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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/12/2026 has been entered.
Status of Claims
Receipt of Remarks/Amendments filed on 05/15/2026 is acknowledged. Claims 2-74, 76-85, 87-88 are canceled. Claims 1, 75, 86, and 89-104 are currently pending and are examined on the merits herein.
Priority
The instant application filed 02/07/2023 claims priority to Provisional Application No. 63/307,919, filed 02/08/2022.
Withdrawn Rejections
All previous rejections of claim 81 are rendered moot in response to its cancelation.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 75, 86, 89-94, and 102-103 are rejected under 35 U.S.C. 103 as being unpatentable over Voswinckel, R., et al. (2006). Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension: Results From Randomized Controlled Pilot Studies. JACC. 48 (8) 1672–1681, (IDS dated 06/12/2023), hereinafter Voswinckel, in view of the European Medicines Agency (EMA). (2008). Summary of Product Characteristics: Ventavis 10 microgram/ml nebulizer solution. Pg. 1-13. First authorization: 2003, Last Renewal: 2008. (on record), hereinafter the EMA, and the Food and Drug Administration (FDA). (2009). FDA label for Tyvaso (treprostinil) inhalation solution and full prescribing information. Pg. 1-16. Revised: 2009. (on record), hereinafter the FDA, as evidenced by the Center for Drug Evaluation and Research (CDER). (2009). Application Number 22-387, Medical Reviews of Tyvaso. Pg. 1-12. (on record), hereinafter the CDER.
Voswinckel discloses three studies investigating the effects of inhaled treprostinil in pulmonary arterial hypertension (title; abstract).
Regarding claim 1: The patient population in these studies include people with different forms of precapillary pulmonary hypertension, all of which had a need for therapy of pulmonary hypertension (discussion, para. 2). In study 1 each patient underwent right heart catheterization and inhaled both iloprost and treprostinil on the same day. The drugs were administered consecutively with a 1-h interval between the drug administrations (methods para. 3). The inhalation of both iloprost and treprostinil in study 1 resulted in a rapid decrease in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) (results, para. 1). In conclusion, both drugs are potent pulmonary vasodilators for treating pulmonary arterial hypertension (discussion, para. 4). Thus, Voswinckel teaches a method of treating pulmonary hypertension comprising administering by inhalation to a subject in need thereof iloprost and treprostinil.
Voswinckel also teaches that the typical 6 to 9 iloprost inhalation sessions daily with 6- to 12-min inhalation times consume considerable time every day. As such, study 3 sought to find the shortest possible inhalation time for a 15-μg dose of inhaled Treprostinil. The drug was applied in 18, 9, 3, 2 or 1 breaths. The aerosol was generated by a pulsed ultrasonic nebulizer in cycles consisting of 2-s aerosol production (pulse) and a 4-s pause. A treprostinil dose of 15 μg was either generated during 18 cycles (Optineb filled with 100 μg/ml treprostinil), 9 cycles (200 μg/ml treprostinil), 3 cycles (600 μg/ml treprostinil), 2 cycles (1,000 μg/ml treprostinil), or 1 cycle (2,000 μg/ml treprostinil) (methods and patients, para. 5). The drug administration with a single breath induced pulmonary vasodilation for longer than 3 h compared with placebo inhalation. Side effects were minor, of low frequency, and not related to drug concentration (discussion, para. 8).
The teachings of Voswinckel differ from that of the instant invention in that Voswinckel does not explicitly teach a liquid pharmaceutical formulation comprising both iloprost and treprostinil as defined in claim 1. Since Voswinckel does not disclose a liquid pharmaceutical formulation comprising both iloprost and treprostinil, Voswinckel also does not disclose the dependent limitations of claims 75, 86, 89-94 and 102-103.
While Voswinckel does not explicitly disclose the formulations of iloprost and treprostinil administered via nebulizer, commercially available nebulizer solutions of iloprost and treprostinil are taught by the EMA and the FDA, respectively:
The European Medicines Agency (EMA) discloses Ventavis 10 microgram/ml nebulizer solution, p. 2, section 1). Each 1 ml solution contains 10 micrograms iloprost (as iloprost trometamol) and is contained in an ampoule either comprising 1 ml or 2 ml of the solution (p.2, section 2). Ventavis is used for the treatment of patients with primary pulmonary hypertension (p. 2, section 4.1). The recommended dose per inhalation session is 2.5 micrograms or 5.0 micrograms of inhaled iloprost (as delivered at the mouthpiece of the nebulizer) (p. 2, section 4.2). The dose per inhalation session should be administered 6 to 9 times per day according to the individual need and tolerability (p. 4, daily dose). Ventavis comprises the following excipients: trometamol, ethanol 96%; sodium chloride; hydrochloric acid (for pH adjustment); water for injections (p. 12, section 6.1). The shelf life of the solution in an ampoule is 2 years (p. 12, section 6.3).
The FDA discloses Tyvaso (treprostinil) inhalation solution (p. 1, title). Tyvaso is used for the treatment of pulmonary arterial hypertension (p. 1, indications and usage). Tyvaso is a sterile formulation of treprostinil intended for administration by oral inhalation using the Optineb-ir device (i.e., a nebulizer). Tyvaso is supplied in ampules, containing 1.74 mg treprostinil (0.6 mg/mL). Each ampule also contains 18.9 mg sodium chloride, 18.3 mg sodium citrate, 0.58 mg sodium hydroxide, 11.7 mg 1 N hydrochloric acid, and water for injection (p. 9, section 11). Tyvaso is initially administered with 3 breaths of Tyvaso (16 mcg of treprostinil), per treatment session, 4 times daily. Dosage is increased by an additional 3 breaths at approximately 1-2 week intervals until the target dose of 9 breaths (54 mcg of treprostinil) is reached per treatment session, 4 times daily (p. 2, section 2.1). Ampules of Tyvaso are stable until the date indicated when stored in the unopened foil pouch at 25oC (p. 12, section 16). More specifically, the self-life of Tyvaso when stored at controlled room temperature in the foil outer packets is 36-month as evidenced by the CDER (p. 2, para. 3; p. 12, para. 4).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to administer a combined iloprost and treprostinil formulation in the method of Voswinckel, since commercially available liquid formulations of iloprost and treprostinil are known and routine in the art as taught by the EMA and FDA. First, one of ordinary skill in the art could have combined the iloprost and treprostinil formulations of the EMA and FDA into a single formulation via known methods to predictably yield the instantly claimed formulation. Since both formulations are individually used for treating pulmonary hypertension (PH) via inhalation, it would have been “prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The combined formulation would necessarily be a liquid since both formulations are liquid. Second, one of ordinary skill in the art would have found it obvious to administer the combined formulation using the method of Voswinckel since Voswinkel teaches that it is known and routine to administer both iloprost and treprostinil to treat pulmonary hypertension via inhalation. Thus, one of ordinary skill in the art could have combined the formulations of iloprost and treprostinil, taught by the EMA and FDA, and administered it via the method of Voswinkel, to yield the predictable result of treating pulmonary hypertension in a subject. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation of iloprost and treprostinil to treat pulmonary hypertension via inhalation since both compounds are used to treat pulmonary hypertension via inhalation when administered independently and Voswinckel teaches that they can both be administered to the same patient separately. As such, the method of claim 1 is obvious.
Regarding claim 75, a liquid formulation comprising iloprost and treprostinil for treating PH is made obvious above. It would have therefore been prima facie obvious to one of ordinary skill in the art to prepare and store the combined formulation according to the teachings of the EMA and FDA since the preparation and storage of a formulation prior to use is known and routine in the art. The EMA and FDA teach the ingredients, amounts, storage containers, and conditions for liquid formulations comprising iloprost and treprostinil, respectively. As such, one of ordinary skill in the art could have prepared and stored the combined formulation above according to the known methods of the EMA and the FDA to predictably yield the instant invention. One of ordinary skill in the art would have had a reasonable expectation of success in preparing a combined formulation of iloprost and treprostinil since their individual formulations are taught by the EMA and FDA and it is well within the skill of an ordinary artisan to adjust a formulation to accommodate two active ingredients. Additionally, both the Ventavis (iloprost) and Tyvaso (treprostinil) formulations are stored in ampules prior to administration, both with a shelf-life over a month, making it obvious that a combined formulation of the two would also be stored in ampules prior to administration and could be stored for at least one month after preparing.
Regarding claim 86, study 3 of Voswinckel investigates the shortest possible inhalation time for treprostinil. As discussed above, Voswinckel was able to decrease the number of inhalations to a single breath which consists of a 2-s aerosol production (pulse) and a 4-s pause (i.e., one minute or less) (methods and patients, para. 5). It would have been prima facie obvious to one of ordinary skill in the art to provide a method that administers the combined iloprost and treprostinil formulation in one minute or less as taught for the treprostinil administration method of Voswinckel since such an administration length is known and routine in the art. One of ordinary skill in the art would have been motivated to administer treprostinil and iloprost in a single breath (i.e., one minute or less), in order to decrease the daily time burden of the treatment method. One of ordinary skill in the art would have had a reasonable expectation of success in administering the combined formulation in one minute or less since Voswinckel teaches methods for administering treprostinil in a single breath.
Regarding claims 89 and 90, Ventavis (iloprost) is administered 6 to 9 times a day as taught by the EMA while Tyvaso (treprostinil) is administered 4 times a day as taught by the FDA, both of which read on at least two or three administering events per day. It would have been prima facie obvious to one of ordinary skill in the art to administer the combined iloprost and treprostinil formulation at a minimum of two or three times per day since administration rates higher than that are known and routine in the art. One of ordinary skill in the art would have been motivated to perform at least two or three administering events per day of iloprost and treprostinil since multiple dosing events are recommended by the EMA and FDA in order to achieve effective treatment. One of ordinary skill in the art would have had a reasonable expectation of success in administering a combined formulation of iloprost and treprostinil at least 2 to 3 times a day since the EMA and FDA teach that both iloprost and treprostinil are typically administered in this range when used independently.
Regarding claim 91, Voswinckel teaches the administration of iloprost at an inhaled dose of 7.5 μg (methods and patients, para. 3), which differs from the instantly claimed amount of 2.5 to 5 μg. However, as discussed above, the EMA discloses Ventavis (iloprost) nebulizer solution which has a recommended dose per inhalation session of 2.5 micrograms or 5.0 micrograms of inhaled iloprost, both of which read on the instantly claimed dose. Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer the combined iloprost and treprostinil formulation above in a method which provides iloprost at a dose of 2.5 or 5 μg since such a dose is known and routine for treating PH as taught by the EMA. One of ordinary skill in the art would have had a reasonable expectation of success in administering such a dosage since both Voswinckel and the EMA teach delivering iloprost via inhalation through a nebulizer, wherein dosage can be customized in and around this range by adjusting the concentration of the nebulizer solution and the time of inhalation as taught by Voswinckel.
Regarding claim 92, Voswinckel delivers a total inhaled dose of 7.5 or 15 μg treprostinil (methods and patients, para. 3). Furthermore, the FDA teaches Tyvaso (treprostinil) is initially administered at a dose of 16 mcg per treatment session and is increased to 54 mcg over time. All of these dosage amounts fall within the instantly claimed range. Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer the combined iloprost and treprostinil formulation in a method which provides treprostinil at a dose that falls within the instantly claimed range (i.e., 5 to 120 μg) since various dosages within this range are known and routine for treating PH. One of ordinary skill in the art would have had a reasonable expectation of success in administering such a dosage since both Voswinckel and the FDA teach delivering iloprost via inhalation through a nebulizer at these various dosages.
Regarding claims 93 and 94, the nebulizer formulation of the EMA contains 10 μg/ml of iloprost and the nebulizer formulation of the FDA contains 0.6 mg/ml (i.e., 600 μg/ml) of treprostinil, both of which read on the instantly claimed concentrations. Thus, it would have been prima facie obvious to one of ordinary skill in the art to provide the combined formulation above with 10 μg/ml of iloprost and 600 μg/ml of treprostinil since such concentrations are known and routine in pharmaceutical formulations of iloprost and treprostinil for treating PH. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation with such concentrations since these concentrations are used to achieve effective dosages for treating PH as taught by the EMA and FDA.
Regarding claims 102 and 103, the EMA teaches iloprost trometamol and the FDA teaches treprostinil, both of which read on the instantly claimed actives. As such, it would have been prima facie obvious to one of ordinary skill in the art to formulate the combined iloprost and treprostinil formulation above using iloprost trometamol (i.e., tromethamine salt) and treprostinil since these actives are known and routine in the art as taught by the EMA and FDA. One of ordinary skill in the art would have had a reasonable expectation of success in formulating these actives together since they are both stable in aqueous nebulizer solutions.
Claims 1, 75, 86, and 89-104 are rejected under 35 U.S.C. 103 as being unpatentable over Voswinckel, the EMA, and the FDA as applied to claims 1, 75, 86, 89-94, and 102-103 above, and further in view of Pilcer G, et al. (2010). Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 392(1-2):1-19 (on record), hereinafter Pilcer.
The combined teachings of Voswinckel, the EMA, and the FDA are discussed above.
The combined teachings of Voswinckel, the EMA, and the FDA differ from that of the instant invention in that none explicitly teach the excipients and properties of claims 95-101 and 104.
Pilcer teaches formulation strategy and use of excipients in pulmonary drug delivery, specifically expedients used in nebulization (title, 5.1). Marketed respiratory solutions are generally composed of drugs dissolved in aqueous, isotonic solvent systems that may contain preservatives to reduce microbial growth (5.1, para. 3). Sodium chloride (NaCl) and other salts are widely used to adjust the osmolarity of solutions to approximately 300 mOsmol/l. Attention must also be paid to the pH of the formulation because, unlike the gastrointestinal tract, the lungs have limited buffering capacity. Therefore, HCl, NaOH, citric acid, phosphates and trometamol are commonly used to adjust the pH of the solution to neutrality (5.1, para. 4). Examples of phosphate buffers include monosodic and disodic phosphate (table 1).
Regarding claims 95-96, 98, and 104, it would have been prima facie obvious to one of ordinary skill in the art to formulate the combined iloprost and treprostinil formulation above with a buffer that maintains a neutral pH since buffers are known and routine excipients in nebulizer solutions for pulmonary drug delivery as taught by Pilcer. Furthermore, one of ordinary skill in the art would have been motivated to select a buffer that maintains a neutral pH (i.e., about 7), such as sodium phosphate, since a neutral pH is desirable as taught by Pilcer and sodium phosphate is known in the art for buffering to a physiological pH (~7).
Regarding claim 97, 99, 101, and 104, the nebulizer formulations of the EMA and FDA both comprise sodium chloride. Furthermore, Pilcer teaches that sodium chloride is widely used in nebulizer solutions to adjust the osmolarity of the solution to around 300 mOsmol/l. As such, it would have been prima facie obvious to one of ordinary skill in the art to adjust the amount of NaCl in the combined formulation in order to reach the desired osmolarity as taught by Pilcer. One of ordinary skill in the art would have therefore arrived at the instantly claimed range of 100 to 150 mM NaCl through no more than routine experimentation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). It would have also been obvious to one of ordinary skill in the art to provide an osmolarity of 300 mOsmol/L as taught by Pilcer, since such an osmolarity is known and routine in the art. Assuming that the solution has a density close to water, an osmolarity of 300 mOsmol/L falls within the instantly claimed ranges.
Regarding claims 100 and 104, it would have been prima facie obvious to one of ordinary skill in the art to formulate the combined iloprost and treprostinil formulation above as an isotonic solution since isotonic solvent systems are known and routine in the art as taught by Pilcer. One of ordinary skill in the art could have appropriately adjusted the osmolarity of the solution known methods to generate the predictable result of generating an isotonic solution.
One of ordinary skill in the art would have had a reasonable expectation of success in making the above modifications since these adjustments are taught in the context of pulmonary drug delivery, specifically in liquid nebulization formulations like those of Voswinckel, the EMA, and the FDA.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1. Claim 1, 75, 86, and 89-104 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 17 of copending Application No. 18/416,054 in view of Voswinckel.
The copending claims recite a method of treating pulmonary hypertension comprising administering to the subject a first therapeutically effective amount of a pulmonary vasodilator, wherein the pulmonary vasodilator is treprostinil (copending claims 1 and 3). The administering further comprises administering by inhalation (copending claim 17).
The copending claims differ from the instant claims in that the copending claims do not recite administering a liquid pharmaceutical formulation comprising iloprost and treprostinil as defined by instant claim 1.
Voswinckel discloses three studies investigating the effects of inhaled treprostinil in pulmonary arterial hypertension (title; abstract). The patient population in these studies include people with different forms of precapillary pulmonary hypertension, all of which had a need for therapy of pulmonary hypertension (discussion, para. 2). In study 1 each patient underwent right heart catheterization and inhaled both iloprost and treprostinil on the same day. The drugs were administered consecutively with a 1-h interval between the drug administrations. Voswinckel further discloses that in study 1, the total inhaled doses of each drug were 7.5 μg iloprost and 7.5 or 15 μg treprostinil (methods and patients, para. 3).
It would have been prima facie obvious to modify the method of the copending claims with the teachings of Voswinckel to administer the treprostinil of the copending claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation, since both are known and routine treatments for PH. The copending claims and Voswinckel teach that treprostinil and iloprost are useful for treating pulmonary hypertension via inhalation. Generally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, one of ordinary skill in the art would have found it obvious to administer a combined iloprost and treprostinil liquid formulation which can be administered via inhalation through a nebulizer. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation of iloprost and treprostinil to treat pulmonary hypertension via inhalation since both compounds are used to treat pulmonary hypertension via inhalation when administered independently.
This is a provisional nonstatutory double patenting rejection.
2. Claim 1, 75, 86, and 89-104 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 22-23 of copending Application No. 18/497,668 in view of Voswinckel.
The copending claims recite a method for treating pulmonary hypertension comprising administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension (copending claim 1). The therapeutically effective amount of the non- oral therapeutic agent is an inhaled prostacyclin, specifically inhaled treprostinil (copending claims 22-23).
The copending claims differ from the instant claims in that the copending claims do not recite administering a liquid pharmaceutical formulation comprising iloprost and treprostinil as defined by instant claim 1.
Voswinckel discloses three studies investigating the effects of inhaled treprostinil in pulmonary arterial hypertension (title; abstract). The patient population in these studies include people with different forms of precapillary pulmonary hypertension, all of which had a need for therapy of pulmonary hypertension (discussion, para. 2). In study 1 each patient underwent right heart catheterization and inhaled both iloprost and treprostinil on the same day. The drugs were administered consecutively with a 1-h interval between the drug administrations. Voswinckel further discloses that in study 1, the total inhaled doses of each drug were 7.5 μg iloprost and 7.5 or 15 μg treprostinil (methods and patients, para. 3).
It would have been prima facie obvious to modify the method of the copending claims with the teachings of Voswinckel to administer the treprostinil of the copending claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation, since both are known and routine treatments for PH. The copending claims and Voswinckel teach that treprostinil and iloprost are useful for treating pulmonary hypertension via inhalation. Generally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, one of ordinary skill in the art would have found it obvious to administer a combined iloprost and treprostinil liquid formulation which can be administered via inhalation through a nebulizer. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation of iloprost and treprostinil to treat pulmonary hypertension via inhalation since both compounds are used to treat pulmonary hypertension via inhalation when administered independently.
This is a provisional nonstatutory double patenting rejection.
3. Claims 1, 75, 86, and 89-104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,609,728 in view of Voswinckel.
US’728 recites a method of treating pulmonary hypertension comprising co-administering to a subject in need thereof a pharmaceutically effective amount of an oral therapeutic agent for treating pulmonary hypertension and a pharmaceutically effective amount of an inhaled therapeutic agent for treating pulmonary hypertension, wherein the oral therapeutic agent is treprostinil or a pharmaceutically acceptable salt or ester thereof and wherein the inhaled therapeutic agent is treprostinil or a pharmaceutically acceptable salt or ester thereof (claim 1).
The US’728 claims differ from the instant claims in that the US’728 claims do not recite administering a liquid pharmaceutical formulation comprising iloprost and treprostinil as defined by instant claim 1.
Voswinckel discloses three studies investigating the effects of inhaled treprostinil in pulmonary arterial hypertension (title; abstract). The patient population in these studies include people with different forms of precapillary pulmonary hypertension, all of which had a need for therapy of pulmonary hypertension (discussion, para. 2). In study 1 each patient underwent right heart catheterization and inhaled both iloprost and treprostinil on the same day. The drugs were administered consecutively with a 1-h interval between the drug administrations. Voswinckel further discloses that in study 1, the total inhaled doses of each drug were 7.5 μg iloprost and 7.5 or 15 μg treprostinil (methods and patients, para. 3).
It would have been prima facie obvious to modify the method of the conflicting claims with the teachings of Voswinckel to administer the treprostinil of the conflicting claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation, since both are known and routine treatments for PH. The conflicting claims and Voswinckel teach that treprostinil and iloprost are useful for treating pulmonary hypertension via inhalation. Generally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, one of ordinary skill in the art would have found it obvious to administer a combined iloprost and treprostinil liquid formulation which can be administered via inhalation through a nebulizer. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation of iloprost and treprostinil to treat pulmonary hypertension via inhalation since both compounds are used to treat pulmonary hypertension via inhalation when administered independently.
4. Claims 1, 75, 86, and 89-104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 11, and 13 of U.S. Patent No. 11,826,327 in view of Voswinckel.
US’327 recites a method of improving exercise capacity in a patient having pulmonary hypertension associated with interstitial lung disease, comprising administering by inhalation to the patient having pulmonary hypertension associated with interstitial lung disease an effective amount of at least 15 micrograms up to a maximum tolerated dose of treprostinil or a pharmaceutically acceptable salt thereof (claim 1). The administering is performed by a pulsed inhalation device, specifically a nebulizer (claims 11 and 13).
The US’327 claims differ from the instant claims in that the US’327 claims do not recite administering a liquid pharmaceutical formulation comprising iloprost and treprostinil as defined by instant claim 1.
Voswinckel discloses three studies investigating the effects of inhaled treprostinil in pulmonary arterial hypertension (title; abstract). The patient population in these studies include people with different forms of precapillary pulmonary hypertension, all of which had a need for therapy of pulmonary hypertension (discussion, para. 2). In study 1 each patient underwent right heart catheterization and inhaled both iloprost and treprostinil on the same day. The drugs were administered consecutively with a 1-h interval between the drug administrations. Voswinckel further discloses that in study 1, the total inhaled doses of each drug were 7.5 μg iloprost and 7.5 or 15 μg treprostinil (methods and patients, para. 3).
It would have been prima facie obvious to modify the method of the conflicting claims with the teachings of Voswinckel to administer the treprostinil of the conflicting claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation, since both are known and routine treatments for PH. The conflicting claims and Voswinckel teach that treprostinil and iloprost are useful for treating pulmonary hypertension via inhalation. Generally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, one of ordinary skill in the art would have found it obvious to administer a combined iloprost and treprostinil liquid formulation which can be administered via inhalation through a nebulizer. One of ordinary skill in the art would have had a reasonable expectation of success in using a combined formulation of iloprost and treprostinil to treat pulmonary hypertension via inhalation since both compounds are used to treat pulmonary hypertension via inhalation when administered independently.
Response to the Declaration under Rule 132
Patrick Poisson provided a Declaration under Rule 132 that is dated 05/15/2026. The Declaration meets the formal requirements. In the most relevant part, the Declaration details the stability of a solution of iloprost (by itself without treprostinil) and a solution including both iloprost and treprostinil. The data is presented in the specification and explained in the declaration. The specification data presents stability results under storage conditions for both (25oC at 60% RH) and (40oC at 75% RH). In these solutions, iloprost has a concentration of 10 ug/ml or 20 ug/ml while treprostinil is provided at 600 ug/ml. The pH of every formulation is 6.5 and the concentration of NaCl is either 125 or 115 mM. The storage vessel is either LDPE or glass ampules.
As described in the declaration, the solution including both iloprost and treprostinil is surprisingly more stable than the solution of iloprost (by itself without treprostinil) under the same conditions. Applicant concludes that the “superior stability of solutions including both iloprost and treprostinil makes it possible to store such solutions in plastic containers, such as LDPE ampules, which is not possible for solutions of iloprost (by itself without treprostinil), such as inhalation solutions of VENTAVIS®” (p. 4 of Declaration).
A Declaration is due full consideration and weight for all that it discloses. Declarations are reviewed for the following considerations: 1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996)), 2) whether the Declaration presents a comparison to the closest art, 3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)), 4) whether the Declaration shows a difference in kind rather than merely a difference in degree (In re Waymouth, 182 USPQ 290, 293 (C.C.P.A. 1974)), and 5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339 (Fed. Cir. 2007)).
The relevant criteria here is No. 3) whether the Declaration is commensurate in scope with the scope of the claims.
The examiner has carefully reviewed the Declaration, including the data pointed to in the specification. However, even if the data were to show superior stability of iloprost + treprostinil solutions, the scope of instant claim 1 is much broader than the evidence which is presented. Claim 1 is drawn to a method of administering a formulation comprising iloprost or a pharmaceutically acceptable salt thereof and treprostinil or a pharmaceutically acceptable salt thereof. The formulation of claim 1 may comprise any concentration of iloprost, any concentration of treprostinil, any known excipients and be stored in any known container under any conditions as well as additional steps where other drugs are administered, etc. as the method as claimed uses comprising as the transitional phrase which is open-ended and excludes nothing from the claimed method. As noted above, the data in the specification only provides results for a narrow subset of formulation parameters and storage conditions. Since “superior stability” is only evidenced for very specific formulations, the examiner cannot assume that all formulations of iloprost and treprostinil will exhibit this same improved stability. For example, it is not likely that every concentration of treprostinil will result in increased stability when only a concentration of 600 ug/mL is evidenced in the data. As discussed in the interview dated 11/10/2025, the independent claim should define the property that differentiates the claimed invention from the prior art, or the structural limitations of a composition which displays said property. Until those limitations are included, the evidence presented is not commensurate in scope with the claims.
While several of the dependent claims define specific formulation parameters, they are each defined in separate claims meaning a single embodiment having all the requirements of the specification examples is not defined. Additionally, several of the parameters claim broader ranges than what is evidenced in the specification. Lastly, if the distinguishing result is that the instant combination makes it possible to store iloprost in a plastic container, as stated in the declaration, then a plastic container should also be defined in the independent claim.
Response to Arguments
Applicant's arguments filed 05/15/2026 have been fully considered but they are not persuasive:
The remarks reiterate what is discussed in the above declaration. Applicants argues that unexpected stability results allow for a superior method of treatment in which the presently claimed combination liquid formulations may be stored for a longer period of time, while also using a more convenient and less costly container.
As discussed in the response to declaration above, the claims do not recite any storage conditions or container, nor do the claims define a composition having all of the formulation parameters of the specification examples. As such, the claimed composition, which is broader in scope than what there is evidence for, cannot be assumed to have the same stability as argued by the applicant as the method as claimed uses comprising as the transitional phrase which is open-ended and does not exclude anything else including other drugs or other steps, etc. from the claimed method. Since stability is a result of specific storage conditions, containers, and formulation parameters, Applicant’s arguments are to features which are not claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNAH S ARMSTRONG whose telephone number is (571)272-0112. The examiner can normally be reached Mon-Fri 9-5 (Flex).
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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/ERIN E HIRT/Primary Examiner, Art Unit 1616
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