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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/26/2025 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/26/2025, is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner. See attached copy of PTO-1449.
Status of Application
Applicants' arguments/remarks filed 08/26/2025 are acknowledged. Claims 1 and 16 are currently amended. Claims 1-4, 6-10, 16-17 and 22-24 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 08/26/2025 and with respect to applicant’s arguments/remarks, the 35 U.S.C. § 112(a) rejection of Claims 16 has been withdrawn in view of the amendments.
Modified Rejections
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 non-obviousness.
Claims 1-4, 6-10, 16-17 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Arnold et al., (US 5,478,578) in view of Walker et al. (WO 2014/140648 Al) and further in view of Spargo et al (WO 2016/128742 Al) and Abbott-Banner (WO 2015/173551 Al).
Claims 1, 2 and 4,
Arnold et al. teach in order to control and optimize the amount of inhalable active substance released when drugs are administered as inhalation powders, the invention calls for the use of auxiliaries consisting of mixtures of coarser particles (average particle size >20 µm) and finer particles (average particle size <10 µm). (Abs). The active substance micronized into inhalable particles is combined with suitable quantities of a mixture of one or more physiologically acceptable excipients, one component of the excipient mixture having a mean particle size of less than about 10 µm and the other having a mean particle size greater than about 20 µm, the average particle size generally being preferably less than 80 µm. (Col. 1, lines 48-54), which are overlapping with the fine and coarse particle sizes that applicants claim. Pharmaceutically suitable and physiologically harmless excipients for inhalation purposes are known. Examples include disaccharides such as lactose; Lactose and glucose are preferred (Col. 2, lines 23-24, 26 & 30). The fine glucose particles are present in an amount of from 0-11% relative to the total weight to the dry powder pharmaceutical composition. The percentages are calculated from percentages of fine glucose particles in the dry powder composition including the drugs in Example 1, col. 2, lines 49-55). The 0-11% of fine particles are overlapped with the 2.0-7.5 wt% in claim 1, and 3.5-4.0 % in claim 2 that the applicants claim. Average particle size is D50. It would be obvious for one of skills in the art to apply these ranges of fine glucose particles taught by Arnold for lactose fine particles.
Arnold et al. do not teach the ensifentrine particles.
Walker et al. teach RPL554/ensifentrine (Abs) and preferably suitable for delivery from a dry powder inhaler (DPI), a solution which is suitable for delivery from a nebulizer, or a solution or suspension which is suitable for delivery from a pressurized metered dose inhaler (PMDI). (pg. 9, line 7-9). A micronized RPL554 combination is blended with milled lactose, in which coarse lactose particle having MMD of about 60 µm to about 90 µm and the fine particles have a MMD of less than 15 µm). (pg. 40, lines 14-16), which are overlapping with applicants’ claim 1-(ii) of Dv50 of from 50 µm to 80 µm and 1-(iii) of fine lactose particles having a Dv50 of from 5 µm to 10 µm, and claim 4 of coarse laclose particle having D50 55-65 µm. MMD is D50 value, also known as mass-median- diameter (MMD) is the diameter which divides the particles into two groups with equivalent weight / mass. Each sieve is weighed, and the volume of each fraction is calculated in percent by weight, providing a mass-related distribution.
Walker et al. do not teach percentage of ensifentrine particles within range of 3.5-6% relative to the total weight of the dry powder pharmaceutical composition.
Spargo et al. teach RPL554/ensifentrine and its salts (Abs), for inhalation (pg. 2, 1st par.).
A dry powder pharmaceutical composition may comprise from 0.2 to 5.0 wt% of a salt of RPL554. (pg. 8, lines 10-15).
Abbott-Banner teaches RPL554/ensifentrine (pg. 1, 3rd last par.), in pharmaceutical compositions, which may be administered to the subject by any acceptable route of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral modes of administration. Administration by inhalation is preferred. (pg. 9, 3rd par.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare pharmaceutical composition for inhaling with monosaccharide fine and coarse particles, their particle sizes and percentage of fine particles taught by Arnold et al., the drug is RPL554/ensifentrine, taught by Abbott-Banner, Spargo et al. and Walker et al., the sizes of fine and coarse lactose particles taught by Walker et al., and the percentage of RPL554/ensifentrine taught by Spargo et al. since they have proven it would be feasible to do so.
With regard to claim 3,
Arnold et al. teach powder for inhalation comprising a micronized active substance and a physiologically acceptable excipient comprising a mixture containing a fine fraction having an average particle size in the range of less than 10 µm and a coarse fraction having an average particle size in the range of from about 20 µm to about 150 µm, wherein the weight ratio of micronized active substance to the physiologically acceptable excipient mixture is from about 0.01:5 to 0.1:5. (Claim 1, Col. 2 and 3), which mean in
5 g of GI+GII, there are 0.01 or 0.1 g of W. Or, in
100 g of GI+GII, there are 0.2 or 2 g of W.
Powder for inhalation according to claim 1 characterized in that the weight ratio of the fine fraction to the coarse fraction in the physiologically acceptable excipient mixture is between 1:99 and 95:5. (Claim 2, Col. 3), which mean in
a)1g of GI there are 99g of GII or
b)95g of GI, there are 5g of GII
a)in 100g of GI+GII has 1g of GI, 99g of GII and 0.2 or 2 g of W, so
99/(100+0.2 or 2) x 100 = 98.8 or 97% of GII in total composition.
b)in 100g of GI GI+GII has 95g of GI, 5g of GII and 0.2 or 2 g of W, so
5/(100+0.2 or 2) x 100 = 5 or 4.9% of GII in total composition.
Percentage of GII in total composition can be from 4.9%-98.8%.
With regard to claims 6 and 22, Abbott-Banner teaches a representative composition for use in a DPI comprises dry lactose particle and micronized particles of the active agent. Such a dry powder formulation can be made by combining lactose with the active agent and then dry blending the components. Alternatively, if desired, the active agent can be formulated without an excipient. (pg. 11, last par.). This means the active agent, ensifentrine particles comprise up to 100% ensifentrine or a pharmaceutically acceptable salt of ensifentrine.
With regard to claims 7 and 23
Arnold et al. teach in Example 1 the mixture contains, per capsule, 0.1 mg of fenoterol of an average particle size of < 6 um and in Example 2, 0.04 mg of ipratropium bromide with an average particle size of <6 um. “W' is the proportion of active substance delivered by inhalation as a percentage of the quantity contained in the mixture. (Col. 2., line 39-46).
Walker et al. teach the active agent(s) / active ingredient(s) (RPL554) can be micronized and combined with a suitable carrier to form a suspension of micronized particles of respirable size, where micronized is typically defined as having particles in which at least 90 % of the particles have a mass median diameter of less than 10 µm. (pg. 11, lines 30-32 to pg. 12, line 1).
Abbott-Banner teaches a composition comprising the active agent(s) / active ingredient(s) (RPL554) may be administered by inhalation using a nebulizer inhaler. The active agent(s) / active ingredient(s) can be micronized and combined with a suitable carrier to form a suspension of micronized particles of respirable size, where micronized is typically defined as having particles in which at least about 90% of the particles have a mass median diameter of less than about 10 µm. The term "mass median diameter" means the diameter such that half the mass of the particles is contained in particles with larger diameter and half is contained in particles with smaller diameter. (pg. 11, 1st par.).
With regard to claims 8 and 24, Arnold et al. teach the pharmaceutical composition including of fine and coarser excipient (Col. 1, lines 55-57). In Example 1 the mixture contains, of fenoterol and in Example 2, of ipratropium bromide. “W' is the proportion of active substance delivered by inhalation as a percentage of the quantity contained in the mixture. (Col. 2, lines 39-46). There are no other excipients in the composition besides the fine and coarse glucose and the active ingredient. So the total amount of the active ingredient particles, the coarse glucose particles and the fine glucose particles is total 100.0 wt% relative to the total weight of the dry powder pharmaceutical composition.
Walker et al. teach a micronized RPL554/ensifentrine combination (100 mg) is blended with milled lactose (25 g) (e.g., lactose in which not greater than about 85% of the particles have a mass median diameter (MMD) of about 60 µm to 90 µm and not less than 15% of the particles have a MMD of less than 15 µm). (pg. 40, lines 14-19). In this case total micronized RPL554/ensifentrine, coarse lactose and fine lactose particles is 100% relative to the total weight of the dry powder pharmaceutical composition.
With regard to claims 9-10 Walker et al. teach a micronized RPL554/ensifentrine combination (100 mg) is blended with milled lactose (25 g) (e.g., lactose in which not greater than about 85% of the particles have a mass median diameter (MMD) of about 60 µm to 90 µm and not less than 15% of the particles have a MMD of less then 15 µm). The contents of the blisters are administered using a dry powder inhaler (DPI). (pg. 40, lines 14-19). The pharmaceutical compositions are suitable for inhaled administration. The pharmaceutical composition may be for administration by dry powder inhaler (DPI) or metered-dose inhaler (MDI). (pg. 11, line 18-20).
With regard to claim 16,
“A method” in claim 16 is a preamble and is not considered in the claim since it is just an introduction.
Walker et al. teach as a combined PDE3/PDE4 inhibitor, RPL554/ensifentrine has both anti-inflammatory and broncho-dilatory activity and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). (pg. 1, lines 16-18).
Abbott-Banner teaches RPL554/Ensifentrine is an active as a disease modifying agent for treating cystic fibrosis, and other diseases mediated by CFTR malfunction. The present invention provides a compound for use in treating or preventing conditions from cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, mild pulmonary disease, bronchitis. (pg. 2nd, 2nd last and last par.).
Spargo et al. teach treatment of the human or animal body typically comprises the treatment or prevention of a disease’s condition selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid resistant asthma, severe asthma, pediatric asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases and auto-immune diseases. (pg. 11, lines 3-9)
With regard to claim 17,
“A method” in claim 17 is a preamble and is not considered in the claim since it is just an introduction.
Arnold et al. teach that in Example 1 the mixture contains fenoterol of an average particle size of <6 µm and in Example 2, of ipratropium bromide with an average particle size also of <6 µm. (Col. 2, lines 39-42). It means about 50% of API particles are less than 6 µm.
Spargo et al. teach the pharmaceutical formulation may be a liquid pharmaceutical composition suitable for administration by inhalation comprising a diluent and a suspension of particles of a salt of RPL554 as described herein. The suspended particles of the salt of RPL554 typically have a particle size distribution with a Dv50 (median particle size by volume) value of from about 0.2 µm to about 5 µm. (pg. 10, line 5-9). Dv50 means 50% of RPL554 particles for inhalation are the fine particle fraction of the ensifentrine particles. The resulting powder may instead have a particle size with a mass median aerodynamic diameter from about 2 µm to about 5 µm, for instance from 2.5 µm to about 4.5 µm. (pg. 8, lines 1-9).
Response to Arguments
Rejections of claim 1-4, 6-10, 16-17, and 22-24 Under 35 U.S.C. § 103
The statements (a) and (b) below are to respond to many arguments as following:
The basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
And, in 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).
Applicant argues that (i) The dry powder inhalers (DPI) formulation of the claims is not suggested by the cited references, which are listed below:
Applicant argues that (A) Arnold et al. would have suggested a DPI formulation comprising coarse particles smaller than those used in the claimed formulations
Applicant's arguments have been fully considered but they are not persuasive since Arnold teaches coarser particles (average particle size >20 μm) and the average particle size generally being preferably less than 80 μm. (Col. 1, lines 48-54), which are overlapping with the fine and coarse particle sizes that applicants claim. Prior arts teach applicant’s limitation of particle size ranges. Please see (a) and (b) above.
Applicant argues that (B) Arnold et al would not have suggested a DPI formulation comprising the specific proportion of fine particles as in the claimed formulations
Applicant's arguments have been fully considered but they are not persuasive since Arnold teaches the fine glucose particles are present in an amount of from 0-11% relative to the total weight to the dry powder pharmaceutical composition. The 0-11% of fine particles are overlapped with the 2.0-4.5wt% in claim 1, and 3.5-4.0 % in claim 2 that the applicants claim. Average particle size is D50. It would be obvious for one of skills in the art to apply these ranges of fine glucose particles taught by Arnold for lactose fine particles. Please see (a) and (b) above.
Applicant argues that (C) Arnold et al would have suggested a DPI formulation with a lower ensifentrine loading than the claimed formulations.
Applicant's arguments have been fully considered but they are not persuasive since Walker does not teach percentage of ensifentrine particles within range of 3.5-6% relative to the total weight and Arnold suggests that generally the active substances administered by inhalation are so potent that the quantity thereof does not significantly help to determine the size of the quantity of preparation. Rather, the pharmacist is able to control the quantity of active substance delivered by inhalation by varying the quantities of excipient and the range of particle sizes. This may be necessary, for example, if the same effect is to be achieved as with a preparation which has already been clinically tested or is on sale. of the dry powder pharmaceutical composition. (Col. 2, lines 5-12). So the active ingredient percentage would depend on the drug efficacy.
Applicant argues that Spargo et al (page 8) describes DPI formulations of ensifentrine comprising 0.2 to 5.0 wt% of ensifentrine salt. However, all descriptions of these formulations only reference a "lactose powder" that is otherwise undefined. There is certainly nothing in Spargo et al that would suggest combining a higher loading of ensifentrine (particularly
from 3.5 to 6.0 wt%) with the specific lactose blend as recited in claim 1.
Applicant's arguments have been fully considered but they are not persuasive as explained by (a) and (b) above. Spargo also teaches an effective amount of RPL554 is typically from about 0.001 mg/kg to 50 mg/kg for a single dose. An effective amount ofRPL554 is often from about 0.001 mg/kg to 1 mg/kg for a single dose. For instance, an effective amout may be a dose of from about 0.01 mg to about 500 mg, or from about 0.01 mg to 100 mg, preferably from about 0.1 mg to about 6 mg. A single dose of RPL554 may be from 0.05 mg to 5 mg or from 0.5 mg to 3 mg, for instance about 1.5 mg. Doses may be administered daily. For instance, the dose ofRPL554 may be from 0.001 mg/kg/day to 50 mg/kg/day, typically from 0.001 mg/kg/day to 10 mg/kg/day or from 0.01 mg/kg/day to 1 mg/kg/day. These doses are typically the nominal dose charged to
the inhaler. The liquid pharmaceutical composition may be administered once, twice or three
times a day, or may be administered twice, three times, four times or five times a week. The
composition may be administered as often as required by the patient. (pg. 11, line 14-24). One with skill in the art would learn of the formulation taught by Arnold and Walker and the drug percentage by Spargo and the drug percentage can be varied depending on the goal to be administered 1, 2, 3 or 4 times per day.
Applicant argues that Abbott-banner et al describes a formulation of ensifentrine with dry lactose "having a particle size between about 1 µm and about 100 µm [ ... ] and micronized particles of the active agent" (page 11, lines 27-31). There is no mention of a coarse/fine lactose blend and no mention of the specific concentrations recited in claim 1.
Applicant's arguments have been fully considered but they are not persuasive as explained by (a). In claim 1, Abbott-Banner teaches RPL554/ensifentrine (pg. 1, 3rd last par.), in pharmaceutical compositions, which may be administered to the subject by any acceptable route of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral modes of administration, even though administration by inhalation is preferred. (pg. 9, 3rd par.). Prior art Abbott-Banner is added to teach claims 6, 7, 16, 22 and 23. One with skill in the art would recognize that Arnold teaches formulation/composition, and would learn from Arnold’s teachings, in combination with Walker and Spargo’s teachings on RPL554/ensifentrine and its salts on this aspect as recited in the rejection of claim 1. One with skill in the art would learn of the formulation taught by Arnold and Walker and the drug percentage by Spargo.
Applicant argues that there is nothing in the cited references that would have suggested that the formulations of the pending claims would afford such favorable FPFs.
Applicant's arguments have been fully considered but they are not persuasive as explained by (a) and (b) above. Arnold teaches specifically about formulation of an active substance for inhale with coarse particle size and fine particle size with lactose. In order to control and optimize the amount of inhalable active substance released when drugs are administered as inhalation powders, Arnold teaches mixtures of coarser particles (average particle size >20 µm) and finer particles (average particle size <10 µm). (Abs). The fine excipient mixture having a mean particle size of less than about 10 µm and the other having a mean particle size greater than about 20 µm, preferably less than 80 µm. (Col. 1, lines 48-54), which are overlapping with the fine and coarse particle sizes that applicants claim. The 0-11% of fine particles are overlapped with the 2.0-4.5wt% in claim 1, and 3.5-4.0 % in claim 2 that the applicants claim. The idea is to apply this composition on the drug ensifentrine, to have the right drug percentage depending on the drug’s efficacy, on its delivery route and on what diseases to treat, with or without a combination with other drugs, some of which has been taught by Walker, Spargo and Abbott-Banner, and each of these prior arts teach different aspect of this drug. Walker teaches RPL554/ensifentrine and preferably suitable for delivery from a dry powder inhaler (DPI), a solution which is suitable for delivery from a nebulizer, or a solution or suspension which is suitable for delivery from a pressurized metered dose inhaler (PMDI).. A micronized RPL554 combination is blended with milled lactose, in which coarse lactose particle having MMD of about 60 µm to about 90 µm and the fine particles have a MMD of less than 15 µm). (pg. 40, lines 14-16), which are overlapping with applicants’ claim 1-(ii) of Dv50 of from 50 µm to 80 µm and 1-(iii) of fine lactose particles having a Dv50 of from 5 µm to 10 µm, and claim 4 of coarse laclose particle having D50 55-65 µm. One with skill in the art would learn from Arnold and Walker on inhale formulation, from Walker on combination with a second drug, from Spargo on different ensifentrine salt forms, on Abbott-Banner on different disease treatments.
Conclusion
No claim is allowed
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615