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 .
Receipt is acknowledged of Amendments and Remarks filed on 01/22/26. Claims 16, 18, 20, 23, 25-26, 30, 32-33 have been amended, new claim 36 has been added and claims 19 and 28 have been canceled. The Specification has been amended at page 35. Accordingly, claims 16-18, 20-27 and 29-36 are pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 is indefinite for depending on a canceled claim. Claim 20 depends on canceled claim 19. For examination purposes, the claim will be interpreted as deepening on claim 16. Corrections are required.
Claim interpretation
Claims 30-35 are drawn to a product obtained by a process. That is claims 30-35 are product-by-process claims. Product-by-process claims are examined on the limitations of the product. MPEP 2113, citing In re Thorpe, 111 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.
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.
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 16-18, 20-27, 29-36 are rejected under 35 U.S.C. 103 as being unpatentable over Arora et al (Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability) in combination with Buchi® B-290 Mini Spray dryer Information Bulletin and Perry et al (WO 2019204597).
Arora et al disclose a study aimed at developing a dry powder inhalable formulation of voriconazole (VRZ) with high drug content and superior aerosolization properties using simple excipients like amino acids. The study investigates the development of highly respirable inhalable formulation of VRZ utilizing one-step spray drying methodology. Formulations were prepared by spray drying varying concentrations of VRZ and leucine and characterized extensively in terms of their physicochemical characteristics, aerosol dispersion, in-vitro drug release, storage stability, in vitro cell viability and in vivo lung bioavailability and tissue distribution (See Page 184, 1st col. 2nd para).
Regarding claims 16 and 30, Arora et al conclude that particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy (See abstract).
It is disclosed that VRZ, when spray-dried alone (Figure 1A), showed to possess a plate-like morphology with a crystalline structure. This is primarily due to the outlet temperature of the spray dryer being above the glass transition temperature of VRZ, thus promoting the crystallization of VRZ. All the spray-dried samples were crystalline (See 3.1 and Fig 1).
Arora et al teach that the aerosolization characteristics of the spray-dried powders were found to improve significantly (p < 0.05) with the inclusion of leucine in the feedstock solutions. MMAD of all the powders were between 3.79 µm and 6.12 µm, and FPF values are from 20.8% to 60.0%. VRZ_LEU_20, prepared with 20% leucine, displayed the best aerosolization properties, with a MMAD of 3.79 µm, FPD around 1893 µg and FPF (% aerosol < 5 µm) around 60% (See 3.2).
Arora et al also disclose the particle size distribution of the powders investigated. See Table 2 below.
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1686
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Regarding claim 34, the above Table shows that D90 of the aid dry powder compositions comprising voriconazole and leucine are below 10 microns.
Regarding claims 18 and 32, Arora et al teach formulations comprising 20% or 30% leucine (See Page 187, para 3.1 and Table 2).
With regard to the method of manufacturing an inhalable powder as claimed in claims 16, 30 and 36, Arora et al teach that leucine modified VRZ microparticles were prepared by spray drying using a Buchi Spray Dryer (Buchi B-290 Mini Spray Dryer, Buchi, Switzerland). Varying concentrations of VRZ and leucine (Table 1) were dissolved in ethanol–water (70%:30% v/v) and spray-dried at inlet temperature 125°C, feed flow rate of from about 10 g/minute to about 23 g/minute and resulting outlet temperatures of 40°C, 60°C or 75°C in the closed-loop configuration using nitrogen as the atomizing gas (See 2.1 and Fig. 1).
Arora et al also disclose aerosol property of optimized formulations after storage (See Table 4 below).
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455
1701
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Regarding claims 22 and 35, Arora et al teach an MMAD of less than 5 µm (See table 4).
Arora et al lack an express disclosure on the feed rate of the spray drying. This is known to one of ordinary skill in the art from Best @Buchi, Buchi ® B-290 mini spray dryer. Arora et al also lack an express disclosure on the presence of a surfactant. This is known in the art as taught by Perry et al.
Best@ Buchi, Buchi® B-290 teaches the specifics of Mini dryer and Mobile Minor® and compares their data. On 5th page of the document, a table of the example with spray dryer B-290 data is provided. It is disclosed that the Mini Spray dryer has an outlet temperature of 40˚C, 60˚C or 75˚C and a feed flow rate of 0.60 Kg/h or 1.41 Kg/h or 9 Kg/h (or 10 g/min or 23 g/min or 150 g/min). Best@ Buchi, Buchi® B-290 also compares different outlet temperatures and different feed (flow) rates in Fig.1, 3rd page). It is shown that the outlet temperatures can be from 40 to 80˚C and the flow rate can be from 20 Kg/h to 40 Kg/h.
Perry et al teach a dry powder composition for delivery of an antifungal agent to the respiratory tract (See abstract).
Perry teaches that the term “homogenous dry particle” as used herein refers to particles containing crystalline drug (e.g., nano-crystalline drug) which is pre-processed as a surfactant stabilized suspension. The homogenous dry particle is then formed by spray drying the surfactant-stabilized suspension with (optional) excipients, resulting in dry particles that are compositionally homogenous, or more specifically, identical in their composition of surfactant-coated crystalline drug particles and optionally one or more excipients (See [0059]).
Regarding claims 16, 20, 25, 30 and 33, the said anti-fungal agent may be itraconazole or voriconazole present at an amount of about 80% by weight (wt%) (See [0080] and [0082]). The said dry powder composition may comprise one or more excipients including amino acids such as leucine present at an amount of about 10% or greater and stabilizers including polysorbates and phospholipids present at an amount of 5 wt% or less, or about 1 wt% (See [0094]-[0095], [0058] and [0085]).
Regarding claim 24, it is taught that the said anti-fungal agent crystallinity can be at least about 50%, at least about 90%, at least about 95%, or about 100% crystalline. Preferably, the anti-fungal agent is about 100% crystalline (See [0083]).
Perry et al disclose that the dry powder is prepared by spray dryers including Buchi B-290 Mini Spray drier (See [00141]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to have combined the teachings of Best@Buchi information Bullet and Perry et al with that of Arora et al to arrive at the claimed method and compositions with a reasonable expectation of success. It would have been obvious to do so because Arora et al teach the potential of inhaled dry powder comprising voriconazole and leucine for the treatment of respiratory fungal infections and disclose the preferred method of making the said dry powder as spray dried with a Buchi® B-290 Mini Spray dryer. The Buchi information bulletin discloses that the outlet temperature and feed rate as 60˚C and 10 or 23 g/min. Thus, one of ordinary skill in the art interested in following Arora et al’s teachings on dry powder compositions and a method of spray drying them by a Buchi® mini spray dryer would have been motivated to have looked in the art for more information of the said apparatus to ensure proper use of the said apparatus. The one of ordinary skill in the art also would have been motivated to have included Perry et al’s surfactants into the disclosed dry powder composition of Arora et al because Perry et al, drawn to a very similar composition and method of preparation provides guidance on adding a stabilizer to the said dry powder composition.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant's arguments filed 01/22/26 have been fully considered but they are not persuasive.
Applicant’s amendments to the claims have necessitated modified grounds of rejections. Applicant’s arguments so far as they pertain to the maintained references and rejections are discussed below.
Applicant’s first relevant argument is that “the claimed method of producing inhalable powders meaningfully differs from the cited prior art with respect to various characteristics in combination, including the outlet temperature and the feed rate. Both Arora and Perry describe pharmaceutical compositions or inhalable powders, including voriconazole and leucine produced by spray drying. These powders are produced using equipment as described by Buchi at an outlet temperature of 78°C and with a feed rate of 5%, i.e., a very low flow characteristic of laboratory instruments such as the one used in these documents” (See Remarks, page 11).
The above argument is not persuasive because both Arora et al and Perry et al teach spray drying the said solution into powder using a Buchi B-290 Mini Sprayer and as shown Buchi B-290 Mini Sprayer can dry the formulation at the claimed outlet temperature range and flow rate. Specifically, Buchi B-290 reference teach that the said mini sprayer operates at outlet temperatures such as 40˚C and 60˚C and flow rates including 1.41 Kg/h, 9 Kg/h and 40 Kg/h. Thus, the combination of references would have led one of ordinary skill in the art to the same method and formulation as claimed.
Next argument is that “The present Application clearly describes numerous examples for obtaining a powder with the desired characteristics as claimed, i.e., a powder with high breathability, each of which include a working flow of the spray dryer being greater than 15 g/minute. In this way a powder comprising voriconazole in a substantially crystalline form is obtained, unlike what normally occurs with the spray drying technique wherein the active ingredient obtained is in an amorphous form” (See Remarks, page 11).
This argument is also not found convincing. Both Arora et al and Perry et al teach a formulation wherein the powder and specifically the voriconazole is in crystalline form. Perry et al teach a formulation wherein the antifungal agent can be at least about 90%, at least about 95%, or about 100% crystalline (See [0044]). Arora et al also disclose that the said dry powder comprising voriconazole and leucine was crystalline.
Applicant points to Example 1 and Table 1 in the Specification comparing the claimed method to other methods with different outlet temperatures resulting in “drastically lower” yield (See Remarks, pages 12-13).
The above arguments are similarly unpersuasive as the combination of references teach each and every limitation of the claims including the outlet temperature between 40˚C and 75˚C.
Applicant argues that “the Office Action provides no citations at all in support of the rejection of claim 29, "wherein the outlet temperature is from 50 to 70 0 C."” (See Remarks, page 13).
Again, the argument is not persuasive as the rejection show that Buchi reference teach the claimed outlet temperatures and the flow rates as claimed.
Claims 16-18, 20-27 and 29-36 are rejected.
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 Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616