DETAILED CORRESPONDENCE
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/24/25 has been entered.
Receipt is acknowledged of Amendments and Remarks filed on 11/24/25. Claims 1-23 remain pending. Claims 1-6, 8-12 and 14 have been amended while no new claims have been added and no claims have been canceled. Claims 16-23 remain withdrawn. Accordingly, claims 1-15 remain under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Objections
Claims 1, 5 and 8-9 are objected to because of the following informalities:
Claim 1 appears to end with a comma instead of a period, as the period has been deleted.
Claim 1 recites “a median volumetric diameter”. this should be a volumetric mean diameter. The specification does not provide support for a median volumetric diameter.
In claim 5, the unit “mg/m” is incorrect and should be mg/mL.
Claims 8-9 are drawn to “the drug-device of …”. This should be -The drug-device combination of …-”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 12 and 14 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.
Claim 12 recites the limitation "of imatinib dose of claim 1" in line 4. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not provide support for an imatinib dose. Claim 1 recites a dose of an imatinib formulation.
Claim 12 is indefinite for reciting “deliver less than 100 mg of the per day as the unit dose of imatinib”. It is not clear what is meant by “of the per day as the unit dose”.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the units for the GSD range.
Claim interpretation
The recitation of “for aerosol delivery to a human patient suffering from pulmonary arterial hypertension” in claim1 is an intended use limitation and does not materially effect the claimed drug-device combination.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Applicant’s Claims
Claim 1- A drug-device combination comprising a dose of an imatinib formulation for aerosol delivery to a human patient suffering from pulmonary arterial hypertension disposed in a device for aerosol delivery comprising: imatinib delivered as a daily unit dose of less than 100 mg per day, wherein the unit dose is contained in the device for aerosol delivery configured to deliver the dose of less than 100 mg per day, wherein the imatinib formulation is not encapsulated and has a median volumetric diameter between about 2 and about 5 microns.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Surber et al (US 20100166673) in view of Jenkins et al (US 20060275372) as evidenced by Newman (Aerosol deposition considerations in inhalation therapy) (of record).
Surber et al teach an aerosol and topical delivery of fluoroquinolone antimicrobials, such as levofloxacin by aerosol through liquid nebulization (See [0011]). Disclosed are the methods of treating lung infections, pneumonia, a chronic obstructive pulmonary disease, etc, (See [0013] and [0028]).
The salts pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, citric acid, ascorbic acid, lactic acid, etc, (See [0113]).
Surber et al further disclose that a vibrating mesh nebulizer is used to deliver an aerosol of the said fluoroquinolone antimicrobial agent. A vibrating mesh nebulizer consists of a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves (See [0160] and [0164]).
It is also disclosed that measures of particle size can be referred to as volumetric mean diameter (VMD), mass median diameter (MMD), or MMAD. In a calibration experiment, the inhaler produced an aerosol output of 4.1 microns VMD, with a geometric standard deviation (GSD) of 1.64 micron VMD. In addition to these measurements, the inhaler produced a fine particle dose (FPD) of 54.9% (percent of emitted dose in particles less than 5 microns). In a single subject, healthy volunteer the feasibility of delivering levofloxacin as an aerosol was established using an Aerogen Clinical vibrating mesh device creating a 3.4 micron volumetric mean diameter (VMD) particle (See [0155], [0357] and [0397]).
The said pharmaceutical composition includes a simple liquid fluoroquinolone antimicrobial formulation having an osmolality from about 200 mOsmol/kg to about 1250 mOsmol/kg, or preferably from about 250 mOsmol/kg to about 1050 mOsmol/kg. In one such embodiment, the solution has a permeant ion concentration from about 30 mM to about 300 mM (See [0029], [0205]-[0206]).The osmolality of the solution formulations is adjusted to 300 mOsmol/kg with sodium chloride (See [0364]).
Surber et al disclose a system for administering a fluoroquinolone antimicrobial that includes a container comprising a solution of a fluoroquinolone antimicrobial and a nebulizer physically coupled or co-packaged with the container and adapted to produce an aerosol of the solution having a particle size from about 2 microns to about 5 microns mean mass aerodynamic diameter (MMAD) and a particle size geometric standard deviation (GSD) of less than or equal to about 2.5 microns mean mass aerodynamic diameter (See [0040]).
Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, etc, (See [0108]).
Surber et al also disclose that the said unit dosage form can also be assembled and packaged together to provide a patient with a weekly or monthly supply and can also incorporate other compounds such as saline, taste masking agents, pharmaceutical excipients, and other active ingredients or carriers (See [0146]).
It is disclosed that in one embodiment, a nebulizer is selected on the basis of allowing the formation of an aerosol of a fluoroquinolone antimicrobial agent disclosed herein having an MMAD predominantly between about 2 to about 5 microns. In one embodiment, the delivered amount of fluoroquinolone antimicrobial agent provides a therapeutic effect for respiratory infections (See [0158]).
Previously, two types of nebulizers, jet and ultrasonic, have been shown to be able to produce and deliver aerosol particles having sizes between 2 and 4 µm (See [0159]). In one embodiment, about 1 to about 5 ml of the fluoroquinolone antimicrobial agent is placed in the storage container and the aerosol generator is engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5 µm (See [0160]).
Surber et al disclose that the said fluoroquinolone antimicrobial agent is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, with MMAD particles sizes between about 2 to about 5 µm (See [0161]), and may be administered in the described respirable delivered dose in less than about 20 min, preferably less than about 3 min, and most preferable in less than about 2 min (See [0162]).
Surber et al further disclose a device or vial having two compartments which are physically separated but in fluid communication such as when so the vial or container are connected by a channel or breakable barrier, the channel or breakable barrier being adapted to direct fluid between the two compartments to enable mixing prior to administration. During storage, the channel is closed with a seal or the breakable barrier intact. In this sense, a seal is any structure that prevents mixing of contents in the two compartments. The seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition or in the case of two liquids permit mixing. The dissolution or mixing process may be improved by shaking the container. Thus, the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel or breakable barrier, depending on how the pack is held (See [0173]).
In one embodiment, aqueous formulations containing soluble or nanoparticulate drug particles are provided, wherein the drug may be present at a concentration of about 1 mg/mL up to about 700 mg/mL. Such formulations provide effective delivery to appropriate areas of the lung, with the more concentrated aerosol formulations having the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time. The solution or diluent used for preparation of aerosol formulations has a pH range from about 4.5 to about 7.5, preferably from about 5.5 to about 7.0. This pH range improves tolerability (See [0197]-[0198]).
The said compositions include a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base, including organic acid salts of citric acid, or phosphate buffers, and pH buffering agents such as sodium acetate, sodium citrate (See [0147] and [0199]).
Surber et al disclose that said liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution to be aerosolized as liquid solutions prior to aerosol production and inhalation. The percentage of active compound contained in such aerosol compositions is highly dependent on the specific nature thereof, and is preferably present in an amount of 1.0% - 50.0% of the solution (See [0149]). Said compositions may further include flavoring agents, taste-masking agents, inorganic salts (e.g., sodium chloride), sodium saccharine, etc, (See [0267]-[0268]).
Surber et al lack a specific disclosure on the active agent being imatinib or its concentration. This would have been obvious to one of ordi9nary skill in the art in view of the teachings of Jenkins et al and as evidenced by Newman.
Jenkins et al teach nanoparticulate formulations of imatinib or a salt thereof having improved pharmacokinetic profiles (See abstract).
Jenkins et al disclose that imatinib, commercially known as Gleevec® is available at a dose of 100 mg to 400 mg.
Disclosed are pharmaceutical compositions comprising particles of a nanoparticulate imatinib mesylate, or a salt or derivative thereof, at least one surface stabilizer, carrier, as well as any desired excipients. The pharmacokinetic profile of the said nanoparticulate imatinib mesylate is not affected by the fed or fasted state of a subject ingesting the composition (See [0020]-[0021]).
Jenkins et al also disclose nanoparticulate imatinib mesylate compositions, or a salt or derivative thereof, together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, the said compositions being formulated for parenteral injection, oral administration in solid, liquid, or aerosol form (See [0029], [0074] and [0125]).
It is disclosed that the concentration of the imatinib mesylate can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the imatinib mesylate and at least one surface stabilizer, not including other excipients (See [0117]).
The said compositions may also comprise excipients including binding agents, filling agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, etc, (See [0103]).
Jenkins et al exemplify tablet dosage forms comprising from about 50 to 500 mg/kg of imatinib mesylate (See [0120]-[0123]).
Jenkins et al also disclose that the said compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions (See [0141]).
As evidenced:
Newman teach that inhalation therapy has several well-established advantages over oral and intravenous routes, including a small dose of drug can be used; a few hundred micrograms of inhaled beta agonist may be as effective as 10 mg oral dose, there is a rapid onset of action, i.e. within 5 minutes (See Page 1, 1st column).
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Surber et al and Jenkins et al and as evidenced by Newman to arrive at the instant invention. It would have been obvious to do so because Surber et al teach compositions and a method of administering an active agent into the lung via a nebulizer and discloses the specifics of nebulizing solutions for effective delivery of sufficient amount of the active agent to the lung and the carrier or excipients that should be added to prepare a formulation with the effective osmolality, pH and droplet size. Surber et al’s disclosure is to a composition comprising fluoroquinolones. The formulations may comprise other active agents. Surber et al do not expressly disclose a composition comprising imatinib, however as taught by Jenkins et al, it is known in the art to make and deliver imatinib as an aerosolized formulation to the pulmonary system. Jenkins et al provide guidance on the dosage of imatinib for oral administration and do not expressly disclose the dosage of imatinib for inhalation. As evidenced by Newman, one of ordinary skill in the art would be motivated to adjust the dosage for inhalation from it’s oral dosage. As such it would have been obvious to one of ordinary skill in the art, given the teachings of Surber et al, to have looked in the art for other active agents suitable for delivery to the pulmonary system including imatinib as taught by Jenkins et al and adjust the dosage with a reasonable expectation of success.
It is generally considered to be prima facie obvious to substitute components which are taught by the prior art to be well known and useful for the same purpose in order to form a composition that is to be used for an identical purpose. The motivation for substituting them flows from their having been used in the prior art, and from their being recognized in the prior art as useful for the same purpose. As shown by the recited teachings, instant claims are no more than the substituting one pharmaceutically active agent for another. It therefore follows that the instant claims define prima facie obvious subject matter. Cf. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958).
Also, one of ordinary skill in the art is more than capable of optimizing the concentration ranges of components, i.e. both the active agent and the excipients such as taste masking agent by routine experimentation.
In other words, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Zisman (9,815,815).
Zisman teach compounds, compositions, and methods for preventing and treating proliferative diseases associated with aberrant receptor tyrosine kinase (RTK) activity, including vascular and pulmonary such as pulmonary arterial hypertension (See abstract, Col. 9, lines 16-35 and Col. 40, lines 54-67).
Zisman also disclose administering to the subject a therapeutically effective amount of a compound of Structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound. The salt is a chloride, hydrochloride, sulfate, phosphate, mesylate, lactate, tartrate, citrate, etc (See Col. 2, lines 20-27, Col. 14, lines 60-65 and Col. 20, lines 30-50).
The said pharmaceutical compositions include at least one of the compounds of Structure 1 and a pharmaceutically acceptable carrier, excipients, binders, preservatives, stabilizers, flavors, etc. Solutions can include a sterile diluent such as water for injection, saline solution, or other synthetic solvents; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide (See Col. 35, lines 19-53).
For administration to the respiratory tract, e.g., inhalation, including intranasal administration, the active compound may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract. Thus, the active compound may be administered in the form of, e.g., a solution, suspension, or as a dry powder. The materials may be administered in a non-pressurized form such as in a nebulizer or atomizer. The formulations may be administered to the airways in the form of a lung surfactant formulation (See Col. 36, lines 6-35).
It is disclosed that formulation for aerosol delivery, “PK10453 (Structure 2) was dissolved at a concentration of 20 mg/ml in 1M tosylic acid. Nebulization was performed with a PARI Nebulizer with an air pressure of 12.5 psi…. The mass median aerodynamic diameter (MMAD) was 2 µm and the associated geometric standard deviation (GSD) was 1.6. Imatinib mesylate was dissolved in water at 20 mg/ml and delivered by a PARI nebulizer then dried by passage through an annular ring of silica bead cartridges prior to inhalation (See Col. 44, lines 43-61).
It is disclosed that dosage levels are from about 0.1 to about 250 mg/kg per day, from about 0.05 to 100 mg/kg per day, or from about 0.1 to 50 mg/kg per day. Within this range, in some embodiments, the dosage is from about 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day (See Col. 38, lines 20-37 and claim 4).
The said unit dose is sufficient to provide one or more of: (a) a Cmax of about 1 to 5000 ng/mL of the compound In a subject's plasma or a Cmax of about 1 to 5000 ng/mL of the compound In the subject's blood when it is administered to the subject; and (b) about 1 to 5000 ng/mL of the compound in a subject's plasma 24 h after administration or about 1 to 5000 ng/mL of the compound in the subject's blood 24 h after administration to the subject (See Col. 38, lines 54-62 and claims 5-6).
In a test the inhaled dose of imatinib was estimated at 167 µg/Kg and the lung deposition disclosed in Table 1 is 0.1 (See Col. 48, lines 15-50 and Table 1).
Keller et al (US 20090232744).
Keller et al teach an aqueous pharmaceutical composition for administration as an aerosol to the respiratory tract (See abstract). Aqueous, i.e. water-based, solutions and suspensions are usually inhaled with nebulisers. Various types of nebulisers are commercially available or presently being developed. A traditional type is the jet nebuliser, which is still being used extensively. More recently, ultrasonic and vibrating membrane-type nebulisers were developed. These systems are capable of delivering drugs in very low and high doses upon spontaneous breathing and offer therefore some advantages over MDIs and DPIs particularly when drugs in doses >1 mg must be delivered into the respiratory tract (See [0008]).
The pH of the composition is in the range of about 3 to 9; and the osmolality of the composition is in the range of about 150 mOsmol/kg to about 1500 mOsmol/kg (See [0025]). The said pharmaceutical composition can be used for aerosolization via a nebulizer producing a pharmaceutical aerosol for pulmonary administration. The dispersed liquid phase essentially consists of aqueous droplets having a mass median diameter from about 1.5 to about 6 µm (See [0026] and [0039]).
It is disclosed that citric acid may be used in combination with saccharin sodium in addition to sodium and magnesium salts (See [0066]).
The osmolality of the said liquid composition is generally in the range of 150 mOsmol/kg to 1500 mOsmol/kg, preferably in the range of 300 mOsmol/kg to 1200 mOsmol/kg (See [0098]). Optionally, the liquid composition may comprise further pharmaceutically acceptable excipients, such as osmotic agents, in particular inorganic salts; excipients for adjusting or buffering the pH, such as organic or inorganic salts, acids, and bases; bulking agents and lyophilisation aids, sugar alcohols, stabilizers and antioxidants, etc, (See [0099]).
In one of the preferred embodiments, one or more osmotic agents such as sodium chloride are incorporated in the composition to adjust the osmolality to a value in the preferred range as outlined herein-above. It was observed that the tolerability of inhaled formulations with high osmolalities was improved when the sodium chloride concentration was greater than 30 mmol (see [0100]).
For adjusting and, optionally, buffering the pH-value, physiologically acceptable acids, bases, salts, and combinations of these may be used including acidic hydrogen phosphates with sodium or potassium, or citrates such as sodium citrate etc. In one of the embodiments, the said liquid composition contains a buffer system consisting of two components, and one of the particularly preferred buffer systems contains citric acid and sodium citrate. Nevertheless, other buffering systems may also be suitable (See [0102] [0103]).
Keller et al also disclose that the said liquid composition may be contained in single dose blow-fill-seal vials with a volume of 0.1-10 ml or in multidose vials from 5-50 ml having a spray or dispensing function (See [0113]). The said liquid composition can be aerosolized via a nebuliser into the upper or lower respiratory tract. Generation and administration of the aerosol is preferably characterized by one or more of the following features: a total output rate of at least 0.1 mL/min, a mass median diameter of about 1.5 to about 6 µm, a geometric standard deviation (GSD) of about 1.3-2.8 µm, the dose exiting the mouthpiece is larger than 25% of the loaded drug dose, and more than 50% of the emitted drug content is contained in droplets <5 µm. The delivered doses may be in a range of about 5-50 mg (See [0114] as well as [0084]-[0089]).
It is also disclosed that the output rate of the nebuliser should be selected to achieve a short nebulisation time of the liquid composition. Obviously, the nebulisation time will depend on the volume of the composition which is to be aerosolised and on the output rate. Preferably, the nebuliser should be selected or adapted to be capable of aerosolising a volume of the liquid composition comprising an effective dose of the active compound within not more than about 20 minutes (See [0085]).
Preferably, the composition is administered using a regimen of repeated administration over a course of at least about five days. Optionally, the duration of the regimen is at least about one week, or about 10 days or about 2 weeks. In further embodiments, the duration is in the range of months or years. Furthermore, the regimen preferably comprises once, twice or thrice daily applications or inhalation; most preferred is once or twice daily administration over the course of therapy. Other preferred regimen are once or twice a week (See [0115]).
Keller et al discloses that preferably, the nebuliser is selected from jet, ultrasonic, piezoelectric, perforated membrane, or perforated vibrating membrane nebulisers. The nebuliser is adapted to deliver the major fraction of the loaded dose of liquid composition as aerosol, such as at least about 40 wt% of the loaded liquid composition. More preferably, at least 60 wt.-% of the liquid composition filled into the nebuliser is actually emitted from the device, which is best achieved by using a modern, optionally customised electronic nebuliser based on the vibrating perforated membrane design. At least about 40 wt% or up to 95 wt%, of the composition charged into the medication reservoir is aerosolised when breath-actuated or controlled breathing modes are applied (See [0079] and [0082]). In Example 4, the device delivers 15 breaths per minute of the formulation.
The concentration of sodium chloride in a formulation is 0.78% (See Table 1).
Response to Arguments
Applicant's arguments filed 11/24/25 have been fully considered but they are not persuasive.
Applicant’s arguments are against the combination of the references and argue that Surber et al do not teach imatinib or its concentration (dose) and Jenkins is teaching nanoparticles and not a drug-device combination.
More specifically, Applicant argues that neither the Jenkins reference nor the Surber reference are related to the underlying physiological mechanisms of pulmonary arterial hypertension (See remarks, page 5).
This argument is not persuasive because the claims are directed to a drug-device combination comprising a dose of an imatinib formulation disposed in a device for aerosol delivery. That is, “for aerosol delivery to a patient suffering from pulmonary arterial hypertension” is intended use limitation. An intended use will not limit the scope of the claim because it merely defines a context in which the invention operates. (Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003)). Moreover “the patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure.” (Catalina Mktg. Int’l, v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002).
Next argument is that nothing in the disclosure of Jenkins et al identifies any composition where the specific imatinib mesylate nanoparticulate are used in a drug-device combination (See remarks, page 5).
This argument is also not persuasive. While the ere is no express disclosure of a drug-device combination, Jenkins et al clearly disclose that the said imatinib mesylate formulation can be formulated for an aerosol. This inherently means that the said formulation is deposited in an aerosol device. Furthermore, the rejection has clearly relied upon Surber et al reference to teach the device.
Applicant the argues that “no rationale exists why the skilled artisan would select the nanoparticulate species, modify the dosage to less than prescribed value known for efficacy, nor formulate the API separate from the nanoparticulate form, which is the entire point of the Jenkins et al reference” (See remarks, pages 5-6).
The above argument has been fully considered and found unconvincing. A reference is relied upon for all that discloses. Jenkins et al teach that the said nanoparticulates of imatinib mesylate can be reconstituted in an aqueous carrier to make an aqueous solution. The dosage is modified to adjust for the route of delivery. As disclosed by Newman, the inhalation dosage is much smaller than that of oral administration. While Jenkins et al teach that the said formulations can be delivered in an aerosol form, they do not expressly disclose its dosage. However, one of ordinary skill in the art, is more than capable of determining the dosage amount from the teachings in the art such as Newman.
Applicant further argues that “no suggestion or motivation can be found in the principal references that vismodegib alone would be effective when inhaled as a dry powder from an aqueous solution” (See remarks, page 6).
The above argument appears to be irelavnat to the rejections of record as neither reference teach vismodegib. Examiner cannot respond to this argument.
Applicant also points to the related Application issued as patent No. 11,980,689 and use for PAH by Pascoe et al and Dr. Surber’s Declaration in the related Application (See Remarks, page 6).
The above argument is also unpersuasive because 1- Pascoe is not a refence of the rejection, 2- The rejection has shown that the claimed formulation would have been obvious over the teachings of Surber et al in view of Jenkins et al, 3- The Declaration is not related to the examined claims, 4-While there is no single reference teaching the entirety of the claimed formulations, the combination of refences would have clearly rendered the claims obvious. In other words, the rejection fully meets the obviousness statue.
The rejection has clearly shown that, Surber et al teach a similar formulation to the claimed formulation comprising a different active agent. Jenkins et al teach imatinib in an aerosolizable formulation. Thus, as clearly established in the rejection, one of ordinary skill in the art is more than motivated to incorporate different active agents into the formulations of Surber et al with a reasonable expectation of success, especially when the said active agent is already taught as a suitable active compound for aerosolization. Jenkins et al also disclose nanoparticulate imatinib mesylate compositions, or a salt or derivative thereof, together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, the said compositions being formulated for parenteral injection, oral administration in solid, liquid, or aerosol form. Jenkins et al also disclose that the said nanoparticulates can be added to an aqueous carrier to make an aqueous solution (See [0029], [0074] and [0125]). Regarding the dosage, it is noted that Surber et al teach the delivery dosage of a formulation to the subject and Jenkins et al teach safe and effective dosage of imatinib for oral administration. Newman provides evidence that one of ordinary skill in the art would be motivated and able to determine the said dosage for inhalation.
Additionally, the courts have held that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). MPEP 2144.05:
The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Applicant further argues that “A section 103 rejection must show that “a skilled artisan would have had a ‘reasonable expectation’ of success” in achieving the claimed invention” (See Remarks, page 7).
The above argument is also not commensurate with the scope of examined claims. The question is, would one of ordinary skill in the art be motivated to combine Jenkins et al and Surber et al’s references to arrive at the claimed formulation comprising imatinib with a VMD of from 2 to 5 microns disposed in a device for aerosol delivery with a reasonable expectation of success. The answer is one of ordinary skill in the art would be motivated to combine the references to arrive et al the claimed invention with a reasonable expectation of success. One of ordinary skill in the art is not limited by treating PAH or possible side effects. Again, “for aerosol delivery to a patient suffering from PAH” is an intended use limitation and does not limit the claimed drug-device combination.
Applicant further argues that “The examiner appears not to have followed the binding Federal Circuit precedent in OSI Pharma controls the outcome of this issue. In OS/ Pharms, OSI Pharms., LLC v. Apotex Inc.,939 F.3d 1375 (Fed. Cir. 2019), the Federal Circuit reversed a PTAB decision that the claimed subject matter was obvious based on prior art references directed to a promising anticancer drug. To the contrary, the Federal Circuit found: “These references provide no more than hope—and hope that a potentially promising drug will treat a particular cancer is not enough to create a reasonable expectation of success in a highly unpredictable art such as this.” (See remarks, page 7).
As stated in the previous office action, the above arguments are also not commensurate with the scope of claims. Additionally, the cited decisions are not found relevant to the examined claims or the current rejections. Treating PAH is an intended use limitation which does not materially or structurally affect the claimed drug-device combination or formulation or distinguish the claimed formulation from that taught by the prior art references. The said treating PAH limitation is not a patentable limitation of the instant claims, which are drawn to an imatinib formulation.
Applicant’s main argument is that the claimed delivery dose is unexpectedly effective in treating PAH (See remarks, pages 8-10).
The argument is not persuasive and does not overcome the rejection because as it has been shown, the formulation is obvious to one of ordinary skill in the art and the treatment of PAH is an intended use limitation. It has been decided that "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." See MPEP § 2123, [R-1]. Consequently, the discovery that the said formulation is effective in treating PAH or other dosages caused side effects are not sufficient to place the claims in condition for allowance.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 1-15 are rejected. Claims 16-23 are withdrawn.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616