DETAILED ACTION
Status of the Application
Receipt is acknowledged of Applicants’ response to the Requirement for Restriction, filed 23 July 2026, in the matter of Application N° 18/849,399. Said documents have been entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
No claims have been added, amended, or canceled.
No new matter has been added.
Applicants’ election of Group I (claims 1-16), without traverse, is acknowledged.
Applicants’ election is made FINAL. The claims of Group II (claims 17-19 and 22) are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. Applicants timely traversed the restriction requirement between the method and composition.
Thus, claims 1-16 are presented and represent all claims currently under consideration.
Information Disclosure Statement
One Information Disclosure Statement (IDS) filed 20 September 2024 is acknowledged and has been considered.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0011] is objected to because it incorrectly refers to Fig. 1B as “Fig. 2B”.
Appropriate correction is required.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. Applicants are 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 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Williams et al. (US Pre-Grant Publication Nº 2021/0322445 A1; IDS/ISR reference) in view of Seem et al. (Powder Tech.; 2015) and Martin (MDDI; 2000).
The instantly claimed invention is directed to a method of producing a dry powder inhaler blend comprising:
introducing an active pharmaceutical ingredient (API), a lubricant, and a carrier into at least one multi-screw extruder;
continuously mixing the API, lubricant, and carrier in the at least one multi-screw extruder to form a dry powder blend;
wherein the API, lubricant, and carrier are in the form of a powder.
Williams discloses a solid dispersion composition comprising niclosamide (API) that may be administered via inhalation (see e.g., Abstract; claims). Table 14, DPI 6 discloses a combination of niclosamide (API), Mg St (magnesium stearate; lubricant), and lactose (carrier).
Paragraph [0017] discloses that the practiced composition will comprise niclosamide and that the composition is formulated for administration via inhalation as a dry powder to be administered via dry powder inhaler. See e.g., ¶[0023], ¶[0097], and ¶[0098].
Claim 144 discloses a method of producing the practiced composition comprising obtaining and combining niclosamide and a pharmaceutically acceptable polymer and subjecting the combination to a hot melt extrusion process to obtain the composition.
The hot melt extrusion process is further defined in the reference as comprising additional instruments such as a Leistritz® twin-screw extruder. See ¶[0136]. Paragraph [0193] additionally discloses physically blending niclosamide with another API (clofazimine) to form a blended powder having a coefficient of variation of less than 5%.
Despite teaching and suggesting the use of a twin-screw instrument such as one provided by Leistritz, the reference does not elaborate on the instantly claimed instrument parameters.
The journal article published by Seem bridges the gap of information, providing the ordinarily skilled artisan with the requisite technical information pertaining to twin-screw extrusion apparatuses.
Specifically, the reference discloses the Leistritz NANO-16 as an example of a twin-screw extruder that is marketed as being used for granulation (see pg. 90, left col.).
At the outset, the Examiner has considered the mixing parameters recited by the instant method, namely: screw speed, feed rate, and %CV. The broadest reasonable interpretation of these parameters is that they are achieved using the aforementioned NANO-16 twin-screw extruder as defined by the instant specification.
As such, its disclosure in the art is considered to place within the hands of the ordinarily skilled artisan the specific device that is used to produce a homogeneous blend of powders (i.e., %CV<5%), by subjecting the powdered ingredients fed at a rate of 1-50 g/min (0.06-3kg/h) to a twin-screw having a screw speed ranging from 50-500 RPM.
Typical aspects of twin-screw granulators are the inclusion of two intermeshed screws enclosed in a barrel, the key advantage to this structuring being that the screws are self-cleaning with the flight of one screw scraping clear the surface of the other in rotation. Figure 1 of the reference depicts a typical TSE setup:
PNG
media_image1.png
422
1124
media_image1.png
Greyscale
Figure 3 depicts the intermeshing of the twin screws:
PNG
media_image2.png
488
558
media_image2.png
Greyscale
PNG
media_image3.png
372
596
media_image3.png
Greyscale
Such is considered to teach the limitations of instant claims 2 and 3.
Regarding the limitations recited by instant claims 7-16, the Examiner understands that the powder extrusion process recited by claim 1 is further limited to one that achieves a coefficient of variance percent (%CV) value of less than 5% or less. Percent CV is additionally understood as being a statistical metric by which the homogeneity or blend uniformity if a powder mixture is evaluated. Therein, the smaller the percent value, the more homogeneous the blend is.
As disclosed by Williams, the pharmaceutical mixture is first formed and then homogenized. See e.g., ¶[0043].
Seem adds to this understanding in its disclosure of twin-screw extruders. On a higher level, Seem discloses that operational variables that are considered when producing granulated powders include both: screw speed and material feed rates. Process and product quality outcomes include, for instance, granule particle size distribution (i.e., particle size uniformity or CV).
Regarding screw speeds, the reference reports that “[l]ow Low screw speeds result in high fill levels in the granulator barrel, leading to material compaction where blockages can form at high mass loads. High screw speeds result in low barrel fill levels, where the screw channels may become starved of powder resulting in low compaction and particle interaction. As variation in fill level can result in considerable differences in binder distribution and granule properties screw speed is an important factor to be considered during scale up of twin screw granulation” (see pg. 100, Section 7.1, second full paragraph).
Regarding feed rates, it was observed that “strength of the granules is dependent on the fill level” and that “the higher the feed rate, the more powder in the barrel and the denser and stronger the granules formed.” (see pg. 100, Section 7.2, first paragraph).
The takeaway from Seem is that feed rate and screw speed are two variables at the disposal of the ordinarily skilled artisan that are used to produce a uniform or homogeneous distribution of particles.
Further state of the art discussion pertaining to this relationship is provided by Martin (Leistritz) who discusses continuous compounding using twin-screw extruders.
Therein it is discussed that “[c]ompounding extruders are used to mix together two or more materials into a homogeneous mass in a continuous process” and that such processes perform a number of basic functions including: feeding and mixing. Different extruders are available to be used including counterrotating intermeshing twin screws and corotating intermeshing twin screws, with the intermeshing modes being typically used for medical applications.
It is additionally taught that “[a]mong the typical process parameters that are controlled in a twin-screw extruder operation are screw speed (in revolutions per minute), feed rate, temperatures along the barrel and die, and vacuum level.
Regarding feed systems, “[s]ingle-screw extruders are generally flood-fed machines, with the single screw speed determining the throughput rate of the machine. Because twin-screw compounders are not flood-fed, the output rate is determined by the feeders, and screw speed is used to optimize the compounding efficiency of the process. The pressure gradient in a twin-screw extruder is controlled and kept at zero for much of the process (Figure 7). This has substantial ramifications with regard to sequential feeding and to direct extrusion of a product from a compounding extruder.”
Further, “[s]election of a feeding system for a twin-screw compounding extruder is extremely important. Components may be premixed in a batch-type mixing device and volumetrically fed into the main feed port of the extruder.”
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success in achieving the instantly recited method of treatment.
At its core, the claimed invention is directed to producing a powder blend destined for inhalation (i.e., pulmonary inhalation via MDI). The combination of the API, lubricant, and carrier are components that are well established in the art for such a use. The method is further limited in terms of the apparatus that is used to mix the components relying upon such device limitations as: being a multi-screw (i.e., twin-screw) extruder, operating under various feed rates and screw speeds in order to achieve a powder having a coefficient of variation percent value of less than 5%. The lower the value for %CV, the more homogeneous the resulting powder is.
Williams discloses preparing powders for inhalation and suggests a %CV of less than 5%. The production method discloses including such instruments in the process as a twin-screw extruder (i.e., produced by Leistritz). Despite this disclosure, the recited operating parameters are not expressly disclosed.
The respective contributing teachings of Seem and Martin both speak to the state of the art of twin-screw extruders as instruments and modes for the continuous mixing of powder formulations. The former, most notably, exemplifying the Leistritz NANO-16 twin-screw extruder.
The Examiner concedes that none of the cited references expressly discloses the settings or parameters of the generically recited extruder used to produce the homogeneous powder blend of the claimed invention.
However, as discussed above, the Examiner, in considering Applicants’ support for the claimed parameters broadly and reasonably interprets such parameters as being met by defining apparatuses set forth within the instant specification. See MPEP §2111.01(IV). Therein, it is noted that Applicants employ the use of the aforementioned Leistritz NANO-16 TSE, and as such disclosure of said device will be considered to place the recited parameters within the purview of the ordinarily skilled artisan.
Seem is thus considered to bolster the teachings of Williams’ inhalation powder production method which discloses using a Leistritz twin-screw extruder. Again, while neither Seem nor Martin expressly disclose the recited parameters, Martin (also cited as a sales manager for Leistritz) discloses that such parameters as screw speed and feed rate independently play into achieving a homogeneous powder product, stating specifically that both parameters are controlled.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of criticality or evidence to the contrary.
All claims have been rejected; no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Jeffrey T. Palenik whose telephone number is (571) 270-1966. The Examiner can normally be reached on 9:30 am - 7:00 pm; M-F (EST).
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Robert A. Wax can be reached on (571) 272-0623. 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 or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Jeffrey T. Palenik/
Primary Examiner, Art Unit 1615
Prosecution Insights