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 .
DETAILED ACTION
Claim Status
Claims 1-16, 18-21 were pending in the prior Office Action.
Upon amendment entrance, Claims 3, 11, 13-14, 16-20 were cancelled.
Upon amendment entrance, Claims 22-25 were added.
Claims 1-2, 4-10, 12, 15, and 21-25 are pending examination.
Priority Status
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Applicant claims priority to the foreign document; however, the foreign document is not in English therefore the effective filing date is 12/29/2021.
Examiner Responses to Arguments/Amendments
The issues raised in the prior Office Action are addressed below:
I. Claim Amendment –
Upon amendment entrance, Independent Claim 1 was modified to recite the following:
“A pharmaceutical composition for inhalation, comprising
sivelestat sodium or a hydrate thereof,
a pH-adjusting agent,
an osmotic pressure-adjusting agent, and
a surfactant,
wherein the pH-adjusting agent is capable to keep sivelestat sodium contained in the pharmaceutical composition having a solubility of more than or equal to 5 mg/mL, and
the pharmaceutical composition for inhalation has an osmolality of 250-450 mOsm/kg,
wherein the surfactant is selected from sodium lauryl sulfate and polysorbate-80, and
wherein the pharmaceutical composition does not comprise mannitol.”
II. Response to 35 U.S.C. §112(b) Rejections –
Claims 5, 8-10, 13-15, and 20 were rejected under 35 U.S.C. §112(b).
In view of Applicant’s amendment/arguments, the rejection over Claims 5, 8-10, 13-15, and 20 are withdrawn.
III. Response to Claim Rejections –
35 U.S.C. §103
Claims 1-4, 8-12, 14-15, & 19 are rejected over US Patent 6,552,082 as evidenced by PubChem (Sivelestat CID-107706).
Claims 1-4, 8-9, 10-12, 14-15, & 19 rejected over Patent '082 in view of W. Tao (hereinafter “Tao”) as evidenced by PubChem (Sivelestat CID-107706).
Claims 5-7, 13-16, & 20-21 rejected over Patent '082 in view of Tao and in further view of US Patent 5,359,121 as evidenced by PubChem (Sivelestat CID-107706).
In light of the limitations added to Claim 1, the 35 USC § 103 rejections are withdrawn. Applicant’s arguments are moot because the new ground of rejection.
IV. New Rejections –
The 103 rejections were withdrawn due to Applicant’s
amended independent claim.
Claim Interpretation
First, the Instant Claims composition contains the compound “sivelestat sodium or a hydrate.” The search document PubChem CID-107706, is the same Sivelestat with CAS RN: 127373-66-4 which is N-[o-(p-pivaloyloxy-benzenesulfonylamino)benzoyl]glycine monosodium salt tetra-hydrate, identical to the compound Instant Claims.
In Claim 1, “for inhalation” is being interpreted as intended use. A recitation of the intended use of the claimed invention must result in a structural between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
According to the MPEP § 2144.08, subsection II.A.4.(c):
The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein).
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.
Graham vs. Deere, Test for Obviousness.
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.
Joint Inventors
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.
The following rejections cover Claims 1-2, 4-10, 12, 15, and 21-25.
Claim(s) 1-2, 4, 8-10, 12, 15, 21-22 and 24-25 are rejected under 35 U.S.C. 103 as being obvious by US Patent 6,552,082 B2 (hereinafter “Pat’082”) in view of WO 2006/108556 A2 (hereinafter “Pub’556”) as evidenced by PubChem (Sivelestat CID-107706; hereinafter “PubChem”).
With respect to Instant Claims 1 and 15, Pat’082 teaches a pharmaceutical composition for inhalation, comprising:
sivelestat sodium (N-[o-(p-pivaloyloxy-benzenesulfonylamino)benzoyl]glycine mono sodium salt tetra-hydrate - col. 1, lns. 8-25; col. 12, Claim 1; Sivelestat- evidenced by PubChem) or a hydrate thereof,
a pH-adjusting agent (col. 2, lns. 14-20; col. 4, ln. 19 – col. 5, ln. 64 section 3 discloses pH adjusters),
an osmotic pressure-adjusting agent (col. 3, lns. 33-39), and
a surfactant,
wherein the pH-adjusting agent is capable to keep sivelestat sodium contained in the pharmaceutical composition having a solubility of more than or equal to 5 mg/mL (col. 14, Claim 11).
and the pharmaceutical composition for inhalation has an osmolality of 250-450 mOsm/kg,
wherein the surfactant is selected from sodium lauryl sulfate and polysorbate-80, and
wherein the pharmaceutical composition does not comprise mannitol.
Pat’082 fails to teach: a.) overlapping ranges of the pH-adjusting agent and the osmotic pressure-adjusting agent; b.) an embodiment without mannitol and c.) specific additions of inactive ingredients or excipients to the pharmaceutical compositions, such as a surfactant. However, it is understood in regards to Pat’082:
Concerning inactive excipients, they do not have a direct beneficial effect on the condition being treated, and used for drug stability. Pat’082 teaches the Instant Application scope and claims in regards to osmolality of the pH-adjusting and osmotic pressure-adjusting agent. In col. 2, lns. 20-24, Pat’082 teaches “to obtain the solution of higher concentration of the sivelestat sodium, the object is accomplished by using a kind of organic solvent in addition to using pH adjusters” (col. 2, lns. 20-24). This indicates the prior art recognizes osmolality as a result-effective variable since changes in solute or concentration levels directly alter a functional property & biological outcome. Hence concentration of particles dissolved in a fluid (which is measured in mOsmol/kg), affects the results seen within stability of the formulations, or cellular permeability.
In regards to adjusting osmolarity, Pat’082 teaches sodium chloride and its concentration as a result effective variable. In col 3, lines 1-3, “to the prepared buffers was added sodium chloride in order to fix the ionic strength of the buffers…”. This indicates a result-effective variable which also affects the desired result.
Further, Pat’082 discloses the higher the pH value of the sivelestat sodium, the better the solubility of the compound. This indicates the prior art recognizes this as a result-effective variable since changes in solute or concentration levels directly alter a functional property & biological outcome. Taking solubility and stability into consideration, the preferable pH range is 7.55-8.10 (col. 9, lns. 32-36), and in this case, the solubility is greater than 2.5 mg/mL (which includes Instant Claim 1 range of 5 mg/mL; col. 3, lns. 1-14; Figure 1). It would therefore be obvious to optimize the pH-adjusting ranges and osmotic pressure ranges in order to improve solubility and optimize ionic strength as taught by the reference. Since dose is a concentration, it is routine optimization to determine for a composition what is considered a dose or doses that improve solubility and to optimize ionic strength, absent of unexpected or superior results. MPEP § 2144.05.II
Concerning the instant claims, Pat’082 teaches an embodiment (which does not require mannitol) with sivelestat sodium, a pH adjuster and an osmotic pressure-adjusting agent “…a drug product given by admixing N-[o-(p-pivaloyloxybenzenesulfonylamino)-benzoyl]glycine monosodium salt tetra-hydrate (10 g), distilled water (500 mL), sodium chloride (7g) and sodium carbonate (also a pH adjusting agent: anhydrous-1.5 g), filled 5 mL portion into each vial…” which includes the API in an embodiment which does not require mannitol, since mannitol is presented as an option in col. 3, lns. 33-39. This is understood as the choice to add mannitol can be exchanged out or not present. Hence, it is a feature not required for the invention to work.
Concerning specific additions of inactive ingredients or excipients to the pharmaceutical compositions, such as a surfactant. Pub’556 teaches a non-ionic surfactant component such as polysorbate 80 (pg. 15, lns. 5-20) to be considered safe for oral or nasal inhalation.
It would therefore be obvious to combine Pat’082 with Pub’556 because (as understood through KSR-Prong B) Pub’556 discloses compositions for an active API agent (which is poorly water-soluble), and a non-ionic surfactant component. It can be substituted with the API of Pat’082 which is the same compound of the Instant Application. The compositions are suitable for nasal inhalation, which is effective for pulmonary administration. This combination also makes use of excipients like surfactants since they are known to lower the surface tension between liquids, solids, and gases. They act as wetting agents, solubilizers, and foaming agents to help the active ingredient disperse and absorb properly into the body.
Additionally, polysorbate 80 has the exact chemical structure regardless of its intended function. Its unique amphiphilic structure enables it to act as both a surfactant and a solubilizer/diluent support. As a surfactant, the hydrophobic tails cluster around oils (non-water-soluble drugs, for example) while the hydrophilic heads face the water, stabilizing the mixture to prevent separation. As a diluent the structure interacts with water to form micelles. These micelles allow a formulator to dilute a thick, oily concentrate evenly into an aqueous solution
Pat’082 continues disclosing the following in Claims 2, 4, 8-9, 12, 21-22 and 24:
Concerning Claim 2: Pat’082 discloses wherein the pharmaceutical composition for inhalation further has at least one of the following features: (1) the pharmaceutical composition for inhalation has a pH of 3.0-10.0 (prior art range of 7.55-8.10 is within the pH range; col. 9, lns. 32-36).
Concerning Claims 4 & 22: Pat’082 discloses wherein the pH-adjusting agent is capable to keep an aqueous solution of the pharmaceutical composition for inhalation at pH 5.0-9.0 (prior art range of 7.55-8.10 is within the pH range; col. 9, lns. 32-36).
Concerning Claim 8: Pat’082 discloses wherein the carrier is water (the solvent as water, a solution wherein the solvent is a mixture of water and an organic solvent or is exclusively water, a solution wherein the solvent is a mixture of water and an organic solvent or a novel drug product using the solution optionally comprising excipients; col. 2, lns. 43-51).
Concerning Claims 9 & 24: Pat’082 discloses wherein the pH-adjusting agent has a content of 0.1-30.0 mg/mL (in this case, the solubility is greater than 2.5 mg/mL; col. 3, lns. 1-14; Figure 1).
Concerning Claims 12 & 21: Patent’082 discloses wherein the osmotic pressure-adjusting agent is sodium chloride (col. 3, lns. 1-3).
With respect to Claims 1, 10, 15, 21 & 25: Pat’082 fails to teach wherein the surfactant is selected from sodium lauryl sulfate and polysorbate-80, and the surfactant/pH-adjusting agent content is of 0.01-10.0 mg/mL.
Pub’556 teaches a non-ionic surfactant component such as polysorbate 80 (pg. 15, lns. 5-20). In the prior art range on pg. 27, lns. 11-22, the content of the non-ionic surfactant component in the liquid composition is in the range of 0.01 to about 5 wt.-%. This embodiment reads on the Instant composition since weight percent and mg/mL are ways of expressing the concentration of an active agent. Also, the relationship between a drug's weight percent, its solubilized concentration in (mg/ml), and the volatility of the liquid carriers (like HFA propellants) determines how droplets evaporate and shrink in the air. This, as seen in Pub’556, is taken into account.
It would therefore be obvious to combine Pat’082 & Pub’556 because (as understood through KSR-Prong B) Pub’556 discloses compositions for an active agent (which is poorly water-soluble), with a non-ionic surfactant component. These can be substituted with the API of Pat’082 which is the same compound of the Instant Application. The compositions are suitable for nasal inhalation, which is effective for pulmonary administration. This combination of Pat’082 & Pub’556 also makes use of surfactants since they are known to lower the surface tension between liquids, solids, and gases. They act as wetting agents, solubilizers, and foaming agents to help the active ingredient disperse and absorb properly into the body.
Claim(s) 1-2, 5-7, 15, and 23 are rejected under 35 U.S.C. 103 as being obvious by Pat’082 in view of Pub’556” and in further view of W. Tao (Pulmonary Pharmacology & Therapeutics 25 (2012) 99e103; hereinafter “Tao”).
The teachings of Pat’082 & Pub’556 combined are disclosed above and at least those teachings are incorporated by reference herein.
Pat’082 & Pub’556, in combination, disclose sivelestat compositions for inhalation or aerosolization and demonstrates osmolality. In that aspect, inhalable dry powders intended for deep lung deposit must possess a Mass Median Aerodynamic Diameter (MMAD) in the range of 1 µm to 5 µm. A person of ordinary skill would recognize to formulate sivelestat sodium into a pharmaceutical inhalation composition, standard milling and blending techniques would be applied to achieve this well-established, art-recognized particle size to ensure optimal drug delivery.
With respect to Claim(s) 1-2, 5-7, 15, and 23, Pat’082 & Pub’556 fail to sufficiently disclose: a) wherein the pharmaceutical composition is used for inhalation or is aerosolized; b) the pharmaceutical composition for inhalation has an osmolality of 250-450 mOsm/kg.
Tao discloses a Pariboy nebulizer influenced by the physical properties of the solution (including osmolality) and its application of use. These features together determine the final particle size delivered. As known in the field and scope of the art, nebulizers are capable of generating aerosols with particle sizes of 1 to 3 µm, and the size produced is inversely influenced by the flow rate/pressure used: the greater the flow rate, the smaller the particle.
Tao additionally teaches delivery of a neutrophil elastases (NE, specifically Sivelestat) in the pathogenesis of acute lung injury (ALI). Inhaled Sivelestat resulted in ameliorated lung injury by reducing edema and infiltration of neutrophils in the lung, as well as improved oxygenation and survival. Disclosed through the patient population (pg. 100, col. 1, cont’d para. 1, “…received Sivelestat [Ono Pharmaceutical Co., Ltd, Osaka, Japan] inhalation; Sivelestat 3mg/kg per hour, nebulized with a pressurized air ejection mobilization (Pariboy 037 type, Sternberg, Germany)),” this reads on points a) and b) above since Pariboy specializes in nebulizers and demonstrates an aerosolized version of the pharmaceutical composition.
Therefore, it would therefore be obvious to combine Pat’082, Pub’556 & Tao for the following:
The prior arts disclose sivelestat (including salts and hydrates) used for respiratory conditions like viral pneumonia and acute lung injury (ALI) with pH-adjusting agents, osmotic-pressure agents and surfactants in an aerosolized form; as well as sivelestat in use through a known nebulizer company indicating a standard for aerosolized solutions.
A specific ratio of sivelestat sodium to stabilizing agents prevents the drug's known hydrolysis during the lyophilization cycle, its criticality though is not sufficiently detailed. Adapting these formulations into an aerosol or inhalation composition via known excipient adjustments does not establish an unexpected therapeutic stability profile.
In aqueous solutions, sivelestat sodium is highly prone to hydrolysis. Due to this, concentrations for inhalation solutions need are complexed or buffered. In this, it hasn’t been shown that inhalation-friendly excipients highlight criticality.
The formulation in Pat’082 discloses a product with stability for storage but also when the prepared for later use, the compositions are stable. In Pub’556, the compositions are suitable for nasal inhalation or aerosolized for nebulizers, which is effective for pulmonary administration. This combination makes use of surfactants, known for their characteristic to lower surface tension between liquids, solids, and gases. In Tao, the drug formulation (same as Instant Application) administrated via inhalation allows direct distribution to the lungs. This enhanced the therapeutic effect in respiratory distress and inflammatory conditions by accomplishing higher local concentrations in the pulmonary tissues.
As seen in the combination, Pat’082, Pub’556 &Tao, the API joined with pH adjusters, osmotic pressure-adjusters, and excipients ensure aerosolization, particle size distribution, and stability.
The Tao prior art also speaks to an inhaled sivelestat composition used with a Pariboy nebulizer for drug delivery into the lungs. It is understood, the Pariboy nebulizer has the desired particle size distribution of an aerosol (expressed in terms of its mass median aerodynamic diameter; MMAD) with particles of the wanted composition deposited in the respiratory tract by inertial impaction (3-6 μm), sedimentation (1-3 μm), or diffusion (<1 μm).
This combination of these teachings suggests what is known in the prior art of inhaled compositions and motivates one with KSR Prong A – the known art in combination, teaches success of the formulation of sivelestat (in hydrate and salt form) and its delivery into the lungs.
Also, using KSR Prong B – it would be obvious to combine Pat’082, Pub’556 & Tao because the combination provides sivelestat, an active agent (which is poorly water-soluble), with pH-adjusters, osmotic-pressure agents and further explaining on non-ionic surfactant component. The compositions are suitable for nasal inhalation, which is effective for pulmonary administration. Since nebulizers can be used to deliver many types of medicines. The medicines and moisture help control breathing problems and help loosen lung secretions; a benefit provided by the combination.
Conclusion
Claims 1-2, 4-10, 12, 15, and 21-25 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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