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 .
Priority
This application is a CON of PCT/US2022/011448 filed 01/06/2022 and claims domestic benefit to provisional application No. 63/134,336 filed 01/06/2021 and to 631/702,46 filed 04/02/2021. Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 (e) as follows:
The later-filed application must be an application for a patent for an invention
which is also disclosed in the prior application (the parent or original nonprovisional
application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the
requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112,
except for the best mode requirement. See Transco Products, Inc. v. Performance
Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, PRO 63/134,336 filed 01/06/2021 and PRO 631/702,46 filed 04/02/2021, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The limitations of the instant claim 31 do not appear in either provisional. Accordingly, claim 31 is not entitled to the benefit
of the prior applications and the effective filing date is 01/06/2022 as the limitation in
claim 31 are supported by PCT/US2022/011448 filed 01/06/2022.
Claims 23-30 and 32-42 have appropriate support in the provisional application
No. 63/134,336 and have been awarded the filing date of 01/06/2021.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claims 23 – 30, 32, 33, and 35 – 42 are rejected as being unpatentable under 35 U.S.C. 103 over Surber, M.W. (US 2015/0044288A1, Feb. 02, 2015) (hereinafter Surber) (IDS reference).
Regarding claim 23,28,32,33,36, Surber discloses formulations of imatinib or a phenylaminopyrimidine derivative compound for aerosolization and use of such formulations for inhaled aerosol administration of imatinib (abstract). Surber teaches several representative Imatinib formulations in Tables 11a – 11d, comprising imatinib or salt thereof, a phosphate buffer that maintains the pH of the solution from about pH 4.0 to about pH 8.0 and water. The concentration of imatinib or salt thereof ranges from 0.01 mg/ml to 200 mg/ml (pg.121 - 128). The concentration of imatinib and the pH values in the instant claim overlaps with the ranges taught by Surber. Because the claimed range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists. See MPEP 2144.05 (I)
Regarding claim 35, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Surber discloses a composition comprising imatinib or salt thereof . Accordingly, a person of ordinary skill would have had a reasonable expectation of success in selecting imatinib free base because both the freebase and salt forms of imatinib have the same mechanism of action.
Regarding claim 23, 24 and 25, Surber teaches the compositions may also include polymeric excipients/additives, e.g.,… dextrates (by non-limiting example cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-1-alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and sulfobutylether-beta-cyclodextrin) (¶[0556]). The polymers may be tailored to optimize different characteristics of the particle including: i) interactions between the agent to be delivered and the polymer to provide stabilization of the agent and retention of activity upon delivery; ii) rate of polymer degradation and, thereby, rate of drug release profiles; iii) surface characteristics and targeting capabilities via chemical modification; and iv) particle porosity (¶[0557]). Additionally, taste-masking may be accomplished by creation of lipopilic vesicles. Additional coating or capping agents include dextrates (by non-limiting example cyclodextrins may include…and sulfobutylether-beta-cyclodextrin) (¶[0567]). One of ordinary skill in the art would have been motivated to make an imatinib aqueous solution comprising a cyclodextrin derivative because Surber teaches several benefits of adding a cyclodextrin or its derivatives to a pharmacological composition.
Regarding claim 29 and 30, Surber teaches that a “carrier” or “excipient” is a compound or material used to facilitate administration of the compound, for example, to increase the solubility of the compound. Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils (¶[0341]). In particular, the compositions of the formulations can include dipalmitoylphosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant (¶[0530]). Surber teaches the benefit of making an aqueous solution comprising dipalmitoylphosphatidylcholine (DPPC) as a surfactant. One of ordinary skill in the art would have been motivated to so because dipalmitoylphosphatidylcholine (DPPC) can increase solubility of the compound and reduce surface tension in the lungs which is necessary in the prevention of alveolar collapse.
Regarding claim 37, Surber teaches that a pharmaceutical composition of liquid imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof may contain a solubility enhancing agent or co-solvent (¶[0302]). In some embodiments, the aqueous pharmaceutical composition includes one or more co-solvents. Co-solvents include, but are not limited to, ethanol, propylene glycol and glycerol (¶[0487]). Table 4 and 5 lists several embodiments with imatinib or salt thereof with suitable solvents (pg.119).
Regarding claim 38 – 42, Surber teaches that administration of the phenylaminopyrimidine derivative compound, most preferably imatinib as disclosed herein, such as a pharmaceutically acceptable salt thereof, can be via any of the accepted modes of administration…for example, as delivered by a nebulizer(¶[0391]). The compound disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for maximum drug deposition at a site of infection, lung cancer, pulmonary fibrosis, pulmonary arterial hypertension, pulmonary or intra-nasal site for systemic absorption for extra-nasal and/or extra-pulmonary indications, and maximal tolerability (¶[0399]). As discussed above, Surber provides all the limitations necessary to make the formulation in instant claim 38. Therefore, It would have been obvious to one of ordinary skill in the art to deliver the aerosolized composition using a nebulizer to a subject having pulmonary disease, pulmonary arterial hypertension or pulmonary fibrosis. One would have been motivated to do so because Surber teaches that the composition is optimized for maximum drug deposition at the intended target site.
Claims 26, 27, and 34 are rejected as being unpatentable under 35 U.S.C 103 over Surber, M.W. (US 2015/0044288A1, Feb. 02, 2015) (hereinafter Surber) (IDS reference) as applied to claims 23 – 30, 32, 33, and 35 – 42 above, in view of Tang et al. (US 20060128653 A1, June 15, 2006) (hereinafter Tang).
The teachings of Surber are discussed above.
Surber does not teach a method wherein said cyclodextrin is sulfobutylether-β- cyclodextrin sodium or wherein said aqueous solution or suspension comprises said salt of said anionic cyclodextrin, wherein said salt is selected from the group consisting of: a sodium salt, a calcium salt, a magnesium salt, an iron salt, a chromium salt, a copper salt, a zinc salt, a lysine salt, an arginine salt, and a histidine salt. Surber also does not teach wherein said aqueous solution or suspension has said cyclodextrin at a concentration of from about 5% (w/v) to about 40% (w/v).
However, Tang teaches a pharmaceutical formulation may also optionally comprise one or more therapeutic agents other than the cytidine analog/derivative (¶[0028]). Examples of the therapeutic agent other than the cytidine analog/derivative include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents,.. (¶[00145]). Examples of antimetabolic agents include, but are not limited to,… imatinib mesylate (or GLEEVAC(R)), and gemcitabine (¶[00148]).
In one embodiment, the formulation comprises decitabine solvated in a solvent that comprises a cyclodextrin compound (¶[0011]). In one embodiment, the cyclodextrin compound is a sulfoalkylether cyclodextrin derivative, preferably mono-, tetra or hepta-substituted [beta]-cyclodextrin sulfobutyl ether sodium salt, and more preferably [beta]-cyclodextrin sulfobutyl ether, 7 sodium salt (¶[0015]). The concentration of the cyclodextrin compound in the aqueous pharmaceutical formulation is between 0.1% and 80% w/w, optionally between 1% and 60% w/w, optionally between 5% and 50% w/w, optionally between 10% and 40% w/w, or optionally between 20% and 40% w/w (¶[0018]). Tang also teaches that the inventive formulations comprising a cyclodextrin compound can enjoy longer shelf life when stored (¶[0133]).
As discussed above, Tang teaches a pharmaceutical composition comprising active therapeutic agents in combination with various cyclodextrin derivatives and optimal concentrations. Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date, to make an aqueous solution comprising imatinib and cyclodextrin or its derivatives, using the teachings of Surber in combination with Tangs. One would have been motivated to so do because Tang teaches that an aqueous solution with therapeutic agents, in combination with cyclodextrin, provides enhanced chemical stability.
Claim 31 is rejected as being unpatentable under 35 U.S.C 103 over Surber, M.W. (US 2015/0044288A1, Feb. 02, 2015) (hereinafter Surber) (IDS reference) as applied to claims 23 – 30, 32, 33, and 35 – 42 above, in view of Carvalho et al. (J Pharm Pharmacol., May 2016) (hereinafter Carvalho).
The teachings of Surber are discussed above.
Surber does not teach a method wherein said aqueous solution or suspension has a viscosity of at most about 10 centipoise.
However, Carvalho explores the nebulization performance of different methods of aerosol generation for solution and dispersed systems based on the bulk characteristics of liquids, with emphasis on the influence of changes in surface tension and viscosity to aerosol production (left column, pg. 558). Carvalho teaches that jet nebulization are more efficient in terms of respirable output with liquids of low viscosity (1–6 cP) (right column, pg. 560).
The viscosity of the aqueous solution or suspension in claim 31 is at most about 10, which overlaps with the range of viscosity of a liquid taught by Carvalho at 1 – 6 cP. One of ordinary skill in the art would have been motivated to formulate Surber’s composition with the viscosity range taught by Carvalho because viscosity of a solution or suspension can highly influence aerosol generation and performance of nebulizers and Carvalho teaches optimal ranges of viscosity necessary in aerosol generation. “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists”. See MPEP 2144.05(I).
Response to Arguments
Applicant's arguments filed 9/10/2025 have been fully considered but they are not persuasive.
Applicant argues that Surber does not provide motivation to combine the an anionic cyclodextrin and imatinib. Applicant argues there is no motivation to add a cyclodextrin or a motivation to add an anionic over a non-anionic.
Surber teaches on [259] and [286]:
As non-limiting examples, a desired imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof compound formulation for aerosol delivery (e.g., by oral and/or intra-nasal inhalation of a mist such as a nebulized suspension of liquid particles, a dispersion of a dry powder formulation or aerosol generated by meter-dose propellant), may be provided in the form of a simple liquid such as an aqueous liquid (e.g., soluble imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof compound with non-encapsulating soluble excipients/salts), a complex liquid such as an aqueous liquid (e.g., imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof encapsulated or complexed with soluble excipients such as lipids, liposomes, cyclodextrins, microencapsulations, and emulsions), a complex suspension (e.g., imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof as a low-solubility, stable nanosuspension alone, as co-crystal/co-precipitate complexes, and/or as mixtures with low solubility lipids such as solid-lipid nanoparticles), a dry powder (e.g., dry powder imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof compound alone or in co-crystal/co-precipitate/spray-dried complex or mixture with low solubility excipients/salts or readily soluble blends such as lactose), or an organic soluble or organic suspension solution, for packaging and administration using an inhalation device such as a metered-dose inhalation device.
[0286] In another embodiment, a pharmaceutical composition is provided that includes a complex liquid imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof compound formulation encapsulated or complexed with water soluble excipients such as lipids, liposomes, cyclodextrins, microencapsulations, and emulsions) as described above having a solution osmolality from about 50 mOsmol/kg to about 6000 mOsmol/kg. In one embodiment, the osmolality is from about 50 mOsmol/kg to about 1000 mOsmol/kg. In one embodiment, the osmolality is from about 100 mOsmol/kg to about 500 mOsmol/kg. In one embodiment, the osmolality is from about 400 mOsmol/kg to about 5000 mOsmol/kg.
Therefore, the combination of cyclydextrin and imatinib is clearly suggested. Cyclodextrin is taught in a limited grouping of 5 and combined with imatinib to form a complex in an aqueous solution. Therefore, applicant’s arguments that there is a ‘laundry list’ of excipients taught is unpersuasive. The motivation to select cyclodextrin is to increase solubility by forming a complex.
Cyclodextrin is also taught for taste masking on [564] and [566-567]
“Additional coating or capping agents include dextrates (by non-limiting example cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-1-alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and sulfobutylether-beta-cyclodextrin), modified celluloses such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyalkylene glycols, polyalkylene oxides, sugars and sugar alcohols, waxes, shellacs, acrylics and mixtures thereof.
Moreover, 12 cyclodextrin species are taught and thus, applicant’s arguments that there is a ‘laundry list’ of cyclodextrins taught is unpersuasive. There is a clear motivation to utilize cyclodextrin to increase solubility of imatinib and use it for its taste masking.
Applicant argues Tang teaches away from the claimed sulfobutylether-beta-cyclodextrin. This argument is unpersuasive and a mischaracterization of the prior art.
Tang clearly teaches the use of cyclodextrin for its ability to stabilize and/or enhance solubility of the drug. See abstract and [158].
[0158] The following examples are intended to illustrate details of the invention, without thereby limiting it in any manner. As described in the examples below, the use of cyclodextrins as excipients in an aqueous solution can significantly increase the solubility and/or stability of a cytidine analog or derivative such as decitabine and 5-azacytidine.
Tang suggests imatnib mesylate as a therapeutic on [148]. Moreover, Tang teaches the preference of beta.-cyclodextrins such as HPBCD and CAPTISOL (sulfobutylether-beta-cyclodextrin) to stabilize and enhance solubility. See [15], [57] and examples.
[0057] In one embodiment, the cyclodextrin compound is a sulfoalkylether cyclodextrin derivative, preferably mono-, tetra or hepta-substituted .beta.-cyclodextrin sulfobutyl ether sodium salt, and more preferably .beta.-cyclodextrin sulfobutyl ether, 7 sodium salt (CAPTISOL.RTM., Cydex, Inc., Lenexa, Kans.).
[0163] Without being bound to the theory or mechanisms of action, the inventors believe that both the solubility enhancement and stability improvement of decitabine in cyclodextrins--containing aqueous solutions are due to complex formation between decitabine and cyclodextrin molecules, and that .beta.-cyclodextrins form a tighter, reversible complex with decitabine than .alpha.-, or .gamma.-cyclodextrins.
The fact that in the examples that both HPBCD and CAPTISOL are taught to be effective, is not a teaching away from an anionic cyclodextrin. See MPEP 2123. Thus a skilled artisan would have been motivated to utilize cyclodextrin for imatinib as suggested by Surber since Surber states that cyclodextrin is one of 5 species that will form a complex and increase solubility in an aqueous solution. It is further obvious to to follow the directions given by Tang and experiment with the 2 cyclodextrins identified by Tang (HPBCD and CAPTISOL) and test which forms a complex and increases solubility and stability better. Therefore, it is within the skill of an artisan to look at the guidance provided by the prior art and arrive at the claimed composition.
Applicant argues that claimed composition has unexpected results. Applicant argues that applicant has discovered that imatinib free base is an irritant when inhaled and has limited solubility. Applicant argues that applicant has discovered that cyclodextrin increases solubility and the examples show that 25-30% HPBCD versus 10% sulfobutylether-beta-cyclodextrin provides the unexpectedness of sulfobutylether-beta-cyclodextrin.
As discussed above, both Surber and Tang clearly provide a motivation to formulate imatinib and cyclodextrin for the reasons discussed above. As discussed above both Surber and Tang recognize cyclodextrin forms complexes to increase solubility. Surber also teaches the taste masking ability of cyclodextrin. Moreover it is the position of the Office the selection of HPBCD versus sulfobutylether-beta-cyclodextrin is obvious based on Tang’s teaching and solubility experiments demonstrated in the examples to specifically select sulfobutylether-beta-cyclodextrin.
However, assuming arguendo that applicant has shown some unexpected results, MPEP 716.02 is pointed out. Claims must be commensurate in scope with the claimed invention.
The instant claims are directed to a composition and method comprising an aqueous solution or suspension, wherein said aqueous solution or suspension comprises imatinib or a derivative thereof at a concentration of 20 mg/mL to 500 mg/mL, a pH buffer, and a cyclodextrin, wherein said cyclodextrin is an anionic cyclodextrin or salt thereof.
Example 5 is testing the maximum concentration of imatinib free base as a function of percent cyclodextrin (HPBCD or sulfobutylether B cyclodextrin (SBEBCD)) at different pH levels. “The relationship between solubility of imatinib free base and the concentration of HPBCD (w/v) in the solution was tested at a pH of 5 and 7.5. The relationship between solubility of imatinib free base. solution was tested at a pH of 5 and 7.5. The relationship between solubility of imatinib free base and the concentration of SBEBCD (w/v) in the solution was tested at a pH of 5. At a pH of 5 and about 5% HPBCD (w/v), the maximum concentration of imatinib free base dissolved was around 2 mg/mL.”
[203] of the instant specification discusses solubility is a function of pH.
The claims do not specify the concentration of cyclodextrin, that imatinib is in free base form, the pH, nor is it limited to sulfobutylether-beta-cyclodextrin.
Clearly the claims are not commensurate in scope with the claimed invention.
Therefore, the rejections are maintained.
Conclusion
Claims 23 – 42 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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 SHARMILA G. LANDAU whose telephone number is (571)272-0614. The examiner can normally be reached Monday-Friday 7-3:30.
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/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653