DETAILED ACTION
Applicant’s arguments, filed 19 May 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 79, 105, 122, 124-125, and 127-132 stand rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0028428 A1 (Hegyi et al., 02/04/2010) (hereinafter Hegyi) in view of WO 2015/179369 A1 (Palombella, 11/26/2015), further in view of Smyth et al. (WO 2019/070693 A1, priority 10/02/2018) (hereinafter Smyth), as evidenced by “Bedaquiline” (PubChem, 06/24/2005) (hereinafter PubChem).
Hegyi discloses a pharmaceutical composition comprising a therapeutically effective amount of a fumarate salt of (αS, βR)-6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol as active ingredient and a pharmaceutically acceptable carrier ([0016]). The particle size of the fumarate salt is preferably less than 200 µm ([0026]). The salt may be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way, such as in the form of a dry powder using any system developed for the delivery of dry powders via oral or nasal inhalation or insufflation ([0018]). The composition contains quantities of the fumarate salt equivalent to form about 1-1000mg of the corresponding free base ([0021]), and the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician ([0020]). The carrier for powder formulations includes diluents and sugars ([0017]) such as dextrose ([0080]). Suitable carrier particle sizes include those passing through a 200 mesh (i.e. < 75 µm) ([0080]). The pharmaceutical composition may further comprise phospholipids including phosphatidylcholine ([0048]). The chemical structure of the salt of the active ingredient is represented by the formula below ([0006]):
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PubChem evidences that the structure of the fumarate salt at paragraph 6 of Hegyi is the same as the structure known as bedaquiline, shown below:
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Hegyi does not explicitly disclose wherein the dry powder contains bedaquiline particles having a mass median diameter of 1 to 5 µm, or wherein the composition contains amikacin.
Palombella discloses compositions for administration by inhalation and kits comprising the same (abstract). Palombella further discloses that the bioavailability of an inhalation drug is optimum when the drug particles delivered to the respiratory tract are between 1 to 5 microns in size (¶ [0073]). Inhaled compositions may be administered via dry powder inhalers (DPIs), and controlled aliquots or doses of a compound may be pre-packaged in a blister pack (i.e. claimed container) (¶ [0074]). The dry powder may include carrier particles for carrying the particles of active material. The carrier particles may be composed of one or more crystalline sugars, including dextrose or lactose (i.e. claimed excipient) (¶ [0081]). The compositions may comprise other pharmaceutically acceptable additives or excipients such as phospholipids (¶ [0095]). The compositions may also include one or more force control additives (FCAs) in addition to the carrier particle, including leucine (¶ [0088]).
Smyth discloses a dry powder composition for inhalation ([0006]), compatible with an inhaler ([0090]), comprising micronized particles of therapeutic agents including clofazimine, and bedaquiline and amikacin. The therapeutic agents may be administered simultaneously or separately ([0099]-[0100]). The therapeutic agents may be within a median particle diameter range of 0.5-10 µm, particularly less than 5 µm, as it is known that particles with a mass median aerodynamic diameter (MMAD) of < 3 µm would target infection site in peripheral lung ([0128], [0078], [0046]). The composition may comprise excipients including glucose, L-leucine, and dipalmitoyl phosphatidylcholine ([0081]). The composition may be in the form of a unit dosage form including a blister or capsule ([0017]).
Accordingly, it would have been obvious to one of ordinary skill in the art to select inhalation delivery of bedaquiline as the active where multiple delivery means are taught, and then to adjust the size of the particles to between 1 to 5 microns (µm) in size for optimal delivery of drug containing particles to the respiratory tract, as taught by Palombella. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I). The overlapping range applies both to the narrower instantly claimed ranges and the fact that the narrower range taught by Palombella as optimal falls within the broader range taught by the primary reference.
It would have been obvious to one of ordinary skill in the art to have included amikacin since it is a known and effective therapeutic agent suitable for inclusion with bedaquiline as taught by Smyth. Generally, it is obvious to combine known compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. See MPEP § 2144.06.
Regarding claims 79, 105, and 132 reciting a particle size range of one or more excipients, the claimed range (i.e. about 50 µm) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art (i.e. <75 µm). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claims 79, 105, and 132 reciting a daily effective dose, it would have been obvious to one of ordinary skill in the art to have selected an amount of the fumarate salt (i.e. active ingredient) from the disclosed range of about 1-1000 mg free base equivalent, which appears to overlap the instantly claimed amounts in mg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I). Moreover, in any case, the selection of appropriate milligram amounts would appear to require no more than routine testing on the part of the skilled artisan, and so alternatively it would have been obvious to determine workable ranges to arrive at the claimed amounts in mg. "[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." See MPEP § 2144.05(II)(A).
With regard to claim 105, the preamble “for use in providing antibiotic activity when treating or providing prophylaxis against a pulmonary infection caused by mycobacteria or other gram-positive bacteria” is merely a recitation of the intended use of the compound. Since the pharmaceutical composition of Hegyi comprises the same active ingredient as the claimed invention, the pharmaceutical composition of the prior art would inherently be capable of treating or providing prophylaxis against a pulmonary infection caused by mycobacteria or other gram-positive bacteria, whether the prior art recognizes such use or not. MPEP 2112(II).
With regard to claim 105 reciting a dry powder inhaler, as discussed above, Hegyi discloses the use of any system developed for the delivery of dry powders via oral or nasal inhalation or insufflation for the administration of the compound. Since Hegyi teaches systems to allow inhaling the pharmaceutical composition as a dry powder, a dry powder inhaler would flow from such teaching.
Regarding claims 122 and 127, it would have been obvious to select any disclosed carrier, such as glucose or lactose as the sugars, as taught by Hegyi.
Regarding claims 128 and 129, Hegyi differs from the instant claims insofar as not explicitly disclosing the composition further comprises leucine.
As discussed above, Palombella discloses inhalation powder compositions may also include leucine as a force control additive, in addition to the carrier particles.
It would have been obvious to one of ordinary skill in the art to have formulated the pharmaceutical composition of Hegyi with leucine to impart force control benefits as taught by Palombella.
With regard to claims 130 and 131, it would have been obvious to include phosphatidylcholine as a phospholipid, as taught by Hegyi.
Response to Arguments
Applicant’s arguments have been considered but are moot because new rejections necessitated by Applicant’s amendment have been made.
Claims 79, 105, 122, 124-125, and 127-132 are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al. (WO 2019/070693 A1, priority 10/02/2018) (hereinafter Smyth).
Smyth discloses a dry powder composition for inhalation ([0006]), compatible with an inhaler ([0090]), comprising micronized particles of therapeutic agents including clofazimine, and bedaquiline and amikacin. The therapeutic agents may be administered simultaneously or separately ([0099]-[0100]). The therapeutic agents may be within a median particle diameter range of 0.5-10 µm, particularly less than 5 µm, as it is known that particles with a mass median aerodynamic diameter (MMAD) of < 3 µm would target infection site in peripheral lung ([0128], [0078], [0046]). The composition may comprise excipients including glucose, L-leucine, and dipalmitoyl phosphatidylcholine ([0081]). The composition may be in the form of a unit dosage form including a blister or capsule ([0017]).
Accordingly, Smyth discloses a dry powder composition suitable with an inhaler (i.e. instantly claimed container of claim 105) in the form of a blister, comprising bedaquiline and amikacin, wherein suitable particle sizes include a diameter of < 3 µm, comprising inert excipients including glucose (i.e. instantly claimed sugar of claims 122 and 127), L-leucine (i.e. instantly claimed amino acid of claims 128 and 129), and/or dipalmitoyl phosphatidylcholine (i.e. instantly claimed DPPC of claims 130 and 131). Together these would provide compositions or combinations as instantly claimed. It would have been prima facie obvious to one of ordinary skill in the art to have selected bedaquiline and amikacin as therapeutic agents since “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art" as supported by MPEP § 2144.06(I). Likewise, the prior art is not anticipatory insofar as this combination must be selected from various lists/locations in the reference. It would have been obvious, however, to make the combination since all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See MPEP § 2143 (I)(A).
Regarding claims 79, 105, and 132 reciting a particle size range of the one or more excipients, although Smyth does not explicitly disclose a particle size range of the excipients, it would have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed range (i.e. about 50 µm) through routine experimentation based on particle sizes desired to facilitate effective delivery of therapeutic agents. "[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." See MPEP § 2144.05(II)(A).
With regard to the bedaquiline particle sizes of claims 79, 124, 125, and 132, the claimed ranges (i.e. 1-5 µm, 1-3 µm, or 2.5 µm, respectively) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art (i.e. <3 µm). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claims 79, 105, and 132 reciting a daily therapeutically effective dose, although Smyth does not explicitly disclose a specific therapeutic agent dose amount for bedaquiline, it would have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed range (i.e. 5 to 10 mg) through routine experimentation based on the amounts of actives desired. "[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." See MPEP § 2144.05(II)(A).
With regard to claim 105, Smyth further discloses wherein the composition treats or prevents a pulmonary infection, including a Mycobacterium infection ([0020], [0022]). Moreover, the preamble “for use in providing antibiotic activity when treating or providing prophylaxis against a pulmonary infection caused by mycobacteria or other gram-positive bacteria” is merely a recitation of the intended use of the compound. Since the dry powder composition of Smyth comprises substantially the same active ingredient as the claimed invention, the dry powder composition of the prior art would inherently be capable of treating or providing prophylaxis against a pulmonary infection caused by mycobacteria or other gram-positive bacteria, whether the prior art recognizes such use or not. MPEP 2112(II).
Response to Arguments
Applicant asserts Smyth does not teach or suggest any combination therapy requiring bedaquiline and amikacin. Nor would it be obvious, based on the clofazimine teachings of Smyth, to combine bedaquiline and amikacin in an inhalable composition. Therefore, the present claims are not obvious over Smyth.
The Examiner does not find Applicant’s assertion to be persuasive. As discussed in the rejection above, Smyth discloses in para. [0099] wherein amikacin is a known and effective therapeutic agent suitable for administration via composition for inhalation. Thus it would have been obvious to one of ordinary skill in the art to have included amikacin as supported by MPEP § 2144.06(I) as discussed above.
Claims 79, 105, 122, 124-125, and 127-132 are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al. (WO 2019/070693 A1, priority 10/02/2018) (hereinafter Smyth) in view of Hassan & Lau (“Inhalation performance of pollen-shape carrier in dry powder formulation,” 04/21/2011) (hereinafter Hassan).
The teachings of Smyth are discussed in detail above. While Smyth is believed to support a finding of obviousness, purely arguendo, for the purposes of complete prosecution, and for the purposes of this ground of rejection only, Smyth will be interpreted as though it does not explicitly disclose a particle size range of the one or more excipients.
However, Hassan discloses that dry powder inhalation requires drug particles to have an aerodynamic size range of 1-5 µm, and a common practice to improve the drug delivery efficiency is to blend the fine drug particles with larger carrier particles (p. 93, left col., ¶1). It has been commonly reported that the most efficient carrier particle sizes is 30-90 µm (p. 93, right col., ¶1).
Accordingly, it would have been obvious to one of ordinary skill in the art to have selected a particle size from the disclosed range of 30-90 µm since it is a known and effective particle size range for excipients including carrier particles as taught by Hassan. Such particle sizes selected would have equated to a mass median diameter that appears to overlap with the claimed particle diameters of the one or more excipients (i.e. about 50 µm), thus making the claimed mass median diameter ranges obvious.
Response to Arguments
Applicant does not present specific arguments with regard to Smyth and Hassan.
Since the Examiner has discussed Smyth above, this rejection is maintained.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Momin et al. (“Development and validation of a RP-HPLC method for simultaneous quantification of bedaquiline (TMC207), moxifloxacin and pyrazinamide in a pharmaceutical powder formulation for inhalation,” 3/2/2018), directed to bedaquiline as an inhalable powder.
Celik et al. (US 2017/0143626 A1, 05/25/2017), directed to dry powder formulations comprising active substance and carrier.
Conclusion
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 LUCY TIEN whose telephone number is (571)272-8267. The examiner can normally be reached Monday - Thursday 8:30 AM - 6:30 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SAHANA KAUP can be reached on (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUCY M TIEN/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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