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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/28/2026 has been entered.
Formal Matters
Receipt of Applicant’s response dated 01/28/2026 is acknowledged.
Claims 10-11 and 21-38 are pending.
Claims 1-9 and 12-20 are canceled.
Claims 10 and 37 are amended.
Claims 10-11 and 21-38 are under consideration in the instant Office action to the extent of the elected species, i.e., the clofazimine is clofazimine orthorhombic crystal polymorph FIII, the pharmaceutically acceptable carrier and/or excipient is a crystalline sugar, and the viral infection is influenza.
Information Disclosure Statement
The information disclosure statement (IDS) filed 04/14/2026 has been considered by the Examiner. A signed copy of the IDS is included with the present Office Action.
REJECTION WITHDRAWN
Claim Rejections - 35 USC § 103
The rejection set forth in the Office action dated 10/31/2025 is hereby withdrawn in light of Applicant’s amendments to the claims and in favor of the new grounds of rejection set forth below.
NEW GROUNDS OF REJECTION
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10-11 and 21-38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 10 recites “wherein a delivered dose of the clofazimine in the patient's lungs is up to about 10 µg clofazimine/g”. In Remarks dated 12/29/2025, it is stated that support for the amendments can be found throughout the specification including Par. [0022]. However, Par. [0022] of the specification states that "Preclinical studies have evaluated CIS [clofazimine inhalation suspension] for the treatment of NTM-PD and TB, and a series of toxicology studies have been performed, which have shown that CIS is safe and well tolerated at doses up to ~3.0 mg/kg (reaching lung levels of ~10 µg clofazimine/g).” This support in the disclosure regards the level of clofazimine inhalation suspension, generally, that has been found to be safe and well tolerated in the lungs, but does not regard the level of clofazimine in the claimed method that reaches the lungs. The Examiner has reviewed the specification for support outside of Par. [0022] for “wherein a delivered dose of the clofazimine in the patient's lungs is up to about 10 µg clofazimine/g”, however, no support has been found. Therefore, claim 10 is rejected for containing subject matter not described in the specification. Claims 11 and 21-38 are rejected for depending from claim 10.
Amended claim 10 now recites limitation(s), which were not clearly disclosed in the specification as filed, and now change the scope of the instant disclosure as filed. Such limitation(s) recited in amended claim 10, which did not appear in the specification, as filed, introduces new concepts and violates the description requirement of the first paragraph of 35 U.S.C 112. Applicant is required to provide sufficient written support for the limitations recited in instant claim 10 in the specification or claims, as-filed, or remove these limitations from the claims in response to this Office Action.
Claim Rejections - 35 USC § 112(b)
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.
Claims 10-11 and 21-38 are 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 10 is indefinite in the recitation of “wherein a delivered dose of the clofazimine in the patient's lungs is up to about 10 µg clofazimine/g” because it is unclear what the concentration is with respect to. Is it 10 µg of clofazimine delivered in the patient’s lungs per gram of the total mass of the dose emitted from the dry powder inhaler, is it 10 µg of clofazimine delivered in the patient’s lungs per gram of the total mass of the dose that is delivered in the lung, is it 10 µg of clofazimine delivered in the patient’s lungs per gram of clofazimine present in the composition before the dose is emitted, is it 10 µg of clofazimine delivered in the patient’s lungs per gram of the patient’s lungs, or is it something else? Claims 11 and 21 create further ambiguity because all of claims 10-11 and 21 regard the amount of clofazimine delivered to the lungs, however, the difference in units used in claim 10 (µg/g) versus claims 11 and 21 (mg) makes it unclear how these amounts relate to one another. As written, one skilled in the art would not be reasonably apprised of the metes and bounds of the claims.
Claims 11 and 21-38 are rejected for depending from claim 10 without resolving the ambiguity of claim 10.
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 10-11 and 21-38 are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al (WO 2019/070693 A1, published 04/11/2019, cited in IDS dated 12/07/2022) in view of Bannigan et al (Cryst. Growth Des., 2016, 16, 7240-7250, published 11/07/2016, cited in IDS dated 05/31/2023), Kinnunen et al (AAPS PharmSciTech, 2014, 15, 898-909, published 04/23/2014, cited in Notice of References Cited dated 05/13/2025), and Fathi et al (US 2016/0113954 A1, published 04/28/2016, cited in Notice of References Cited dated 05/13/2025).
Smyth et al teach an inhalable composition of clofazimine, methods of producing the inhalable clofazimine composition by jet milling, and methods of treating pulmonary diseases by administering the inhalable clofazimine composition (See entire document, e.g., Abstract).
Smyth et al teach a pharmaceutical composition comprising micronized clofazimine particles that may comprise lactose (i.e., a crystalline sugar of the instant claims; see par. [0030] of the instant spec) (e.g., [0006]-[0007]).
The micronized clofazimine particles may be crystalline, essentially crystalline, or substantially crystalline (e.g., [0008]). The method of preparing the composition may include subjecting the clofazimine to a jet mill (e.g., [0019]).
The micronized clofazimine particles have a median particle diameter of 0.5 to 10 microns (e.g., [0006], [0017], [0019]). Smyth et al report mass median aerodynamic diameter values of the clofazimine fine particles of 1.74 and 2.57 microns and of the clofazimine milled particles of 1.74 and 2.19 microns (e.g., [0036], Figure 7). The median particle size of lactose is from 70 to 110 microns (e.g., [0042] on Page 28).
The composition may be a dry powder formulated for inhalation (e.g., [0006]). The dry powder composition may be loaded in a dry powder inhaler (e.g., [0015]).
Smyth et al teach a method for treating or preventing a pulmonary infection in a patient comprising administering an effective amount of the composition to the patient, including administering the effective amount by inhalation of the composition into the patient’s lungs with a dry powder inhaler (e.g., [0020]-[0021]).
The composition is packaged as a unit dosage form, the unit dosage form being a cartridge, blister or capsule, comprising 5-30 mg of micronized clofazimine particles (e.g., [0014]). Smyth et al teach a dry powder inhaler comprising a unit dosage form delivers a fine particle dose from 5 to 15 mg of clofazimine with one actuation of the device (e.g., [0018]).
The composition may be administered on a routine schedule, meaning a predetermined designated period of time. The routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In some embodiments, clofazimine is administered once per day. In preferred embodiments, clofazimine is administered less than once per day, such as every other day, every third day, or once per week (e.g., [0094]).
Smyth et al teach that treatment of a patient with micronized clofazimine may comprise modulated drug release including slow-/delayed-release, fast-release or both slow and fast release (i.e., dual release profile) (e.g., [0087]).
Smyth et al teach that the micronized clofazimine is rapidly transformed into a low toxicity and anti-inflammatory crystalline-like form when taken up by alveolar macrophages, and this crystalline-like form of clofazimine is beneficial for rapid onset of action of therapeutic effects, which can be delayed for up to two weeks (e.g., [0044]).
Smyth et al also teach that that the treatment may further comprise administering at least a second therapeutic agent, wherein the second therapeutic may be, but is not limited to, bedaquilline, pyrazinamide, linezolid, clarithromycin, amikacin, kanamycin, capreomycin, streptomycin, ethambutol, ethionamide, thioacetizone, isoniazid, imipenem, clavulanate, cycloserine, terizidone, amoxicillin, prothionamide, rifampicin, rifabutin, rifapentine, 4-aminosalicylic acid, moxifloxacin, ofloxacin, levofloxacin, vancomycin, tobramycin, ciprofloxacin, fosfomycin, and rifaximin (e.g., [0099]). The combination therapies may be administered simultaneously, sequentially, or separately (e.g., [0099]).
Although Smyth et al teach that the micronized clofazimine particles may be crystalline, essentially crystalline, or substantially crystalline (supra), they do not specifically teach the particles as the orthorhombic crystal polymorph form F III of clofazimine.
Smyth et al teach the median particle size of lactose being from 70 to 110 microns (supra). Smyth et al do not teach use of lactose particles having a mass median diameter of 0.5 to 10 microns in the composition.
Smyth et al do not teach the pulmonary infection being an influenza infection nor do they teach the administration of the composition in combination with another antiviral therapy.
These deficiencies are made up for in the teaching of Bannigan et al, Kinnunen et al, and Fathi et al.
Bannigan et al teach that clofazimine, like many pharmaceutical compounds, exhibits polymorphism, meaning it can exist in different crystalline forms, and that different polymorphs of the same drug substance can have different physical properties which can have a great impact of the bioavailability of the drug (See entire document, e.g., Par. 3 of Introduction). Bannigan et al teach two novel polymorphs of clofazimine (F III and F IV) and compare their properties with previously reported polymorphs of clofazimine (F I and F II) (e.g., Abstract). Bannigan et al found that F III, an orthorhombic crystal polymorph, had the highest thermodynamic stability, thermal stability, and overall stability (e.g., Conclusions).
Kinnunen et al teach the effect of different sized lactose particles on the fluidization and aerosolization properties of dry powder inhaler formulations (See entire document, e.g., Abstract). Kinnunen et al found that use of fine particle lactose having a median particle size of 2.41 microns had the largest increase of delivery of an active pharmaceutical ingredient to the lungs and that only low concentrations of this fine particle lactose having a median particle size of 2.41 microns is required to significantly improve dry powder inhaler performance (e.g., Abstract, Par. 1-2 of Particle Size Distributions and Morphology of the Raw Materials, Par. 2 of In Vitro Performance of DPI Formulations Prepared with the Lactose Pre-blends as Carriers).
Fathi et al teach compositions and methods for treating symptomatic and/or asymptomatic infections of negative-sense single-stranded RNA viruses including influenza viruses (See entire document, e.g., [0002], [0009], [0025], [0048]-[0049]). A treatment for a ssRNA viral infection includes concomitantly administering a therapeutically effective amount of an anti-viral drug and a therapeutically effective amount of clofazimine (e.g., [0162]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to 1) use clofazimine as its orthorhombic crystal polymorph form F III in the composition of Smyth et al, 2) add fine particle lactose having a median particle size of about 2.41 microns to the composition of Smyth et al and 3) use said modified composition of Smyth et al for treating symptomatic and/or asymptomatic infections of negative-sense single-stranded RNA viruses, like influenza, including the administration of an anti-viral drug in combination with the composition comprising clofazimine. One of ordinary skill in the art would have been motivated to 1) use clofazimine as its orthorhombic crystal polymorph form F III because Bannigan et al teach its superiority in its stability compared to other crystalline forms of clofazimine, 2) add fine particle lactose having a median particle size of about 2.41 microns because Kinnunen et al teach its superiority in improving dry powder inhaler composition performance and delivery of an active pharmaceutical ingredient to the lungs, and 3) use the modified composition to treat a ssRNA viral infection, e.g. influenza, including co-administering with an anti-viral drug because Fathi et al teach the administration of clofazimine in combination with an anti-viral drug for treating infections of negative-sense single-stranded RNA viruses including influenza. There would have been a reasonable expectation of success because the composition of Smyth et al is compatible with crystalline micronized clofazimine particles and lactose particles and is taught in a method for treating pulmonary infections.
The modified method for treating or preventing a pulmonary infection in a patient of Smyth et al comprising administering an effective amount by inhalation of the modified pharmaceutical composition of Smyth et al, the pharmaceutical composition comprising clofazimine as its orthorhombic crystal polymorph form F III, lactose particles with a median particle size of from 70 to 110 microns, and lactose particles with a median particle size of about 2.41 microns, into the patient’s lungs with a dry powder inhaler along with the concomitant administration of an anti-viral drug, wherein the infection is a symptomatic and/or asymptomatic infection of negative-sense single-stranded RNA viruses, like influenza, render obvious the method of instant claims 10-11 and 21-38.
One actuation of the dry powder inhaler comprising a unit dosage form of the composition delivering a fine particle dose from 5 to 15 mg of clofazimine to the lungs renders obvious the dose of the dry powder pharmaceutical composition delivered to the lungs being from about 1 to 20 mg of clofazimine (instant claim 11) and being from 3 to 8 mg of clofazimine (instant claim 21). The teachings discussed supra of median particle diameter and mass median aerodynamic diameter values of clofazimine particles and the median particle size of lactose particles renders obvious the ranges of instant claims 29-30 and 32-35. A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art (In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003)).
Regarding instant claim 10, because the method of administering the modified pharmaceutical composition of Smyth et al is the same as the method of the instant claims, i.e. delivers the same amount of clofazimine to the lungs, the method would necessarily deliver a dose of clofazimine in the patient's lungs up to about 10 µg clofazimine/g. Additionally, regarding instant claim 24, because the method of administering the modified pharmaceutical composition of Smyth et al is the same as the method of the instant claims, the method would necessarily create a depot of clofazimine in the lungs to release clofazimine over time. 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 administration of the modified pharmaceutical composition of Smyth et al according to the treatment schedule discussed supra renders obvious the elements of instant claims 23 and 25-26.
The treatment further involving administering a second therapeutic agent along with the modified pharmaceutical composition of Smyth et al renders obvious the method of instant claim 38 because the exemplified second therapeutic agents include suitable antibiotic agents of the instant claims as evidenced by Par. [0026] of the instant specification.
Response to Applicant’s Arguments
Applicant’s arguments dated 12/29/2025 have been considered.
Applicant argues that Fathi does not teach clofazimine for treating negative-sense single-stranded RNA viruses, particularly influenza, but rather Fathi teaches the use of clofazimine combination therapies for filoviruses, including Ebola and Marburg, and that influenza only appears as an example of negative-sense single-stranded RNA viruses among a laundry list of viral families and genera under the category. Applicant argues that “influenza” only appears four times in Fathi, while “filovirus” appears 76 times in Fathi and that all the experimental data provided by Fathi regard Ebola viral infections, and therefore, a skilled artisan would determine the compositions and methods of Fathi are for filoviruses rather than the exhaustive laundry list of viruses provided by Fathi and a skilled artisan would not be led to apply clofazimine to the pulmonary viral diseases or influenza of the instant claims. Applicant argues that because Fathi teaches a combination therapy including, but not exclusively, clofazimine, the skilled artisan would be motivated to pursue the synergistic combination and would not be motivated to apply clofazimine individually, with a different delivery method, to very different diseases, and arrive at the present claims. Applicant argues that Smyth teaches inhalable clofazimine not including form F III for bacterial infections, Bannigan teaches form F III and no deliverable form, and Kinnunen teaches inhalable formulations including lactose without clofazimine, which in no way leads a skilled artisan to the application of clofazimine form F III to pulmonary viral infections and arrive at the present claims. Applicant argues that the amendment to claim 10 to recite “wherein a delivered dose of the clofazimine in the patient's lungs is up to about 10 µg clofazimine/g” is not taught or suggested in any of the cited prior art references.
The above arguments have been fully considered by the Examiner but are not found persuasive because, firstly, regarding the teaching of Fathi, the fact influenza is mentioned four times, the fact the examples do not regard influenza, and the fact influenza is taught among a list of viruses, are not sufficient reasons for alleging a person of ordinary skill in the art would not be led to influenza based on the teaching of Fathi. It is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands (Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985)). Further, as can be seen in the rejection under 35 USC 103 above, the rejection does not rely on the stance that, based on the teaching of Fathi, one skilled in the art would be “motivated to apply clofazimine individually” but rather that one skilled in the art would have been motivated to use the modified composition to treat a ssRNA viral infection, e.g. influenza, including co-administering with an anti-viral drug because Fathi et al teach the administration of clofazimine in combination with an anti-viral drug for treating infections of negative-sense single-stranded RNA viruses including influenza. The arguments regarding each of the individual teachings of Smyth, Bannigan, and Kinnunen are not found persuasive because the rejection under 35 USC 103 is based on the combined teachings of Smyth et al, Bannigan et al, Kinnunen et al, and Fathi et al, not based on their individual teachings. Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As can be seen in the above rejection under 35 USC 103, one of ordinary skill in the art would have been motivated to look to the teachings of Bannigan et al, Kinnunen et al, and Fathi et al in order to cure the deficiencies in the teaching of Smyth et al, and it would have been prima facie obvious to one of ordinary skill in the art to 1) use clofazimine as its orthorhombic crystal polymorph form F III in the composition of Smyth et al because Bannigan et al teach its superiority in its stability compared to other crystalline forms of clofazimine, 2) add fine particle lactose having a median particle size of about 2.41 microns to the composition of Smyth et al because Kinnunen et al teach its superiority in improving dry powder inhaler composition performance and delivery of an active pharmaceutical ingredient to the lungs, and 3) use said modified composition of Smyth et al for treating symptomatic and/or asymptomatic infections of negative-sense single-stranded RNA viruses, like influenza, including the administration of an anti-viral drug in combination with the composition comprising clofazimine because Fathi et al teach the administration of clofazimine in combination with an anti-viral drug for treating infections of negative-sense single-stranded RNA viruses including influenza. Applicant is reminded that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). Lastly, regarding the argument that the amendment to claim 10 to recite “wherein a delivered dose of the clofazimine in the patient's lungs is up to about 10 µg clofazimine/g” is not taught or suggested in any of the cited prior art references, the modified method of Smyth et al in view of Bannigan et al, Kinnunen et al, and Fathi et al meets this limitation as currently recited because the method taught by the prior art is the same as the method of the instant claims (See new grounds of rejection under 35 USC 103 above) and Applicant needs to resolve the issue of indefiniteness of the aforementioned recitation (See new grounds of rejection under 35 USC 112(b) above).
Conclusion
No claims are allowable.
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/K.E.O./Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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