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 1-21 were pending in the following Instant Case.
Claim 17 was cancelled.
Claims 1-16, 18-21 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.
Information Disclosure Statement
All references have been considered in the four (4) IDS(s) filed 07/05/2023, 10/14/2024, 06/30/2025 and 10/27/2025 unless marked with a strikethrough.
Drawings
There are zero (0) drawing submission filed with this Instant Application.
Claim Interpretation
First, the Instant Claims composition contains the compound “sivelestat sodium or a hydrate.” The search document PubChem CID-107706, is Sivelestat with CAS RN: 127373-66-4 which is N-[o-(p-pivaloyloxy-benzenesulfonylamino)benzoyl]glycine monosodium salt tetra-hydrate which is the identical compound of the Instant Claims.
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).
Second, in Claims 2, 11-13, and 19-20 of the Instant Application, contains the term “optionally” The pharmaceutical composition consist of agents that will be interpreted under Broadest Reasonable Interpretation as being “optional” limitations that may or may not be present.
Claim Rejections - 35 USC § 112
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.
112(a) for Written Description –
Claim 18 is 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties,
characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163.
While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Level of skill and knowledge:
The artisans using applicant’s method would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which specific mechanism of action, combination of inhibitors influence the desired pharmacological activity and which diseases would benefit from this activity.
Current State of the Art:
Tarhini M, Fessi H, Bentaher A, Greige-Gerges H, Elaissari A (2018) A potential new strategy for using elastase and its inhibitor as therapeutic agents (pub’d 11/12/2018; hereinafter “Tarhini”)
Kanojia, Neha; Singh, Sukhbir; Singh, J.; Sharma, N; Grewal, Ajmer; Rani, Lata; Thapa, Komal; Arora, S.. (2020. Recent Advancements and Applications of Inhalable Microparticles Based Drug Delivery Systems in Respiratory Disorders (pub’d 10/12/2020; hereafter “Kanojia”).
Myrdal PB, Sheth P, Stein SW. Advances in metered dose inhaler technology: formulation development (pub’d 2014 Jan 23; hereafter “Myrdal”).
The state of the art for pharmaceutical compositions for inhalation is extensive, dating back to ancient practices like smoking herbs for their medicinal properties and advancing through the growth of current devices like nebulizers and metered-dose inhalers. Significant developments include the use of atropine and other alkaloids, the invention of the first nebulizer in the 19th century, and later modernizations like dry powder and soft mist inhalers that use specific excipients and particle-size control methods to optimize drug delivery.
In Kanojia, a survey of literature revealed the pharmacokinetic processes involved in the pulmonary drug delivery route, mechanisms of drug deposition in the respiratory tract, types, and production methodology of inhalable microparticles.
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As seen in Figure 1 (pg. 10100), the application based on pulmonary drug delivery systems for the management of various types of respiratory disorders is seen above.
This treatment application is seen in a six-stage pharmacokinetic process facilitated by an inhalation device. Seen in Figure 2 (pg. 10101, see below), the process involves: “ 1.) Accumulation of drug particles or droplets has been the first stage after inhalation. A small proportion of the dose gets reposed in the system, whereas the remaining drug particles or droplets get distributed to the pulmonary tract; 2.) Following drug particle or droplet deposition, particles must disperse within the fluids of epithelial cells; 3.) The removal of drug molecules has been primarily achieved by mucociliary clearance, an essential mechanism of pulmonary defense throughout the respiratory tract against tiny particles or microbes; 4.) Active ingredients which adequately evade mechanisms of respiratory clearance as well as distribute throughout the fluid of epithelial cells might also promptly be absorbed into lung tissue; 5.) The retention, as well as the distribution of absorbed drug throughout the pulmonary tissue, depends on the physicochemical characteristics of an inhaled drug or on patient-specific features of air passages; 6.) Pulmonary or absorptive clearance is the elimination through perfusion of the drug from the lung tissues into the bloodstream.”
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This is further supported in Table 1 (pg. 10107-10108) disclosing model drug, treatments, methodology and disease application which in this case, is lung disease. The patents and inventions each list (prior to the date of the Instant Application), that this pharmaceutical composition for an inhaled treatment for lung disease is taught.
In the prior art of Tarhini (pg. 5, col. 2, under Therapeutic Strategies of NE and SLPI-para. 1), treatment for a lung disease, specifically acute lung injury (ALI) and adult respiratory distress syndrome (ARDS), are explored from the immunological aspect. Tarhini details (pg. 4, col. 2, full para. 2) “the activity of neutrophil elastase can be reduced by different endogenous inhibitors such as α-1 proteinase inhibitor, human monocyte/neutrophil elastase inhibitor, and secretory leukocyte proteinase inhibitor (SLPI)...”
Neutrophil elastase (NE) is considered a host defense because it helps fight pathogens by directly killing bacteria, degrading virulence factors, and activating antimicrobial peptides. However, NE is often called a "double-edged sword" because its uncontrolled activity can also lead to tissue damage and chronic inflammation. At inflammatory sites, an imbalance between NE and its inhibitor lead to a continuous activity of NE caused by and elevation in its level. This unregulated activity can lead to different changes that are linked to pathophysiology of acute injury in lungs. With that, a drug of interest seen in the art, and already used in clinical setting, is sivelestat. Tarhini states (pg. 5, col. 2, full para. 2) “despite the presence of a wide range on NE inhibitors, only few have been validated for therapeutic use in clinical settings. In fact, Sivelestat is the only synthetic NE inhibitor in market and approved by Japan and South Korea. Sivelestat have been suggested as a treatment for acute lung injury and acute respiratory distress syndrome.”
Finally, Myridal discloses surfactants which stabilize compositions and suspensions like oleic acid. Surfactant polarity, indicated by their respective hydrophilic–lipophilic balance (HLB), correlates with the incompatibility of surfactants in a more polar environment.
Myridal discloses (pg. 444, Fig. 6 – col. 2, para. 2), “drug concentration along with the properties of the micronized drug (i.e., raw drug MMAD, GSD, and density) impact the residual particle size distribution. For formulations with dilute suspended drug content, the MMAD (mass median aerodynamic diameter) of the residual particles is very close to that of the micronized drug. This occurs as most of the drug-laden atomized droplets contain only a single suspended drug particle. However, as the drug concentration increases, more of the atomized droplets contain multiple drug particles which lead to an increase in the residual particle MMAD. Consequently, the residual MMAD increases more rapidly with change in drug concentration for suspension formulations containing smaller micronized drug than that for larger micronized drug. The prior arts listed above disclose and teach formulations for the treatment of lung disease within a suffering patient. This treatment with additional excipients such as a pH-adjusting agent, osmotic-pressure agent as well as a surfactant are within the scope of the claims.
The Instant Specification though, does not indicate what agents are or are not capable of keeping the desired concentration of the API to be used its inhalation for drug treatment. There is no showing that there is a structure function correlation such that one was in possession of the knowledge of which a pharmaceutical composition would or would not function to treat all lung disease states.
For example, Myrdal (pg. 444) Figure 6 discloses the effect of concentration and MMAD of micronized drug on the residual APSD (aerodynamic particle size distribution). Some of the key performance attributes of an MDI (metered-dose inhalation) include the delivered dose content uniformity, APSD of the delivered aerosol, chemical and physical stability of the drug over the product shelf life, and extent of leachables from device components.
This, under BRI, while considering the physicochemical properties of excipients and how the addition of these excipients may impact overall product performance of the MDI, the art indicates that concentration changes which occur due to small changes in a molecule lead to differences in activity.
Existence of working examples in Specification:
Within the Instant Specification, there are 12 working examples (for inhalation) of the pharmaceutical composition. It is unclear whether the Applicant was in possession of all the possible combinations provided by the composition comprising an API, a pH-adjusting agent, osmotic-pressure agent, and surfactant.
Applicant has not demonstrated use of a pH-adjusting agent, osmotic-pressure agent, and surfactant combinations that are possible in providing whether the composition can function in providing an effective therapeutic dose for one suffering from lung disease.
Furthermore, the Instant Application does not provide evidence of possession as well in providing administering an effective amount of a pharmaceutical composition for inhalation to subject in need thereof. On pg. 17 (of the Instant Specification) there is one (1) animal experiment of unknown number of SD rats being given either an injection or inhalation of a single specified dose.
Conclusions:
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”)
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
112(b) for Indefiniteness –
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 5, 8-10, 13-15, and 20 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.
Antecedent Basis
Claim 8 recites the limitation of a pharmaceutical formulation “…wherein the carrier is water." The independent Claim 1 does not recite the composition compromising a carrier.
There is insufficient antecedent basis for this limitation in the claims.
Claims 10, 14-15 recite the limitation of a pharmaceutical formulation:
Claim 10: “…wherein the surfactant has a content of 0.01-10.0 mg/mL, preferably 0.01-5.0 mg/mL.".
Claim 14: “… wherein the pharmaceutical composition for inhalation comprises sivelestat sodium or a hydrate thereof, a pH-adjusting agent, an osmotic pressure-adjusting agent, and a surfactant…”
Claim 15: “… wherein the pharmaceutical composition for inhalation comprises sivelestat sodium or a hydrate thereof, a pH-adjusting agent, an osmotic pressure-adjusting agent and a surfactant…”
The independent Claim 1 does not recite within the pharmaceutical composition, compromising a surfactant.
There is insufficient antecedent basis for this limitation in the claims.
Broad & Narrow Range
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, Claims 5 and 9-10, recite the following broad recitations:
Claim 5: wherein the pharmaceutical composition for inhalation has an osmolality of 250-400 mOsm/kg; Claim 9: wherein the pH-adjusting agent has a content of 0.1-30.0 mg/mL; Claim 10: wherein the surfactant has a content of 0.01-10.0 mg/mL,
and the Claims also recite: Claim 5: …preferably 250-350 mOsm/kg; Claim 9: …preferably 0.1-25.0 mg/mL; Claim 10: preferably 0.01-5.0 mg/mL, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Trademark
Claims 13 and 20 contains the trademark/trade name Tween-80. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982).
The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe is a nonionic surfactant or an ionic surfactant such as polysorbate-80 and, accordingly, the identification/description is indefinite.
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.
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.
First 35 U.S.C. 103 Rejection -
Claim(s) 1-4, 8-12, 14-15 and 19 are rejected under 35 U.S.C. 103 as being obvious by US Patent 6,552,082 B2 (pub’d: 04/22/2003; hereinafter “Patent’082”) as evidenced by PubChem (Sivelestat CID-107706; hereinafter “PubChem”).
With respect to Claims 1, 11, 14-15, Patent’082 teaches a solution of “N-[o-(p-pivaloyloxy-benzenesulfonylamino)benzoyl]glycine mono sodium salt tetra-hydrate” (col. 1, lns. 8-25; as evidenced by PubChem as the same compound).
Patent’082 also teaches the “pH-adjusting in the providing solution…are selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide to the solution” (col. 2, lns. 14-20; also col. 4, ln. 19 – col. 5, ln. 64 section 3 discusses the investigation of the pH adjusters).
Patent’082 continues reading on the scope and claims “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).
The application also discloses “osmotic pressure-adjusting agent” meaning adjusting or maintaining a desired osmotic pressure. To achieve isotonicity with physiological fluids, an osmotic pressure regulating agent is crucial.
Maintaining an isotonic formulation minimizes local irritation. Sodium chloride is a common excipient used to adjust osmolarity. As described, (col. 3, lns. 1-3), “to the prepared buffers was added sodium chloride in order to fix the ionic strength of the buffers…” inclusion of sodium chloride helps match the osmotic pressure of plasma.
The Instant composition is seen in practice with sivelestat sodium, a pH adjuster and an osmotic pressure-adjusting agent as seen in Patent’082 (col. 3, lns. 33-39) “…discloses 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 reads also on the claims and scope of the Instant Application.
Patent’082 discloses that the higher the pH value of the sivelestat sodium, the better the solubility of the compound. So taking the solubility and the 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 (this also indicates a wide range above 2.5 mg/mL which includes Claim 14 5 mg/mL; Claim 11; col. 3, lns. 1-14; Figure 1).
Patent’082 fails to teach the functional ranges of the pH-adjusting agent, an osmotic pressure-adjusting agent and a surfactant.
However, it would be obvious to optimize ranges in order to improve solubility and to optimize ionic strength as taught by the reference. Since dose is a concentration, it is customary through routine optimization to determine for a specific 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.
Patent’082 continues disclosing the following in Claims 2-4, 8-9, 11-12, and 19:
With respect to Claim 2: according to claim 1, Patent’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 7.55-8.10 (col. 9, lns. 32-36).
With respect to Claim 3: according to claim 1, Patent’082 discloses wherein the pH-adjusting agent is capable to keep sivelestat sodium or the hydrate thereof contained in the pharmaceutical composition having a solubility of more than or equal to 5 mg/mL (Claim 11; col. 3, lns. 1-14; Figure 1).
With respect to Claim 4: according to claim 1, Patent’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, (col. 9, lns. 32-36).
With respect to Claim 8: according to claim 1, Patent’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).
With respect to Claim 9: according to claim 1, Patent’082 discloses wherein the pH-adjusting agent has a content of 0.1-30.0 mg/mL, preferably 0.1-25.0 mg/mL (in this case, the solubility is greater than 2.5 mg/mL; Claim 11; col. 3, lns. 1-14; Figure 1).
With respect to Claim 10: according to claim 1, Patent’082 discloses wherein the surfactant has a content of 0.01-10.0 mg/mL, preferably 0.01-5.0 mg/mL (pg. 100, col. 1, cont’d para. 1; Tao uses 1.0 ml/kg of oleic acid (monosaturated omega-9 fatty acid) admixed with the sivelestat prepared as a 3 mg/kg in 3 ml saline, followed by inhalation. Oleic acid's amphiphilic nature allows it to reduce surface tension and act as an emulsifying agent. In doing so, oleic acid combines multiple substances and also acts like an emulsifier/binding agent in the pharmaceutical composition)
With respect to the remainder of Claim 11: Patent’082 discloses the pharmaceutical composition for inhalation has at least one of the following features: (1) the pharmaceutical composition for inhalation has a pH of 5.0-9.0 (col. 9, lns. 32-36).
With respect to Claim 12: according to claim 1, Patent’082 discloses wherein the osmotic pressure-adjusting agent is sodium chloride (col. 3, lns. 1-3).
With respect to Claim 19: according to claim 11, Patent’082 discloses wherein the osmotic pressure-adjusting agent is optionally selected from sodium chloride (col. 3, lns. 1-3) and glucose.
Second 35 U.S.C. 103 Rejection -
Claim(s) 1-4, 8-9, 10-12, 14-15 and 19 are rejected under 35 U.S.C. 103 as being obvious by Patent’082 and in view of W. Tao “Inhaled neutrophil elastase inhibitor reduces oleic acid-induced acute lung injury in rats” (pub’d: 12/27/2011; hereinafter “Tao”) as evidenced by PubChem (Sivelestat CID-107706; hereinafter “PubChem”).
With respect to Claims 1, 11, 14-15, Patent’082 teaches a solution of “N-[o-(p-pivaloyloxy-benzenesulfonylamino)benzoyl]glycine mono sodium salt tetra-hydrate” (col. 1, lns. 8-25; as evidenced by PubChem as the same compound). Patent’082 also teaches the “pH-adjusting in the providing solution…are selected from tri-sodium phosphate, a hydrate thereof, sodium hydroxide or potassium hydroxide to the solution” (col. 2, lns. 14-20; also col. 4, ln. 19 – col. 5, ln. 64 section 3 discusses the investigation of the pH adjusters).
Patent’082 continues reading on the scope and claims “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).
The application also discloses “osmotic pressure-adjusting agent” meaning adjusting or maintaining a desired osmotic pressure. To achieve isotonicity with physiological fluids, an osmotic pressure regulating agent is crucial. Maintaining an isotonic formulation minimizes local irritation. Sodium chloride is a common excipient used to adjust osmolarity. As described, (col. 3, lns. 1-3), “to the prepared buffers was added sodium chloride in order to fix the ionic strength of the buffers…” inclusion of sodium chloride helps match the osmotic pressure of plasma.
The Instant composition is seen in practice with sivelestat sodium, a pH adjuster and an osmotic pressure-adjusting agent as seen in Patent’082 (col. 3, lns. 33-39) “…discloses 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 reads also on the claims and scope of the Instant Application.
Patent’082 discloses that the higher the pH value of the sivelestat sodium, the better the solubility of the compound. So taking the solubility and the 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 (this also indicates a wide range above 2.5 mg/mL which includes Claim 14 5 mg/mL; Claim 11; col. 3, lns. 1-14; Figure 1).
Also, though Patent’082 does not disclose osmolality, osmolality as it is a function of only the number of particles and not related to its size, shape, or charge.
Patent’082 fails to disclose:
wherein the pharmaceutical composition is used for inhalation or is aerosolized;
the pharmaceutical composition for inhalation has an osmolality of 250-450 mOsm/kg.
Tao discloses the delivery of neutrophil elastases (NE, specifically Sivelestat) play a role 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, improved oxygenation and survival. Also, this was demonstrated through the patient population (pg. 100, col. 1, cont’d para. 1) used “…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 1, and 2 above, since Tao discloses the Pariboy nebulizer (pg. 100, col. 1, cont’d para. 1; as seen in Tao, the Pariboy company specializes in nebulizers) this demonstrates an aerosolized version of the pharmaceutical composition.
Therefore, it would therefore be obvious to combine Patent’082 & Tao for the following:
Both prior arts disclose sivelestat (including salts and hydrates) used for respiratory conditions like viral pneumonia and acute lung injury (ALI).
The formulation in Patent’082 shows a freeze-dried product which indicates stability for storage and stability but also when the prepared compositions were also stable for later use. In Tao, the formulation of a drug (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 Patent’082 & Tao, the active pharmaceutical ingredient (API) is combined with pH adjusters, osmotic pressure-adjusters, and excipients that ensure proper aerosolization, particle size distribution, and stability (Patent’082 discloses preservation of the API and composition; Tao discloses inhaled compositions by Pariboy Company and Made of Record in IDS submitted WO 2006/108556 A2).
The Tao prior art also speaks to the inhaled composition used with a Pariboy nebulizer as a way of delivery into the lungs. It is under the Broadest Reasonable Interpretation, the nebulizer used would have the desired particle size distribution of an aerosol (usually expressed in terms of its mass median aerodynamic diameter; MMAD) with particles of the desired 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 suggest what is known in the prior art of inhaled compositions and motivates one because as seen with KSR Prong A – the combination teaches success of the formulation of sivelestat (in hydrate and salt form) and its delivery into the lungs. Also, if using KSR Prong B - substituting the method of delivery of administration as seen in Patent’082 (via injection) with the method of delivery used in Tao (via inhalation) this also provides success. Since nebulizers can be used to deliver many types of medicines. The medicines and moisture help control breathing problems and help loosen lung secretions.
Patent’082 continues disclosing the following in Claims 2-4, 8-9, 11-12, and 19:
With respect to Claim 2: according to claim 1, Patent’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 7.55-8.10 (col. 9, lns. 32-36).
With respect to Claim 3: according to claim 1, Patent’082 discloses wherein the pH-adjusting agent is capable to keep sivelestat sodium or the hydrate thereof contained in the pharmaceutical composition having a solubility of more than or equal to 5 mg/mL (Claim 11; col. 3, lns. 1-14; Figure 1).
With respect to Claim 4: according to claim 1, Patent’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, (col. 9, lns. 32-36).
With respect to Claim 8: according to claim 1, Patent’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).
With respect to Claim 9: according to claim 1, Patent’082 discloses wherein the pH-adjusting agent has a content of 0.1-30.0 mg/mL, preferably 0.1-25.0 mg/mL (in this case, the solubility is greater than 2.5 mg/mL; Claim 11; col. 3, lns. 1-14; Figure 1).
With respect to Claim 10: according to claim 1, Patent’082 discloses wherein the surfactant has a content of 0.01-10.0 mg/mL, preferably 0.01-5.0 mg/mL (pg. 100, col. 1, cont’d para. 1; Tao uses 1.0 ml/kg of oleic acid (monosaturated omega-9 fatty acid) admixed with the sivelestat prepared as a 3 mg/kg in 3 ml saline, followed by inhalation. Oleic acid's amphiphilic nature allows it to reduce surface tension and act as an emulsifying agent. In doing so, oleic acid combines multiple substances and also acts like an emulsifier/binding agent in the pharmaceutical composition)
With respect to the remainder of Claim 11: Patent’082 discloses the pharmaceutical composition for inhalation has at least one of the following features: (1) the pharmaceutical composition for inhalation has a pH of 5.0-9.0 (col. 9, lns. 32-36).
With respect to Claim 12: according to claim 1, Patent’082 discloses wherein the osmotic pressure-adjusting agent is sodium chloride (col. 3, lns. 1-3).
With respect to Claim 19: according to claim 11, Patent’082 discloses wherein the osmotic pressure-adjusting agent is optionally selected from sodium chloride (col. 3, lns. 1-3) and glucose.
Third 35 U.S.C. 103 Rejection -
Claim(s) 5-7, 13-16 and 20-21 are rejected under 35 U.S.C. 103 as being obvious by Patent’082 and in view of Tao as evidenced by PubChem (Sivelestat CID-107706; hereinafter “PubChem”) and in further view of US Patent 5,359,121 B1 (pub’d 10/25/1994; hereinafter “Patent’121”).
The teachings of Patent’082 & Tao in combination, are disclosed above and those teachings are incorporated by reference herein.
Tao discloses the delivery of neutrophil elastases (NE, specifically Sivelestat) play a role 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, improved oxygenation and survival. Also, this was demonstrated through the patient population (pg. 100, col. 1, cont’d para. 1) with groups of patients given the sivelestat with the pharmaceutical composition as described in the scope of Instant Claims as “…received Sivelestat inhalation (Sivelestat 3mg/kg per hour, nebulized with a pressurized air ejection mobilization (Pariboy 037 type, Sternberg, Germany)).” Tao also discloses the use of oleic acid
Since Tao discloses the Pariboy nebulizer (pg. 100, col. 1, cont’d para. 1; as seen in Tao, the Pariboy company specializes in nebulizers) this demonstrates an aerosolized version of the pharmaceutical composition and also reads on the claims.
With respect to Claims 5-7, Tao teaches a Pariboy nebulizer which makes clear the nebulization process is influenced by the physical properties of the solution (including osmolality) and the type of nebulizer used, which 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 or pressure used: the greater the flow rate, the smaller the particle.
Patent’082 & Tao, in combination, fail to explicitly disclose oleic acid as the specific surfactant, even though it is used in the field.
Patent’121 discloses for Claims 13-16 and 20-21 inert non-aqueous diluent/excipients (understood under RBI as being an emulsifier or surfactant) of the pharmaceutical composition.
With respect to Claim 13: according to claim 11, wherein the surfactant is polysorbate-80 (col. 11, lns. 43-50).
With respect to the remainder of Claim 14: according to claim 1, also comprising a surfactant (col. 11, lns. 43-50).
With respect to the remainder of Claim 15: according to claim 1, also comprising a surfactant (col. 11, lns. 43-50).
With respect to Claim 16: according to claim 14 or 15, …and the surfactant is polysorbate-80 (col. 11, lns. 43-50).
With respect to Claim 20: according to claim 11, wherein the surfactant is polysorbate-80 (col. 11, lns. 43-50).
With respect to Claim 21: according to claim 15, … and the surfactant is polysorbate-80 (col. 11, lns. 43-50).
Therefore, it would therefore be obvious to combine Patent’082, Patent’121 & Tao for the following:
All the prior arts disclose sivelestat (including salts and hydrates) used for respiratory conditions like viral pneumonia and acute lung injury (ALI).
The formulation in Patent’082 & Patent’121 disclose a freeze-dried product which indicates stability for storage and stability and when prepared through dissolving in water, the compositions were also stable.
Patent’121 discloses varied routes of administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. In such compositions, one more of active compound(s) is or are admixed with at least one of inert aqueous diluent(s).
In Tao, the formulation of a drug (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.
Patent’082, Patent’121 & Tao disclose the active pharmaceutical ingredient (API) is combined with pH adjusters, osmotic pressure-adjusters, and excipients that ensure proper aerosolization, particle size distribution, and stability (Patent’082 discloses preservation of the API and composition; Tao discloses inhaled compositions by Pariboy Company; Patent’121 composition and treatment of diseases that induce the abnormal enhancing of eleastin/collegen fiber by the action of elastase).
And finally, the Tao prior art with Patent’121 speaks to the inhaled composition used with a Pariboy nebulizer as a way of delivery into the lungs. It is under the Broadest Reasonable Interpretation, the nebulizer used would have the desired particle size distribution of an aerosol (expressed in terms of its mass median aerodynamic diameter; MMAD) with particles of the desired composition deposited in the respiratory tract.
This combination of Patent’082, Patent’121 & Tao suggest the prior art of inhaled compositions and motivates one because as seen with KSR Prong A – the combination teaches success of the formulation of sivelestat (in hydrate and salt form) and its delivery into the lungs. Also, if using KSR Prong B - substituting the method of delivery of administration as seen in Patent’082 (via injection), with the method of delivery used in Tao (via inhalation) and Patent’121 (add inert excipients or diluents) also provides success. Since nebulizers can be used to deliver many types of medicines. The medicines and moisture help control breathing problems and help loosen lung secretions.
Conclusion
Claims 1-16, 18-21 are rejected.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights