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 .
Receipt is acknowledged of Amendments and Remarks filed on 07/13/26. Claims 1-23 remain pending. Claims 1, 5, 8-9 and 12 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 Claims 16-23 remain withdrawn.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Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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 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.
Claim 14 is 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 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 …. delivery to a human patient suffering from pulmonary arterial hypertension” in claim 1 is an intended use limitation and does not materially affect 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 volumetric mean 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 ordinary 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 regimens 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 07/13/26 have been fully considered but they are not persuasive.
The first argument is against the rejection of claim 14 under 112(b). Applicant argues that “GSD is an inherently dimensionless quantity. Because it is a ratio of two quantities having the same units, the units cancel and GSD is unitless by definition. It would therefore be scientifically incorrect to assign units to a GSD value, and no units appear in the aerosol science literature, or in claim 14, for GSD” (Se remarks, page 7).
This appears to be contradicting the Specification which discloses GSD does have a unit. The Specification discloses “(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm, about 1.2 μm to about 2.3 μm, about 1.4 μm to about 2.1 μm, or about 1.5 μm to about 2.0 μm”, “(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm” and “with a GSD of less than or equal to about 2.5 microns. In another embodiment, an aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than or equal to 2 microns is provided. In another embodiment, an aerosol having an MMAD from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 microns is provided” (See at least [0020], [0021] and [0404] of published Spec). Thus, the Specification does not support the claimed GSD of 1-2.5.
Next Applicants argue that “Examiner’s reliance on Boehringer and Catalina Is Misplaced”. Applicant argues that “The Examiner cites Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough …. and Catalina Marketing Int'l V. Coolsavings.com, Inc., …. for the proposition that "for aerosol delivery to a [human] patient suffering from pulmonary arterial hypertension" is merely an intended-use limitation that is not entitled to patentable weight. Applicant respectfully submits that the cited authorities do not support the Examiner's conclusion. As an initial matter, both Boehringer and Catalina address whether language appearing in a claim preamble limits the scope of the claim. The present claims do not present a preamble issue. Rather, the disputed language appears in the body of the claim, where limitations are presumed to define the claimed invention and ordinarily cannot be disregarded absent a showing that they merely state an intended use without imposing any structural or functional requirement” (See remarks, pages 7-8).
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 … delivery to a patient suffering from pulmonary arterial hypertension” is an 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. Regardless of whether the limitation is in the preamble or body of the claim, it is only the intended use limitation and does not materially affect the scope of the claim. Since Applicant is critical of the Examiner’s reliance on Boehringer and Catalina, the below arguments will be included.
“A claim is only limited by positively recited elements. Thus, “[i]nclusion of the material or article worked upon by a structure being claimed does not impart patentability to the claims.” In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963); see also In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935);
“the manner or method in which such machine is to be utilized is not germane to the issue of patentability of the machine itself.” See In re Casey, 152 USPQ 235 (CCPA 1967) and In re Otto, 136 USPQ 458, 459 (CCPA 1963).
Thus, the intended use of the claimed composition has not been given patentable weight because what condition may be treated by the delivery of the claimed composition is not germane to the claimed drug-device combination and because the prior art composition and device would be capable of performing said use.
Applicant’s other argument is that “The Examiner's combination relies on Surber for the formulation and delivery platform and on Jenkins for the identity of the active agent, imatinib. A careful reading of Jenkins confirms that this is the entirety of Jenkins's contribution. Moreover, using Jenkins's imatinib in the claimed combination would require the skilled artisan to abandon Jenkins's entire technical architecture” (See remarks, page 8).
The above argument is also not found persuasive. Firstly, Jenkins is directed to formulations comprising imatinib and discloses that it can be administered by aeroslization. Secondly, it has been held that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Since Surber et al teach the drug-device combination and all the limitations of it, it would have been obvious to one of ordinary skill in the art to look at other potential active agents that can be incorporated into the compositions of Surber. Jenkins et al do that. That is, the combined teachings of the references (Surber and Jenkins) would have suggested the claimed drug-device combination comprising imatinib to those of ordinary skill in the art.
The next argument directed at Jenkins et al’s disclosure is that Jenkins et al is exclusively directed at solving the problem of fed/fast variability in oral imatinib, they do not teach aqueous solutions and the formulation is not “not encapsulated”. Applicant argues that Jenkins nanoparticulate architecture presents a fundamental incompatibility with the claimed formulations (See remarks, page 9).
The argument has been given full consideration and found unconvincing. Jenkins et al is the secondary reference and brings in what is missing from the primary reference. It is not required for the secondary reference to teach the claimed product. The rejection was not based on bodily incorporating Jenkins compositions into Surber’s compositions, as stated above. Rather that Jenkins teach that imatinib is a drug compound that is well known and has been used in oral administration and can be used in aerosolized formulations. Thus, while Jenkins et al do concentrate on the fed/fast variability of imatinib formulations, that is not all they teach to one of ordinary skill in the art. In this regard the courts have held that “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments”. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)); and that “A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings”. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Additionally, it is noted that Jenkins et al disclose that the imatinib can be formulated into many different dosage forms including aerosol.
Regarding the argument that Jenkins et al do not teach an aqueous solution, it is noted that 1- Surber, the primary reference teaches those, 2- Jenkins et al do in fact teach where imatinib can be added to an aqueous solution media, including an aqueous solution of a salt, acid or base to achieve the desired pH. Jenkins et al teach that the pH of this solution is preferably about 4-6; and 3- claims 1-4 do not support an argument of aqueous solution, as they are not limited to any dosage form.
Regarding the argument that Jenkins et al do not teach an aqueous solution wherein the formulation is “not encapsulated”, it is noted that Jenkins et al do not teach encapsulation of the formulation. The presence of a surface stabilizer cannot be interpreted as encapsulation. In fact, surface stabilizers are surfactants, which are required by the examined claims, such as claim 7.
Applicant further argues that “Surber expressly reports "differences among drugs in pulmonary pharmacokinetics" and "variable efficacy among the compounds" in aerosol delivery (see paragraph [0128]). Surber identifies numerous drug-specific physicochemical factors that must be individually evaluated for any candidate drug, including aqueous solubility, viscosity, osmolality, surface tension, pH, dissolution rate, tissue binding, sputum binding, taste, and pulmonary tolerability. These are acknowledged sources of unpredictability that are drug-specific, not universal constants that apply equally to every compound that might be loaded into a nebulizer” (See remarks, page 10).
The above argument is similarly unpersuasive. Firstly, Surber discloses that “As was previously shown in a rat system, there were differences among drugs in pulmonary pharmacokinetics, with some agents showing lower AUCs (e.g., levofloxacin), while others such as gemifloxacin or tobramycin show higher concentrations resulting from slower pulmonary clearance” (See [128]). Thus, Surber is referring to the different PK parameters of different drugs, which is obvious to one of ordinary skill in the art. Secondly, while Surber’s disclosure is regarding the fluoroquinolone antibiotics, one of ordinary skill in the art is more than capable of determining which other active agents can be included in the same formulations. There are many references that teach different classes of drug compounds can be incorporated in the same formulation. For example, Keller et al (US 20090232744), (cited above), teach similar liquid compositions for nebulization comprising a macrolide and other active agents including, quinolons, aminoglycosides, peptide antibiotics, monobactams, cefalosporins, antifungals, immunmodulators, non-steroidal anti-inflammatory drugs, steroids, and pharmaceutically acceptable salts thereof (See at least claims 1 and 9). Keller et al (6,585,958) teach a medicinal formulation wherein the active agent may be any medicinal active agent such as beta-mimetics, corticosteroids, anticholinergics, cyclooxygenase, mast cell, lipoxygenase and proteolytic enzyme inhibitors, arachidonic acid, leukotriene, thromboxane, sodium/potassium channel, neurokinin, tachykinin, bradykinin, muscarine, histamine, phosphodiesterase, platelet-activating factor and selectin antagonists, potassium channel blockers, antiinfectives, antibiotics, pentamidine, cytostatics, fungistatics, free-radical scavengers, vitamins, hormones, immunostimulants, immunosuppressants, mucolytics, heparin, antidiabetics, analgesics, soporifics and the like (See columns 8-9). Backstrom et al (6,932,962) teach an inhalable formulation that may comprise a medicament selected from the group consisting of salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol, procaterol, broxaterol, picumeterol, mabuterol, ipratropium bromide, beclomethasone, fluticasone, budesonide, tipredane, dexamethasone, betamethasone, fluocinolone, triamcinolone acetonide, mometasone, anti-allergic medicaments, expectorants, mucolytics, antihistamines, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, leukotriene antagonists, phospholipase-A2 (PLA2) inhibitors, platelet aggregating factor (PAF) antagonists, prophylactics of asthma, antiarrhythmic medicaments, tranquilisers, cardiac glycosides, hormones, anti-hypertensive medicaments, antidiabetic medicaments, antiparasitic medicaments, anticancer medicaments, sedatives, analgesic medicaments, antibiotics, antirheumatic medicaments, immunotherapeutic agents, antifungal medicaments, antihypotension medicaments, vaccines, antiviral medicaments, proteins, peptides, vitamins, cell surface receptor blockers, antioxidants, free radical scavengers, and organic salts of N.N'-diacetylcystine (See Columns 2-3 and claims 12-13).
As such one of ordinary skill in the art would have been more than motivated to have selected a different active agent such as imatinib for the formulations of Surber for its known benefits and excepted effectiveness. The factual underpinning is that different active agents are considered alternatively usable species and as such one of ordinary skill in the art is more than capable of substituting one species / active agent for another with a reasonable expectation of success. As taught by the evidentiary prior art references it would have been obvious to one of ordinary skill in the art to have selected any of the known and disclosed pharmaceutically active agents for the same base dosage formulation with a reasonable expectation of success.
In this regard, the courts have held that "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 conventional components of pharmaceutical active agents. 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).
Applicant also argues that “Surber's formulation platform is optimized specifically for fluoroquinolone class antibiotics (i.e. levofloxacin, ciprofloxacin, ofloxacin, and their congeners) for treatment of pulmonary bacterial infections” (See remarks, page 10).
This argument is also not persuasive, as the claimed composition is the same as the formulation taught by Surber. The only difference is the active agent.
An ordinarily skilled artisan would reasonably expect success in modifying the formulation of Surber by substituting the active agent of Jenkins et al as proposed because it is well known in the art that the same dosage forms can include many different active agents, as exemplified by the evidentiary references.
The next argument is that of “no reasonable expectation of success in combining Surber and Jenkins”. Applicant argues that “As the Federal Circuit held in OSI Pharm., LLC V. Apotex Inc., 939 F.3d 1375, 1383 (Fed. Cir. 2019), "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." Although OSI Pharm. arose in the context of cancer treatment, the Federal Circuit's reasoning applies with equal force here. Where the Examiner's combination rests not on any data demonstrating that inhaled imatinib would achieve therapeutic concentrations at the pulmonary vasculature, but on the mere possibility that a drug might, if nebulized in a formulation neither reference discloses, produce a therapeutic effect in a vascular disease, the rejection is based on the same type of impermissible hindsight-driven optimism rejected in OSI Pharm” (See remarks, page 11).
As stated in the previous office action, the above arguments are also not commensurate with the scope of claims. 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.
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.
The argument of reasonable expectation of success is also not persuasive because 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 … delivery to a patient suffering from PAH” is an intended use limitation and does not limit the claimed drug-device combination.
Applicant’s other point is that none of the references teach the dosage of less than 100 mg/day, far below any doses of 200-400 mg/day for oral administration (See remarks, page 11, step 3).
The argument is not persuasive and does not overcome the rejection. The rejection is over Surber et al in view of Jenkins et al as evidenced by Newman (Aerosol deposition considerations in inhalation therapy). Newman teaches that the inhalation doses are far less than those required for oral doses. In view of the knowledge provided by all references, one of ordinary skill in the art would be more than motivated to use far less than 200-400 mg/day of imatinib for inhalation purposes.
Applicant appears to assign a very narrow skill set to one skilled in the art. Regarding an ordinary artisan MPEP 2141 states that ““A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 418, 82 USPQ2d at 1396; and 2) MPEP 716.07: “It is to be presumed also that skilled workers would as a matter of course, if they do not immediately obtain desired results, make certain experiments and adaptations, within the skill of the competent worker.” In the instant case, the references one of ordinary skill in this art is more than capable of determining the appropriate dosage amount form the guidance provided and routine experimentation. That is, “Where 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, 105 USPQ 233 (CCPA 1955).
Furthermore, it is noted that “less than 100 mg/day” dosage as claimed encompasses 0.0001 mg/day, which has not been shown by the Specification to treat any condition, much less PAH.
It has been shown that the claimed drug-device combination comprising a dose of imatinib formulation has been rendered obvious by the combination of prior art references. 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 causes less 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.
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.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
Prosecution Insights