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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 10/30/25 is acknowledged.
Accordingly, claims 1, 3, 21-22, 25-29, 31, 34-36 and 39 are under examination on the merits. Claims 54, 63, 70 and 75 are withdrawn from further consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 34 is drawn to the composition of claim 1, wherein the composition comprises a dissolution rate of less than 30% in 24 hours in phosphate buffered saline pH 7.4 with 0.2% polysorbate 80 dissolution medium. The recitation of dissolution rate of the composition does not materially affect the scope of the claimed composition and as such the said recitations (i.e. property of the composition) fails to further limit the scope of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claim 28 is directed to a composition having a Hausner ratio of from 10-20. The Specification contains the same recitation. However, an exemplified formulation has a Hausner ratio of 1.5, which is outside of the disclosed 10-20 range. Example 2 has the below reproduced statement:
Surface area analysis using single-point BET method showed an average specific surface area of 2.149 m2/g. Density analysis of excipient-free milled clofazimine demonstrated an average bulk density of 0.09 g/mL and an average tapped density of 0.14 g/mL. This results in a compressibility index of 33.97 and a Hausner ratio of 1.5. Angle of repose analysis of excipient-free milled clofazimine demonstrated an angle of repose of 22.82˚ (See [0121] of the P.G. Pub version). Thus, it is not clear which value/range is correct.
Claim 39 is a product-by-process claim. According to MPEP § 2113 [R-1], product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. Therefore, claim 39 is examined based on the composition of claim 1.
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.
Applicant’s claims:
1. A pharmaceutical composition comprising micronized, crystalline clofazimine particles with a median particle diameter of 0.5 to 10 um, wherein the composition comprises less than 10% amorphous material, wherein the composition is substantially free of excipients, and wherein the clofazimine is in the non-salt form.
Depending claims add other limitations including particle or formulation characteristics.
Claims 1, 3, 21-22, 26-29, 31, 34-36 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Yazdi et al (Carrier-free high-dose dry powder inhaler formulation of ibuprofen: physicochemical cauterization and in vitro aerodynamic performance) in view of Keswani et al (US 20160220710).
Yazdi et al teach an investigation into influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations (See abstract).
Regarding claims 1, 3 and 21-22, it is disclosed that IBU samples were micronized via air-jet milling, the samples including the milled IBU from 5, 10, and 20 g batches (IBU5, IBU10.1, IBU10.2, IBU20). The particles have a D50 of 1.9-2.7 micron (See page 404, 2nd col, 2.).
Regarding claims 1, 3 and 39, Yazdi et al teach that the jet-milled samples possessed a plate-like morphology and were crystalline as determined by XRD. The crystalline structure corresponded with the conventional phase (phase I) of IBU (See page 410, 4.)
Regarding claims 26-29 and 31, Yazdi et al summarize powder characteristics for the sample IBU20 and unmilled IBU in Table 3. The specific surface area (SSA) for IBU20 is 2.02, the compressibility index is 45, the Housner ratio is 1.82, the angle of repose is 37.8±5 as shown below:
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Formulation comprising IBU20 also had an FPF of about 70%, an MMAD of 2.9 micron and GSD of 1.8 (See page 407).
Yazdi et al lack a disclosure on the active agent being clofazimine. This is provided by Keswani et al.
Keswani et al teach microcrystalline forms of drugs and microcrystalline drug formulations for delivery to macrophages and treatment of disease (See Abstract and [0008]).
The said compositions comprise a biomimetic crystal of a pharmaceutical agent, wherein the said biomimetic crystal is a pure drug crystal. In some embodiments, the small molecule pharmaceutical agent is clofazimine. The density of the crystals is between 1.25-1.4 g/ml and the crystals have a size of 0.001-20 µm in each dimension (See [0009] and claim 5).
Regarding claims 1 and 3 it is disclosed that the administering may be inhalation, via an inhaler (See [0011]). Disclosed are biomimetic drug microcrystals of small molecule pharmaceutical agents (e.g., clofazimine (CFZ)). In some embodiments, the agents are present as salt, hydrate, solvate or cocrystal (See [0009] and claim 1).
It is disclosed that many FDA-approved drugs (e.g., clofazimine) fall within the class of poorly soluble compounds that are actively sequestered within macrophages (See [0098]).
Regarding claims 35-36, it is disclosed that crystalline forms of active agents are formed using any suitable method. Crystals are generated by mechanical milling and homogenization (See [0105]).
Regarding claims 1, 3 and 22, Keswani et al teach that crystalline formulations of CFZ have a bulk density in the range of 1.33-1.4 g/ml and a size range between 0.001-20 µm in one and/or two dimensions (See [0106]).
Administration to the respiratory tract may be achieved by means including a metered inhaler or a dry powder inhaler. The active ingredients may be provided in the form of a dry powder. The powder composition may be presented in unit dose form for example in capsules, cartridges or blister packs from which the powder may be administered by means of an inhaler (See [0153]-[0155]).
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 Yazdi et al and Keswani et al to arrive at the instant invention. It would have been obvious to do so because Yazdi et al teach a dry powder formulation free of carrier materials, i.e. 100% active agent, ibuprofen, with improved delivery performance. The particles of IBU are crystalline and have particle features including SSA and compressibility index that led to a carrier-free and effective formulation. Keswani et al teach making particulate formulations of clofazimine which are milled to the suitable particle size range and are suitable in crystalline form. The said dry powder formulation comprising clofazimine is placed in a dry powder inhaler and administered to a subject’s respiratory system via inhalation. Keswani et al teach a method of making a dry powder composition comprising crystalline clofazimine at a particle size from 0.001 to 20 microns for inhalation via dry powder inhaler into the subject’s respiratory system.
Accordingly, one of ordinary skill in the art would have been motivated to have incorporated the active agent of Keswani et al into the powder formulations of Yazdi et al to arrive at an effective and powder formulation not containing any excipients. That is, one of ordinary skill in the art would have been motivated to incorporate other active agents, including clofazimine as taught by Keswani et al, into the formulations of Yazdi et al with a reasonable expectation of success, as it is taught that excipient free powder formulations for inhalation delivery of active agents into the respiratory system is effective and beneficial.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations.
Regarding the limitation of the dissolution rate in claim 34, it is noted that the claim is drawn to a powder composition and is examined based on its components not its properties. However, it is also expected that the composition taught by the references would have the same properties. In this regard the courts have held that "A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Claims 1, 3, 21-22, 25-29, 31, 34-36 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Keswani et al (US 20160220710), Yazdi et al (Carrier-free high-dose dry powder inhaler formulation of ibuprofen: physicochemical cauterization and in vitro aerodynamic performance) and DeHaan et al (US 20150136130) in combination.
Keswani et al and Yazdi et al’s disclosures are delineated above and incorporated herein.
The combined references lack a disclosure on certain particle features/limitations including volume equivalent diameter, and percentage of amorphous material. However, these are all known in the art as taught by DeHaan et al.
DeHaan et al teach inhalable dry powders that contain a therapeutic agent. Disclosed are the dry powders characteristics, e.g., they are processable and/or dense in therapeutic agent that provide advantages for formulating and delivering therapeutic agents to patients (See title and abstract).
Regarding claims 1, 3, 21-22 and 29, DeHaan et al state that the total content of therapeutic agent in the respirable dry powder is at least 80% by weight (See [0012]), the powder may be essentially free of non-respirable carrier particles, such as lactose (See [0013]), and that the said powders can be metered in a multi-dose reservoir dry powder inhaler (DPI). Preferably, the mass of the metered dose from a multi-dose reservoir DPI is within 85% to 115% of a target mass 90% or more of the time, or within 90% to 110% of a target mass 90% or more of the time (See [0014]). The said dry powders can further be characterized by an angle of repose of 30º or less (See [0015]). The volume median geometric diameter of the respirable dry particles emitted from the inhaler is 5 microns or less (See [0022] and claim 1).
Regarding claim 39, it is disclosed that the said respirable dry particles and dry powders can be prepared using any suitable method, including milling (e.g., jet milling), blending, etc. (See [0187]-[0188]).
Further regarding claims 1 and 21, DeHaan et al state that the said respirable dry powders or respirable dry particles are produced by preparing a feedstock solution or suspension using an excipient, in an amount of about 0% by weight and optionally a pharmaceutically therapeutic agent in an amount of about 99% by weight (See [0194]).
Regarding claim 27, it is disclosed that a suitable dry powder comprising the dry particles can have a Carr Index (compressibility index) that is between about 15 and 50, e.g. between 30 and 40 (See [0225]-[0226]).
Meeting claims 1 and 22, it is further disclosed that the said respirable dry particles can have an MMAD of about 10 microns or less, such as an MMAD of about 0.5 micron to about 10 microns, preferably, about 5 microns or less (e.g., about 0.5 micron to about 5 microns, preferably about 1 micron to about 5 microns) (See [0240]).
Regarding claims 1 and 31, DeHaan et al teach that the said respirable dry powders and dry particles can have an FPF of less than about 5.6 microns (FPF<5.6 µm) of at least about 50%, at least about 60%, or at least about 70% (See [0241]-[0242]).
Regarding claims 1 and 35-36, it is stated that the pharmaceutically therapeutic agent can be crystalline or amorphous or present in a combination of these forms. In some embodiments, the respirable dry particles are substantially crystalline (See 0259]).
DeHaan et al state that this provides several advantages. For example, the crystalline phase can contribute to the stability of the dry particle in the dry state and to the dispersibility characteristics, whereas the amorphous phase (e.g., amorphous therapeutic agent and/or excipient) can facilitate rapid water uptake and dissolution of the particle upon deposition in the respiratory tract. It is particularly advantageous when salts with relatively high aqueous solubilities that are present in the dry particles are in a crystalline state (See [0260]).
It is disclosed that the respirable dry particles contain a therapeutic agent rich amorphous phase and a crystalline phase wherein the ratio of amorphous phase to crystalline phase (w:w) is about 5:95 (See [0262]).
DeHaan et al also disclose that the said respirable dry particles and respirable dry powders can contain an antibiotic, including tuberculosis-mycobacterium antibiotics and the like (See [0105]-[0106]).
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 Yazdi et al and DeHaan et al with that of Keswani et al to arrive at the instant invention. It would have been obvious to do so because Keswani et al teach making particulate formulations of clofazimine which are milled to the suitable particle size range and are suitable in crystalline form. The said dry powder formulation comprising clofazimine is placed in a dry powder inhaler and administered to a subject’s respiratory system via inhalation. Keswani et al teach a method of making a dry powder composition comprising crystalline clofazimine at a particle size for inhalation via dry powder inhaler into the subject’s respiratory system. Yazdi et al teach a powder formulation comprising 100% active agent, ibuprofen, and provide guidance on particle specifics and characteristics for improved delivery of the formulation. DeHaan et al teach inhalable dry powders wherein the amount of excipient may be 0% and disclose suitable particle characterizations for an efficacious dry powder delivery to the lungs, such as the angle of repose and FPF. DeHaan et al disclose that the crystalline form of a dry powder active agent results in better stability of the particle and that an angle of repose of less than 30º is preferred because angle of repose is a characteristic that can describe both respirable dry powder as well as the powder's processability. DeHaan et al further discloses that the FPF of the powder is preferably at least about 50% or most preferred at least about 70%. DeHann et al state that the said powders provide advantages for formulating and delivering therapeutic agents to patients.
Accordingly, one of ordinary skill in the art would have been motivated to have incorporated the particle characteristics of DeHann et al including an excipient free formulation into the dry powder formulations of Keswani et al in order to more effectively deliver clofazimine in crystalline form into the patient’s respiratory system in need of such treatment.
In other words, 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 would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Additionally, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations.
Regarding the limitation of the dissolution rate in claim 34, it is noted that claim 34 is drawn to a powder composition and is examined based on its components not its properties. However, it is also expected that the composition taught by references of record would have the same properties. In this regard the courts have held that "A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Liu et al (US 20100330156).
Liu et al teach phenazine derivatives and their uses (See Title). One such compound is clofazimine (See [0137]-[0153]).
The said compositions may be administered orally, parenterally, by inhalation spray, etc, (See [0162]).
In order to enhance the solubility of clofazimine, it is desirable to create particles with favorable surface area to volume ratios. A typical process is provided for making dry, micronized particles of clofazimine. The method includes milling clofazimine in a ball mill either with or without surfactant. The surfactant will allow further micronization of the clofazimine to particle sizes below 10 µm (See [0203]).
Liu et al teach a process that yields microparticles having a homogenous size distribution less than 2 µm in size. In certain embodiments, such microparticles have well defined, predictable properties (See [0204]).
It is disclosed that clofazimine is formulated in alternative solid-state crystal forms with, for example, novel hydration states of clofazimine, novel solvation states of clofaziminie, crystallization with salts, or co-crystallization with other drugs or excipients (See [0208]).
Liu et al state that in order to prolong the effect of clofazimine, it is often desirable to slow the absorption of clofazimine from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form (See [0221]).
The said formulations may be formulated as dosage forms for oral administration including powders, and granules (See [0223]). Dosage forms include powders, sprays, inhalants, etc (See [0226]).
Verma et al (Inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice).
Verma et al teach evaluating inhalable clofazimine-containing dry powder microparticles (CFM-DPI) and native clofazimine (CFM) for activity against Mycobacterium tuberculosis in human monocyte-derived macrophage cultures and in mice infected with a low-dose aerosol. Both formulations resulted in 99% killing at 2.5 μg/ml in vitro. In mice, 480 μg and 720 μg CFM-DPI inhaled twice per week over 4 weeks reduced numbers of CFU in the lung by as much as log10 2.6; 500 μg oral CFM achieved a log10 0.7 reduction (See abstract).
Verma et al also disclose that CFM as a dry powder microparticle formulation for inhalation (CFM-DPI) might hold advantages for generating drug levels at the primary site of infection that would not otherwise be achievable. Preliminary findings presented show that (i) CFM-DPI retains the antimicrobial properties of native CFM in vitro and (ii) CFM-DPI is more efficacious in treating experimental tuberculosis than if given orally. It is further stated that CFM-DPI was prepared by spray drying. The resulting particle size (1 to 5 μm) of CFM-DPI was suitable for deep lung delivery (See page 1050, 1st col, 2nd and 3rd para).
Claims 1, 3, 21-22, 25-29, 31, 34-36 and 39 are rejected. Claims 54, 63, 70 and 75 are withdrawn.
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 on M-F, 7-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue X. Liu can be reached on 571-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616