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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 has been entered.
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 12 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 12 depends on both claim 10 and claim 8; examiner will interpret the claim as dependent upon claim 10 for the purposes of examination.
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.
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.
Claim(s) 1, 3 – 8, 13 – 15, and 17 – 18 is/are rejected under 35 U.S.C. 103 as obvious over Martin (WO 2017140430) in view of Surber (US 20090196930).
1. Martin discloses a method of treating an individual having an inflammatory pulmonary disease by administering to such individual a pharmaceutically effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione (see p. 1: 4, “luminol”) or one of its pharmaceutically acceptable salts in a monotherapy by inhalatory administration (c. 22: 15 – 16 discusses treatment of inflammatory pulmonary disease via inhalatory administration; c. 6: 32 – 35, c. 8: 5 – 11, and c. 16: 20 -21 give the general teaching of luminol as the single therapeutic agent) by using a nebulizer, wherein said nebulizer releases an aerosol containing liquid droplets of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts (see p. 21: 28 – 29, 36).
However, Martin does not disclose the nebulizer is a vibrating mesh nebulizer, and furthermore fails to disclose that said vibrating mesh nebulizer releases an aerosol between 3.0 μm and 3.3 μm, where said aerosol is characterized in that the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm, wherein said median mass aerodynamic diameter and said fine particle mass were determined by means of an NGI cascade impactor at 4C. Nonetheless, Surber discloses a method of deposition, with particle size optimized at the site of pulmonary pathology or respiratory infection (see [0233]), wherein a vibrating mesh nebulizer releases for the inhalatory administration an aerosol containing liquid droplets [0237], and the median mass aerodynamic diameter of the liquid droplets of the aerosol is between 3.0 μm and 3.3 μm (see for example, [0233], an optimum particle size is used in the range of 2.8 to 4.3 microns), wherein the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm (see for example, [0233], wherein a GSD of 2 microns would indicate 64% of the liquid droplets having a diameter in the range of 1.0 to 4.0 um distributed around the MMAD therebetween; see evidencing reference in Hennig, US 20240216290, [0614]). It is furthermore noted that the method of measurement discussed in Surber is substantially similar to determining median mass aerodynamic diameter and fine particle mass by means of an NGI cascade impactor (see [0613] in Suber discussing Andersen compaction; see evidencing reference to the provided NPL of Guo, “Abstract”, p. 3324, c. 2, para. 3, NGI and Andersen compaction yield MMAD and fine particle fractions that are not statistically significant, indicating good repeatability and reproducibility between the tests). Therefore, according to the teachings of Surber, it would have been obvious to a person having ordinary skill in the art at the time the invention was filed to modify the luminol of Martin using a vibrating mesh to achieve the aerosol MMAD/FPM sizes determined by NGI compaction as claimed for the benefit of reliably tailoring the aerosol size to avoid deposition of larger particles in the upper airway and exhalation of smaller particles, as well as limiting particle range to ensure the optimized deposition/tolerability (see Surber, [0233]). Diameter sizes can be engineered according to the disease to be treated, as well as the aerosol of interest, see Martin, p. 21: 34 – 36. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
3. Martin as modified by Surber discloses the method of 1, wherein at least 50% of the liquid droplets of the aerosol have a mass aerodynamic diameter between 1.0 μm and 3.2 μm (see obviousness statement above, wherein it would have been obvious to provide the claimed range since diameter sizes can be engineered according to the disease to be treated, as well as the aerosol of interest).
4. Martin discloses the method of claim 1, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (see p. 1: 14 – 16; examiner also notes that applicant has not required the salt, merely specified the type of salt, since the claims still broadly direct to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts).
5. Martin discloses the method of claim 3, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydrate polymorph forms I, II or III characterized by crystallography values determined by means of x-ray powder diagrams: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and/or 2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 for form I, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or 2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8 for form II, and d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and/or 2-theta values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93 for form III (see p. 1: 14 – 19; examiner also notes that applicant has not required the salt, merely specified the type of salt, since the claims still broadly direct to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts).
6. Martin discloses the method of claim 1, wherein the inflammatory pulmonary disease is selected from a group comprising inflammations of the lower airways due to a bacterial, viral, fungal or parasitic infection, chronic lower respiratory diseases, lung diseases due to an external agent, respiratory diseases principally affecting the interstitium, suppurative and/or necrotic conditions of lower respiratory tract, pleura diseases, postprocedural or related lower respiratory diseases, pulmonary diseases specific to the perinatal period, trauma and injuries of the lower respiratory tract and/or the thorax, and malignant neoplasms of the lower respiratory tract (c. 22: 15 – 27).
7. Martin discloses the method of claim 6, wherein the inflammatory pulmonary disease is selected from a group comprising chronic obstructive pulmonary disease, asthma, sarcoidosis of the lung, cystic fibrosis, bronchiectasis, adult respiratory distress syndrome, pulmonary fibrosis, berylliosis, chronic lung allograft dysfunction, pulmonary edema, lung ischemia reperfusion injury and primary graft dysfunction after lung transplantation (c. 22: 15 – 27).
8. Martin in view of Suber renders obvious a method of treating an individual having an inflammatory pulmonary disease by administering to such individual an aerosol produced by a vibrating mesh nebulizer containing a pharmaceutically effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in a monotherapy for inhalatory administration for the prophylaxis or treatment of inflammatory pulmonary diseases, wherein the median mass aerodynamic diameter of the liquid droplets of the aerosol is between 3.0 μm and 3.3 μm, and wherein the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm, wherein said median mass aerodynamic diameter and said fine particle mass were determined by means of an NGI cascade impactor at 4C (see discussion in section 35 USC 103 in claim 1 above).
13. Martin discloses a kit comprising a nebulizer and an aqueous solution containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, wherein said nebulizer releases an aerosol containing liquid droplets of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts (see p. 21: 28 – 29, 36).
However, Martin does not discloses a kit comprising a vibrating mesh nebulizer and a pharmaceutically acceptable container, wherein said vibrating mesh nebulizer is able to produce an aerosol from said aqueous solution wherein the median mass aerodynamic diameter of the liquid droplets of the aerosol is between 3.0 μm and 3.3 μm, and in that the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm, wherein said median mass aerodynamic diameter and said fine particle mass were determined by means of an NGI cascade impactor at 4C. Nonetheless, Surber discloses a kit, comprising a vibrating mesh nebulizer and a pharmaceutically acceptable container (see [0170] in Surber) with an aqueous solution (see [0245], the drug solution is formed prior to use of the nebulizer; see also claim 44), and the median mass aerodynamic diameter of liquid droplets of an aerosol is between 3.0 μm and 3.3 μm (see for example, [0233], an optimum particle size is used in the range of 2.8 to 4.3 microns), wherein the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm (see for example, [0233], wherein a GSD of 2 microns would indicate 64% of the liquid droplets having a diameter in the range of 1.0 to 4.0 um distributed around the MMAD therebetween; see evidencing reference in Hennig, US 20240216290, [0614]). It is furthermore noted that the method of measurement discussed in Suber is substantially similar to determining median mass aerodynamic diameter and fine particle mass by means of an NGI cascade impactor (see [0613] in Suber discussing Andersen compaction; see evidencing reference to the provided NPL of Guo, “Abstract”, p. 3324, c. 2, para. 3, under normal operating conditions NGI and Andersen compaction yield MMAD and fine particle fractions that are not statistically significant, indicating good repeatability and reproducibility between the tests). Therefore, according to the teachings of Suber, it would have been obvious to a person having ordinary skill in the art at the time the invention was filed to modify the luminol of Martin using a vibrating mesh to achieve the aerosol MMAD/FPM sizes determined by NGI compaction as claimed for the benefit of reliably tailoring the aerosol size to avoid deposition of larger particles in the upper airway and exhalation of smaller particles, as well as limiting particle range to ensure the optimized deposition/tolerability (see Surber, [0233]). Diameter sizes can be engineered according to the disease to be treated, as well as the aerosol of interest, see Martin, p. 21: 34 – 36. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
14. Martin in view of Surber discloses a kit, comprising a vibrating mesh nebulizer, a first pharmaceutically acceptable container with water for injection or physiological saline solution and a second pharmaceutically acceptable container with a solid form (see [0170, [0245], and [0247] of Surber, as outlined in claim 13 above) of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts (see Martin claims 1 and 13 above), and said vibrating mesh nebulizer is able to produce an aerosol from a solution resulting from the mixing of the content of the first container and the second container (Suber, [0245]), and the median mass aerodynamic diameter of the liquid droplets of the aerosol is between 3.0 μm and 3.3 μm, and in that the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm, wherein said median mass aerodynamic diameter and said fine particle mass were determined by means of an NGI cascade impactor at 4C (see 35 USC 103 rejection in claims 1 and 13 above).
15. Martin in view of Surber discloses a kit as defined claim 13, additionally comprising a mouthpiece for inhalation fitting to said mesh nebulizer (see Martin, c. 22: 3; see also Surber, [0480]).
17. Martin in view of Surber discloses the kit of claim 13 wherein the aqueous solution further comprises at least one pharmaceutically acceptable excipient (see Martin, p. 22: 6 – 7, Surber, [0245]).
18. Martin in view of Surber discloses the kit of claim 14 wherein at least one pharmaceutically acceptable excipient is contained in the first pharmaceutically acceptable container and/or the second pharmaceutically acceptable container (see Martin, p. 22: 6 – 7, Surber, [0245]).
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martin in view of Surber further in view of Abidov (RU 2266119).
9. Martin in view of Surber discloses a method of treating an individual having an inflammatory pulmonary disease by administering to such individual an aerosol produced by a vibrating mesh nebulizer in a monotherapy, containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, the median mass aerodynamic diameter of the liquid droplets of the aerosol is between 3.0 μm and 3.3 μm and wherein the fine particle mass is at least 50% of the liquid droplets of the aerosol, wherein the fine particle mass indicates the percentage of the liquid droplets with a diameter in the range of 1.0 to 5.0 μm, wherein said median mass aerodynamic diameter and said fine particle mass were determined by means of an NGI cascade impactor at 4 degrees C (see Martin in view of Surber rejection under 35 USC 103 in claim 1 above).
However, Martin does not disclose containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the range of 0.01% per weight to 10% per weight, an aqueous solution in the range of 70% per weight to 99.99% per weight, wherein said percentages add up to 100%. Nonetheless, Abidov discloses luminol for use in inhalatory treatment, containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the range of 0.01% per weight to 10% per weight (see section “substance”, 1.0 to 10.0 wt%). Upon providing Martin with the concentration of luminol disclosed in Abidov, the references disclose an aqueous solution in the range of 70% per weight to 99.99% per weight, wherein said percentages add up to 100% (see section “substance”, Abidov discloses providing water for the balance, which would be 90 – 99% adding up to 100% when used with luminol). Therefore, it would have been obvious to a person having ordinary skill in the art at the time the invention was filed to modify the luminol spray of Martin according to the concentration of Abidov for the benefit of using a pharmaceutically safe and effective concentration of luminol.
Claim(s) 10 – 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martin in view of Surber in view of Abidov further in view of Rairkar (US 20060286038).
10. The modified Martin discloses a method for producing an aerosol as defined in claim 9, comprising the following steps: a) filling 0.1 ml to 5 ml of an aqueous solution and optionally at least one pharmaceutically acceptable excipient into a nebulization chamber of a mesh nebulizer (Surber, [0237]; wherein filling of the therapeutic aqueous solution would correspond to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts upon modification), and c) discharging the generated aerosol at the side of a mesh of the mesh nebulizer opposite to a nebulization chamber of the nebulizer (Surber, [0237]).
However, the modified Martin does not disclose b) starting vibration of the mesh of the mesh nebulizer at a frequency from 80 kHz to 200 kHz. Nonetheless, Rairkar discloses b) starting vibration of the mesh of the mesh nebulizer at a frequency from 80 kHz to 200 kHz [0265]. Therefore, it would have been obvious to a person having ordinary skill in the art at the time the invention was filed to modify the ultrasonic vibrating mesh of the modified Martin with the drive frequency of Rairkar for the benefit of appropriately driving the solution through the mesh in order to efficiently create the mist without breaking up the particles.
11) The modified Martin discloses the method according to claim 10, wherein at least 90% in weight of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts contained in said aqueous solution are nebulized in the generated aerosol (see Surber, [0237 – 0238], 1 to 5 mLs are placed in the vibration container, which is the same range for the dosing solution; it would have been obvious to use 100% of the dosing solution for the benefit of preventing waste of the drug, as well as a measurable drug delivery amount).
12) The modified Martin discloses the method according to claim 10, wherein at least 80% of the generated aerosol as defined in claim 10 are produced during three minutes after starting nebulization in the mesh nebulizer (see Surber, [0492, 0238], 100% of the generated aerosol needed for the adequate dosage of 12.5 mgs would be produced by running the Aeroneb for 3 minutes).
Response to Arguments
Applicant's arguments have been fully considered but they are not persuasive.
On page 8, last paragraph, to page 13, first paragraph, applicant argues that one of ordinary skill in the art would not have known to engineer the claimed MMAD between 3.0 to 3.3 um since the claimed range would be dependent upon the luminol solution, and not the engineered properties of the vibrating mesh nebulizer. The assertion is incorrect. For example NPL to Yu (see “Characteriziation of Vibrating Mesh Aerosol Generators” provided on 07/26/2022) discloses that droplet size is determined by the vibrating mesh aperture diameter (see abstract). Droplet diameter increases linearly with increasing aperture size for a given solution (see p. 1681, Fig. 3, where Fig. 3 illustrates apparent empirical diameters of 2.5 um, 3.2 um, 3.4 um, 4.2 um, and 4.4 um, with the aerosol diameter as a function of aperture size clearly including 3.0 to 3.3 um and surrounding values). Further aspects of the nebulizer such as flow rate may also be engineered. Aerosol values such as the claimed MMAD and FPM are not special or unique to luminol by any stretch of the imagination, and such values can be achieved by appropriately selecting/modifying the mesh nebulizer.
On page 13, paragraphs 2, applicant appears to argue that luminol is superior to other drugs because it produces the claimed MMAD and FPM when tested using the known nebulizer discussed in examples found in applicant’s specification. Applicant points out that comparative examples 3 and 4 produced a higher MMAD using the same known nebulizer. The comparative examples are of little to no probative value. Examples 3 and 4 merely illustrate a different MMAD for different drug(s) using the same nebulizer. Luminol – or any therapeutic aerosol for that matter – can be nebulized according to different protocols and/or mesh sizes in order to optimize aerosol values such as MMAD. See the discussion in Yu above.
As established in the rejection above, it would have been obvious to modify the luminol of Martin using a vibrating mesh to achieve the aerosol MMAD/FPM sizes determined by NGI compaction as claimed, for the benefit of reliably tailoring the aerosol size to avoid deposition of larger particles in the upper airway and exhalation of smaller particles, as well as limiting particle range to ensure the optimized deposition/tolerability (see Surber, [0233]). The motivation discussed in Surber is the same as applicant’s motivation for providing the MMAD measured via NGI at 4 degrees C, see p. 26, para. 6 of the instant specification. Diameter sizes can be engineered according to the disease to be treated, as well as the aerosol of interest, see Martin, p. 21: 34 – 36. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
With regard to applicant’s arguments on page 15, it is noted that Martin provides luminol in a monotherapy, as explained in the rejection above.
As such, examiner hereby maintains rejection over 1, 3 – 15, and 17 – 18.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
See WO 2020002351, p. 61 (provided 03/10/2026) – aerosolized MMAD at 3.25 um, measured via NGI impactor, albeit different drug and temperature.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRADLEY H PHILIPS whose telephone number is (571)270-5180. The examiner can normally be reached 8:00 - 5:00 M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brandy Lee can be reached at (571) 270-7410. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRADLEY H PHILIPS/Primary Examiner, Art Unit 3799
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