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 .
Information Disclosure Statement
The information disclosure statement(s) filed on 02/10/2024 and 06/17/2025 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
Claims
This office action is in response to the preliminary amendment filed on 01/19/2024. As directed by the preliminary amendments, claims 11 and 19-20 have been amended, claims 1-10, 14-18, 22 and 27-83 have been cancelled and claims 84-91 have been added. As such, claims 11-13, 19-21, 23-26 and 84-91 are being examined in this application.
Claim Objections
Claim(s) 89 is/are objected to because of the following informalities:
Claim 89 recites “…having a pH between 4.0-9.0” but should recite “…wherein the composition has .
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) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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.
Claim(s) 11-12, 84-87 and 89-91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1).
Regarding claim 11, Lehrer teaches a pulmonary delivery system for delivery of a biguanide composition (Lehrer teaches using a metered dose inhaler filled with an aerosol formulation/composition wherein the composition comprises at least one anti-diabetic agent, wherein the anti-diabetic agent is biguanide as seen in [0010]-[0011] and [0020]. Lehrer further teaches the aerosol pharmaceutical formulation can be delivered in a nebulizer as seen in [0027]) comprising a biguanide or a pharmaceutically acceptable salt thereof in a form suitable to be aerosolized for pulmonary delivery to a human subject (Lehrer teaches a pharmaceutical composition including the anti-diabetic agent biguanide ([0010]-[0011]) to be aerosolized for delivery as seen in [0020] and [0028]) and nebulizer (Lehrer further teaches the aerosol pharmaceutical formulation can be delivered in a nebulizer as seen in [0027]), wherein at least 19% of the emitted dose of biguanide is contained in droplets or particles having aerodynamic particle sizes of 5 microns or less (Lehrer teaches the anti-diabetic drugs to comprise of finely divided particles having an average size of between 1 and 5 microns, preferably between 2 and 3 microns as seen in [0025]).
But does not teach a vibrating mesh nebulizer.
However, Zemel teaches “A protocol for treatment via inhalation can include preparation of an aerosol having particle sizes of predetermined mass medial aerodynamic diameter (MMAD) between 3 and 8 .mu.m delivered predominantly to the conducting and central lungs with or without overpressure using a jet, ultrasonic, electronic, vibrating porous plate, vibrating mesh nebulizer or energized dry powder inhaler (see [0118]).”
Lehrer teaches using a nebulizer (see [0027]) and using pulverization and screen filtration techniques known in the art for the finely divided particles of the anti-diabetic drugs (see [0025]). Lehrer further teaches for administration of the inhalation, the compounds can be delivered through a nebulizer and dispersed through by electrostatic, mechanical means as seen in [0018]. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer to use specifically a vibrating mesh nebulizer as taught by Zemel for an inhalation treatment that can prepare an aerosol of particles (see [0118]).
Regarding claim 12, Lehrer in view of Zemel teaches the delivery system of claim 11, and Lehrer further teaches wherein the biguanide is metformin or a pharmaceutically acceptable salt thereof (“Biguanides include, without limitation, metformin, phenformin, buformin, proguanil, and pharmaceutically acceptable salts or esters thereof. In a particular embodiment, the biguanide is metformin.” See [0010]).
Regarding claim 84, Lehrer in view of Zemel teaches the delivery system of claim 11, and Lehrer further teaches wherein the biguanide composition is (a) in the form of a dry powder, (b) in aqueous solution or (c) maintained at an increased pressure (Lehrer teaches the aerosol formulation can be presented as an aqueous solution or dry powder as seen in [0017] and [0024]-[0025]).
Regarding claim 85, Lehrer in view of Zemel teaches the delivery system of claim 84, and Lehrer further teaches wherein the biguanide composition is in the form of a dry powder (Lehrer teaches the aerosol formulation can be presented as a dry powder as seen in [0017] and [0024]-[0025]).
Regarding claim 86, Lehrer in view of Zemel teaches the delivery system of claim 84, and Lehrer further teaches wherein the composition is in aqueous solution and further includes one or more cosolvents (Lehrer teaches the aerosol formulation can be presented as an aqueous solution as seen in [0017] and [0024]. Lehrer further teaches a method of preparing a medical aerosol formulation by combining a cosolvent such as ethanol as seen in [0013] and [0033]).
Regarding claim 87, Lehrer in view of Zemel teaches the delivery system of claim 86, and Lehrer further teaches wherein the cosolvents include one or more of ethanol, propylene glycol and a pH buffer (Lehrer teaches a method of preparing a medical aerosol formulation by combining a cosolvent such as ethanol as seen in [0013] and [0033]).
Regarding claim 89, Lehrer in view of Zemel teaches the delivery system of claim 84, and Lehrer further teaches having a pH between 4.0-9.0 (see claim objection above; Lehrer teaches aerosol formulation for nasal solutions are to maintain a pH of about 5.5 to 6.5 as seen in [0037]).
Regarding claim 90, Lehrer in view of Zemel teaches the delivery system of claim 84, and Lehrer further teaches wherein the composition includes a propellant and is maintained at an increased pressure (Lehrer teaches the composition to include a propellent as seen in [0031], [0039] and [0045], wherein the propellent is used to maintain increased pressure).
Regarding claim 91, Lehrer in view of Zemel teaches the delivery system of claim 90, and Lehrer further teaches wherein the propellant includes a hydrofluoroalkane (Lehrer teaches the composition to include a propellent such as 1,1,1,2-tetrafluoroethane (known as a hydrofluoroalkane) as seen in [0031]).
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1), as applied to claim 11 above, and further in view of He (CN 103316344 A).
Regarding claim 13, Lehrer in view of Zemel teaches the delivery system of claim 11, but does not teach wherein the biguanide is metformin hydrochloride.
However, He teaches wherein the biguanide is metformin hydrochloride (He teaches the most preferred biguanide is metformin hydrochloride as seen in [0013]- [0015]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to use metform hydrochloride as taught by He as the most preferred biguanide (see [0015]).
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1), as applied to claim 12 above, and further in view of Dunne (WO 2019211424 A1).
Regarding claim 19, Lehrer in view of Zemel teaches the delivery system of claim 12, but does not teach wherein the nebulizer includes impinging jets to generate the aerosol.
However, Dunne teaches wherein the nebulizer includes impinging jets to generate the aerosol (Dunne teaches using a nebulizer with two impinging jets for droplets of 5 microns and below as seen on page 5, lines 19-23 and page 33, lines 27 to page 35 line 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to use a nebulizer with impinging jets to generate aerosol as taught by Dunne to nebulize a broader range of fluids (see page 6, lines 5-10 and page 7, lines 19-22).
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1), as applied to claim 12 above, and further in view of Schuler (US 20180325818 A1).
Regarding claim 20, Lehrer in view of Zemel teaches the delivery system of claim 12, but does not teach wherein the nebulizer employs Rayleigh instability to generate the aerosol.
However, Schuler teaches wherein the nebulizer employs Rayleigh instability to generate the aerosol (Schuler teaches using a nebulizer for pulmonary administration (see [0035]) and further teaches using Rayleigh break-up to break a liquid into fine droplets as seen in [0344] and [0352]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to use a Rayleigh breakup type nebulizer as taught by Schuler to decrease the likelihood of the droplets being driven to an undesired region (see [0359]-[0360]).
Claim(s) 21, 23, 26 and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1), as applied to claim 11 above, and further in view of Toddywala (US 20160250142 A1).
Regarding claim 21, Lehrer in view of Zemel teaches the delivery system of claim 11, but does not teach wherein between about 10 mg to about 100 mg of biguanide is emitted per minute.
However, Toddywala teaches administering formulations with one or more therapeutic agents in about 10 minutes (see [0062]),
Lehrer teaches the effective dose of an anti-diabetic agent ranges from 100 mg to about 250 mg/dose (see [0052]). Lehrer further teaches the effective dose of an anti-diabetic agent to be dependent on the mode of administration and weight of the individual being treated as seen in [0051]-[0052]. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to administer biguanide in about 10 minutes. Modified Lehrer teaches wherein between about 10 mg to about 100 mg of biguanide is emitted per minute (Lehrer teaches a dose range of about 100 mg to 250 mg/dose and Toddywala teaches administering the agent within 10 minutes. As such, modified Lehrer teaches between about 10 to 25 mg of biguanide is emitted per minute).
Regarding claim 23, Lehrer in view of Zemel teaches the delivery system of claim 11, but does not teach wherein the emitted dose of biguanide has a mass median aerodynamic diameter (MMAD) of between 1.1 and 7 microns.
However, Toddywala teaches for pulmonary administration, particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung and therefore need to be about 2 to 5 microns (see [0047]-[0048]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to have the mass median aerodynamic diameter of particles be 2 to 5 microns as taught by Toddywala to reach a user’s lungs (see [0047]).
Regarding claim 26, Lehrer in view of Zemel teaches the delivery system of claim 11, but does not teach wherein the administered pulmonary dose provides at least a 50 fold increase in exposure to lung tissue, as compared to the same dose when administered to the same subject orally.
However, Toddywala teaches an increase of about 500% or more for a composition delivered orally, wherein the increase is measured in homogenates of whole lung tissue as seen in [0044]-[0046].
Lehrer teaches administering the anti-diabetic agent in an effective dose for treating an individual having lung cancer as seen in [0051]. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to have a dose increase of 500% or more as taught by Toddywala to have a certain respirable delivered dose (see [0044]-[0046]). Modified Lehrer teaches wherein the administered pulmonary dose provides at least a 50 fold increase in exposure to lung tissue, as compared to the same dose when administered to the same subject orally (Modified Lehrer teaches an effective dose for treating an individual having lung cancer (see [0051] of Lehrer) such that the dose can be increased up to 500% more (as taught by Zemel). Therefore, modified Lehrer teaches administered dose provides at least a 50 fold increase in exposure due to the increased dose and having an effective dose for treating an individual (see [0030] and [0051]-[0055] of Lehrer).
Regarding claim 88, Lehrer in view of Zemel teaches the delivery system of claim 84, but does not teach wherein the composition is in the form of an aqueous solution having an osmolality of at least 280 mOsm/kg.
However, Toddywala teaches wherein the composition is in the form of an aqueous solution having an osmolality of at least 280 mOsm/kg (Toddywala teaches Table 3 and 4 in [0072]-[0073] with solutions having an osmolality of 399 mOsm/kg and 582 mOsm/kg).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to have the solution be of an osmolality of 399 mOsm/kg as taught by Toddywala as a known osmolality for a pharmaceutical treatment that is used for efficient penetration into a user’s lungs through inhalation (see [0007], [0040] and [0072]-[0073]).
Claim(s) 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lehrer (US 20110229418 A1) in view of Zemel (US 20150018375 A1), as applied to claim 11 above, and further in view of Nyambura (US 20180235879 A1).
Regarding claim 24, Lehrer in view of Zemel teaches the delivery system of claim 11, but does not teach wherein the emitted dose of biguanide has a droplet size distribution, as determined by laser diffraction, of:
d10: 1.5 - 5.5;
d50: 3.5 - 9.5;
d90: 7.0 - 17.0.
However, Nyambura teaches using laser diffraction for particle size distribution as seen in [0196]. Nyambura further teaches the particles to have a particle size distribution with a d10: less than 2 μm; d50: 2.5-4 and d90: at less than 8 μm [0024-0027].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the delivery system taught by Lehrer in view of Zemel to have a droplet size distribution as determined by laser diffraction of d10: less than 2 μm; d50: 2.5-4 and d90: at less than 8 μm as taught by Nyambura for geometric particle size distribution that is acceptable for inhalation (see [0024]-[0027]).
However, modified Lehrer does not explicitly disclose the droplet size distribution to be d10: 1.5 - 5.5; d50: 3.5 - 9.5; d90: 7.0 - 17.0.
It would have been obvious to one having ordinary skill in the art before the effective
filing date of the claimed invention to modify the droplet size distribution of modified Lehrer from d10: less than 2 μm; d50: 2.5-4 and d90: at less than 8 μm to d10: 1.9 μm; d50: 3.9 and d90: 7.5 as applicant appears to have placed no criticality on the claimed range (Table 2 in applicant’s specification shows a variety of parameter numbers within the claimed range) and since it has been held that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists”. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Regarding claim 25, modified Lehrer teaches the delivery system of claim 24, and Nyambura further teaches wherein the span (d90-d10)/d50 is 1.0-2.0 (Nyambura teaches the span to be (7.5-1.9)/3.9 = 1.44 which is between the range of 1.0-2.0).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Duarte-Vazquez (US 20120021049 A1) teaches using biguanide metformin to be administered via pulmonary route.
Rosell (US 20060169800 A1) teaches a nozzle using Rayleigh breakup.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tina Zhang whose telephone number is (571)272-6956. The examiner can normally be reached Monday - Friday 9:00AM-5:00PM.
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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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/TINA ZHANG/Examiner, Art Unit 3785
/BRANDY S LEE/Supervisory Patent Examiner, Art Unit 3785
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