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 .
Summary
Receipt of Applicant’s arguments and amendments filed 09/08/2025 is acknowledged. After further consideration, the previous rejections are hereby withdrawn in favor of the new rejections outlined below. Because of this, the instant rejections is nonfinal.
Applicant’s election of claims 35-49 in the reply filed on 03/24/2025 is made FINAL.
Claims 35-49 are pending.
Claims 1-34 are cancelled.
Claims 35, 36, 40, 41 and 42 are amended.
Claims 35-49 are pending and under examination in this application.
Claim Objections
Claim 35 is objected to because of the following informalities:
Claim 35 is amended to recite “a uniform size of not more than 500 µ min” in line 5. This recitation of “µ min” does not make any sense, there is no designation of such unit to measure size of the carrier particles. Examiner believes applicant meant to designate the abbreviation “µm” for micrometer as the size measurement. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 35-49 are rejected under 35 U.S.C. 103 as being unpatentable over Carriers in Drug Powder Delivery, Implications for Inhalation System Design (hereinafter the reference is referred as Smyth) in view of Gieschen et al. (US 2001/0027790 A1) hereinafter the reference is referred as Gieschen and further in view of the evidentiary reference Complex carrier particles for respiratory drug delivery analyzed with sequentially bult DEM-simulation models (hereinafter the reference is referred as Wostry).
Smyth teaches the performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol, and multiple factors associated with drug and carrier particles are known to influence dry powder performance the influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop Dry Powder Inhaler (DPI) systems that perform device-independent formulations and/or provide patient-independent delivery (controlled carrier systems) (Abstract).
Regarding claim 35, as noted above, Smyth teaches powdered pharmaceutical formulation (abstract) comprising a) interactive carrier particles coated with micronized drug particles; b) matrix carrier particles system containing drug and excipient, thus the particles shown in b) could also be the drug particles shown coating the interactive carrier particles of a) (page 118, Fig. 1). Moreover, Smyth teaches the effect of size, wherein the increased drug deposition is generally observed with smaller carrier size and increased proportion of fine particles. However, carrier size did not affect the fine particle fraction in some formulations, and higher fine particle fraction was produced with larger carrier sizes (63–90μm), for example poor dispersion of nedocromil (API) was obtained using coarse carrier systems, whereas the use of fine carrier particles and high shear mixing techniques physically disrupted the drug-drug contacts and promoted de-aggregation. Therefore, Decreasing the particle size of the lactose carrier was associated with significant improvements in de-aggregation and fine particle drug deposition, and the carrier’s functional effects were achieved by intercalating self-agglomerates within the drug and disrupting cohesive drug-drug interactions (¶ 2.1.1).
Furthermore, Smyth discloses in (page 122, Fig. 3) Summary of significant physicochemical properties of interactive carrier particle (carrier shape, types and size) systems and their influence on inter-particulate forces, DPI=dry powder inhaler, and more specifically, the effects of particle shape on formulation performance, wherein the particle shape of the carrier particles and the carrier surface smoothness were important in determining the extent of dispersion and disaggregation of salbutamol sulfate (API), elongated carriers may be exposed to air stream drag forces for longer periods, with resultant increased dispersibility and drug fine particle fraction (¶ 2.1.3). Additionally, Smyth further disclose surface roughness has been shown to influence dispersion and powder performance, and in some reports, carriers with smooth surfaces produced higher respirable fractions, low respirable fractions were obtained from carriers with macroscopic surface roughness or smooth surfaces, whereas high respirable fractions were obtained from carriers with microscopic surface roughness, where smaller contact area and reduced drug adhesion occurred at the tiny surface protrusions (¶ 2.1.4).
Therefore, it would have been obvious to a person having ordinary skill in the art to formulate a powder pharmaceutical formulation comprising an API to adhere to surfaces of the carrier particles and taking into consideration of the influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems.
Regarding claim 36, Smyth teaches lactose carrier corresponding to a sugar (¶ 2.1.1), surface-modified drug particles were prepared by depositing nanoparticles on the surface of the drug, wherein the nanoparticles materials used were colloidal silica particles and hydroxypropyl methyl cellulose phthalate nanospheres, where this surface modification method remarkably improved the inhalation properties of the drug (page 124, left column, ¶ 5), and alternatives to lactose have included fructose, galactose, sucrose, trehalose, raffinose and gelatin (page 122, right column, ¶ 2). Moreover, Smyth discloses Matrix carrier particles are particles comprising drug and excipient in a matrix that functions to increase one or more the following performance attributes: blend uniformity and dispersibility (via improved flow properties, reduced cohesive interactions, etc.); controlled release kinetics of drug in the airways; avoidance of endogenous degradation mechanisms; control over targeted drug delivery; and control over particle clearance (¶ 2.3).
Regarding claims 37, 38, 39, 40 and 41, Smyth teaches effects of carrier particle shapes on formulation performance, wherein the elongation of lactose carriers increased the fine particle fraction and dispersibility of salbutamol sulfate after aerosolization of the formulations, and the particle shape of the carrier particles and the carrier surface smoothness were important in determining the extent of dispersion and de-aggregation of salbutamol sulfate (API), owing to relatively small aerodynamic diameters, elongated carriers may be exposed to air stream drag forces for longer periods, with resultant increased dispersibility and drug fine particle fraction
and the morphology of lactose has been shown to be controllable using different crystallization methods and conditions (¶ 2.1.3), and effects of surface roughness, where smaller contact area and reduced drug adhesion occurred at the tiny surface protrusions (¶ 2.1.4). Therefore, the subject matter of morphology and the effects of size and shape of carrier particles is taught.
Smyth specifically fails to disclose a mixing element.
Gieschen teaches a dry powder inhaler has a dispersion chamber containing beads, that roll, bounce, and collide repeatedly with the drug particles on the chamber surfaces or on the beads, and the smaller active drug particles are separated from the larger carrier particles and from each other, and a powder aerosol is created and inhaled by the patient, wherein the beads are lightweight, so that they can be rapidly accelerated and moved, even with nominal inspiration, and the flow resistance of the inhaler is also reduced via the beads, allowing greater air flow and powder dispersion, without any increased effort by the patient (Abstract). Notably, Gieschen discloses
the dispersion chamber contains one or more beads which can move about in the bead race, wherein a powder formulation containing smaller active pharmaceutical particles, and optionally also containing larger inert carrier particles, is placed into or adjacent to the chamber (¶ 0007). Furthermore, Gieschen teaches when a patient inhales on the mouthpiece, air and powder are drawn into, or flow about within, the dispersion chamber. The beads collide with the interior chamber sur- faces, and/or each other, and the powder particles on the chamber surfaces or on the beads. The movement of the beads separate the smaller active drug particles from each other and/or the larger inert carrier particles, if any. In addition to these mechanical forces, other causes of dispersion may include fluid shear between the beads, the powder particles, and the chamber walls. Larger carrier particles, if included in the powder formulation, can further enhance dispersion via enhanced impact energy and abrasion. The active particles are entrained into the airflow through the dispersion chamber, for inhalation by the patient. The larger inert or excipient carrier particles may or may not be entrained and inhaled. The carrier particles are advantageously provided to scour the powder path clean of the fine active particles, so that a more uniform dose may be delivered (¶ 0008).
Regarding claims 42-49, as noted above, Gieschen teaches the dispersion chamber contains one or more beads which can move about in the bead race, the
beads within the dispersion chamber are induced to move chaotically, so that most or all of the interior surfaces of the dispersion chamber, and the surfaces of the beads are
contacted. As a result, less of the powder may be held up within the dispersion chamber, and a more uniform dose may be delivered. Flow rate performance may also be improved (¶ 0008-0009). Furthermore, Gieschen teaches one or more beads can be in the inhaler (¶ 0010), deagglomerizing features and a bead is a loose component not physically attached to any other component or surface of the inhaler, so that it is free to move within the inhaler, with at least one degree of freedom, wherein the bead race is a surface, which a bead contacts, continuously or intermittently, and a bead race may be well-defined or consistent path in or on which beads uniformly move about, or it any be a surface not part of such path (¶ 0011). Moreover, Gieschen discloses one or more beads (40) are contained within the chamber (30), wherein the beads are preferably spherical, but may have other shapes as well, i.e., the beads (40) may be oval or elliptical, disk-shaped, ring-shaped, etc., and the race surface has a radius of curvature greater than the radius of curvature of the beads (40) (or of the largest bead 40 if the beads are of different size), so that all of the beads can make contact with all surfaces of the race (34), and the dispersion chamber (30) holds from 2-10 beads (40), wherein the beads (40) are made of a lightweight material, for example, plastic so that they can be rapidly accelerated, and easily moved by the air stream flowing through the chamber (30) (¶ 0070), and depending on the specific drug formulation, the bead surfaces may be rough or smooth. Similarly, the beads (40) may be hollow, or solid, or they may be eccentrically shaped, or eccentrically weighted, to achieve desired bead movement and interaction within the chamber (30) (¶ 0074). Additionally, Gieschen teaches the bead (40), or the largest of the beads (i.e., the bead with the largest characteristic dimension) for example has a characteristic dimension of from 50-90% of the height or thickness of the dispersion chamber, i.e., the dimension between the surfaces (31) and (33), which allows for some vertical bead movement on the race (34), and between the surfaces (31) and (33), and the beads can be mixed, with the beads having different sizes, shapes, and materials (¶ 0072). Furthermore, the beads may include one or more "agitator" beads, i.e., a bead with an irregular shape, intended primarily to agitate the other beads, rather than primarily to directly disperse powder(¶ 0072). Therefore, the beads reads on the limitations of a mixing element with the enabling feature to mix, agitate or induce chaotic movement to disperse and deagglomerate the fine powder particles inside the mixing chamber of an inhaler.
Gieschen fails to specifically teach additive manufacturing of carrier particles.
Evidentiary reference Wostry teaches the applicability of different tailor-made carrier particle geometries in interactive powder mixtures for respiratory drug delivery, and after the evaluation of 2700 individual simulations, the findings showed significant influences of the carrier geometry, and as a main indicator of the performance, the detachment of the drug from the carrier particle’s surface was evaluated. One particle, namely the Pharmacone, showed in particular superior performance. The Pharmacone is characterized by its spikes protruding from the main body. These spikes significantly influence the Pharmacone’s movement during the collision either with another Pharmacone or with a flat wall and thus the detachment of the drug that covered the Pharmacone’s surface prior to the collision (Abstract). Notably, Wostry exemplifies carrier shape geometries in Fig. 2. (See below), highlighting the (b) pharmacone shape.
PNG
media_image1.png
702
1568
media_image1.png
Greyscale
Regarding claim 35, Wostry teaches the superior Pharmacone particle geometry is of high interest, and with further insight, precise redesign of the geometry, better performance, and also better loading could possibly be achieved. With the knowledge of superior carrier geometries compared to the commercially used irregular tomahawk geometry represented by α-lactose monohydrate crystals, the performance of dry powders for inhalation could be improved and standardized. Therefore, a crucial step will be the mass production of such carrier particles in sufficient numbers. With additive
manufacturing techniques, that showed great improvement in size range, detailedness and printing rates over the last years, an approach bearing the potential to produce desired carrier particles (page 12, left column, 1st ¶). Therefore, Wostry is relied upon for the obvious teachings using lactose in carrier particle and the widely known additive manufacturing technique create the desired geometric shape of the carrier particle.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate the powdered pharmaceutical formulation comprising an API to adhere to the surface on carrier particles and take into consideration of the influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems as taught by Smyth. One of ordinary skill in the art would have found it obvious to improve the DPI formulation by incorporating a mixing element to enhance dispersion of the active particles, so as to entrained and fluidized into the airflow through the dispersion chamber as taught by Gieschen. One would have been motivated to optimize the desired morphology of the geometric shape and size of the carrier particles to achieve the most advantageous improvement in respirable API to target delivery of DPI, wherein the surface roughness of the carrier particle can influence powder flow and dispersion properties and incorporating a mixing element to the powder formulation helps to improve dispersion, de-agglomeration and fluidization as taught by Smyth in view of Gieschen. The subject matter of formulating a powdered pharmaceutical composition comprising an API to adhere to the surfaces of carrier particles of a particular geometric shape and size and with a mixing element is taught by Smyth in view of Gieschen. One of ordinary skill in the art would have found it obvious that in order to standardized and mass produce the most efficient carrier particle design for a DPI formulation, with improved performance, the use of additive manufacturing techniques (3D printing) would yield results on a massive scale, as evidenced by Wostry. As such, the reference is analyzed using its broadest teachings. MPEP 2123 [R-5]. Where, as here, the specific combination of features claimed is disclosed within the broad teachings of the reference but the reference does not disclose the specific combination of variables (for example, the plethora of exemplary shapes and for carrier particles of mixing elements in instant Figure 1, in a specific embodiment or in a working example, “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). However, "when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious". KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious", the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that "[a] person of ordinary skill is ... a person of ordinary creativity, not an automaton." Id. at 1742. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the disclosed elements and embodiments of Smyth in view of Gieschen and further in view of Wostry, to include an example the exemplary shapes for mixing elements and for carrier particle in Figure 1, to prepare the claimed composition. Such a combination by a person of ordinary skill in the art who is not an automaton to yield the instantly claimed compositions and methods is within the purview of the ordinary skilled artisan upon reading Smyth, Gieschen, and Wostry as cited above, and would yield predictable results.
Response to Arguments
Applicant’s arguments, see Remarks, filed 09/08/2025, with respect to the rejection(s) of claim(s) 35-49 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejections has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Smyth in view of Gieschen and further in view of Wostry.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615