (page 92, thin film freezing section). Overhoff et al. also teach that cryogen temperature, solution fluid dynamics; droplet velocity, mass flow ratio of cryogen and liquid feed are all critical process parameters (Table 1).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have created pharmaceutical compositions comprising nintedanib, pirfenidone and/or mycophenolic acid with the method taught by Overhoff et al. to arrive at the method as claimed in this instant application. This is combining prior art elements according to known methods to yield predictable results such as a pharmaceutical powder composition by using thin film freezing method.
Regarding claim 175-176, organic solvents are taught above.
Regarding claim 178, solvents are taught by Overhoff et al. as discussed above.
Regarding claim 179, water with acetonitrile is discussed above.
Regarding claims 182-183, Surber et al. teach that 0.25%-50.5% of the active agent in an aqueous solution is acceptable for aerosolization ([0103]).
Regarding claims 187, 192, 195, and 198 one of ordinary skill in the art would, through routine experimentation, test different feed rates, feed height, and temperature when preparing a pharmaceutical composition through freezing methods. Furthermore, Overhoff et al. teach that these are critical parameters for freezing methods as discussed above.
Regarding claim 202, Surber et al. teach lyophilization ([0151]).
Regarding claim 203, Surber et al. teach that the mixture can be vacuum dried ([0304]). Furthermore, one of ordinary skill in the art would experiment with various pressure to dry pharmaceutical mixtures. And it would have been obvious to do so in this instant case.
Response to Arguments
Applicant’s arguments filed 01/02/2026 have been fully considered and a new reference is incorporated to address the new limitation of claim 1.
On page 6 of remarks, Applicant argues that specific types of excipients have been shown to generate compositions that are both showing good deposition of all the active pharmaceutical ingredients along with the ability to obtain deep lung penetration. Applicant points to Table 13, and Figure 22 in the instant specification. Table 13 displays compositions of various formulations. Of note, T10, T11, T35, T36, T37, T40 formulations contain the same % w/w of each nintedanib, pirfenidone, mycophenolic acid but with different excipients; each excipient an amino acid, or sugar or sugar alcohol. Table 14 displays the aerodynamic performance of each of these formulations – In particular, T10 has a smaller Mass Median Aerodynamic Diameter (MMAD) compared to T35 and the resulting % FPF is noticeable. Despite containing the same % w/w of each active ingredient, and the excipients as claimed in claim 1, the particle size seems to be the limiting factor in aerodynamic performance. So, the applicant’s argument that only a select few excipients have an unexpected better result cannot be confirmed or determined by the examiner. Additionally, Jones et al. disclose the use of specific excipients in dry powder inhalation formulations. Excipients (e.g., sugars and polyols such as lactose, mannitol and cyclodextrin) need to be added to the formulations to produce particles with the correct aerodynamic properties and are used to reduce particle aggregation (pg 2, Excipients In Inhaled Formulations section). One of ordinary skill in the art would routinely experiment with any of those excipients to improve the properties of a pharmaceutical inhaler.
On page 7 of remarks, applicant argues that Surber notes that nintedanib is unstable under certain conditions. The examiner agrees that any and all drugs would be unstable under certain conditions. Surber discloses that nebulized aqueous nintedanib is unstable at certain permeant ion concentrations ([0125]). Surber discloses many formulations comprising nintedanib – including a nebulized formulation as well as a dry powder formulation ([0151]). One of ordinary skill in the art would routinely optimize different formulations. Surber concludes the precipitation tests of different formulations by stating that nintedanib esylate is incompatible with sodium citrate or sodium chloride at 60 mM or higher. However, nintedanib/pirfenidone combination formulations that contain a nonionic excipient, remained clear and did not precipitate ([0309]). One of ordinary skill in the art would recognize that sugar and sugar alcohol would be considered nonionic.
The examiner cannot determine unexpected results of the amended excipients and therefore the claims remain rejected.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615