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 .
Status of Claims
Claims 1, 75, 81, 86, 91, and 92 are amended. Claims 2-74, 76-80, 82-85, and 87-88 are canceled. Claims 93-104 are new. Claims 1, 75, 81, and 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Withdrawn Objections/Rejections
Claim 81 was rejected under 35 U.S.C. 112(b) for being indefinite. Applicant’s amendment to claim 81 has overcome the rejection and the rejection is withdrawn.
Claim 1 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by Voswinckel. Applicant’s amendment to claim 1 has overcome the rejection and the rejection is withdrawn.
Claims 1, 58, 85, and 87-88 were rejected under 35 U.S.C. 103 as being unpatentable over Roscigno in view of Ruegg. Applicant’s amendment to claim 1 has overcome the rejection and the rejection is withdrawn.
The following rejections are necessitated by amendment:
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, 81, 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). 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).
Voswinckel further discloses that in study 1, the total inhaled doses of each drug were 7.5 μg iloprost and treprostinil (when using a 4 μg/ml dose) and 15 μg treprostinil (when using a 8 μg/ml and 16 μg/ml dose) (methods and patients, 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).
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. The 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 reduction of PVR and PAP was comparable among all groups (Fig. 6; results, para. 6). This 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).
Voswinckel further discloses that all inhalations were performed with the Optineb ultrasonic nebulizer (methods and patients, para. 1).
The teachings of Voswinckel differ from that of the instant invention in that Voswinckel does not disclose 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, 81, 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 obvious to combine the teachings of Voswinckel, the EMA, and the FDA before the effective filing date of the claimed invention by administering a combined iloprost and treprostinil formulation in the method of Voswinckel, provided by combining commercially available formulations of iloprost and treprostinil taught by the EMA and FDA, respectively. First, it would have been prima facie obvious to one of ordinary skill in the art to combine iloprost and treprostinil into a single formulation since both are taught in formulations used for treating pulmonary hypertension (PH) 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). It would have been obvious that the combined formulation be liquid, since Voswinckle teaches an inhalation method using a nebulizer and the EMA and FDA teach liquid formulations administered via a nebulizer. Second, it would have been prima facie obvious to administer the combined formulation according to 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, to provide a combined formulation which may be used in 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 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 to yield the instant invention. 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 would have been able to prepare and store the combined formulation above prior to administration since these steps 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 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 81, a liquid formulation comprising iloprost and treprostinil for treating PH is made obvious above. Regarding storage stability, when the composition made obvious by the prior art is identical to the composition claimed, the composition must necessarily have the characteristics claimed as an inherent property. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
Additionally, storage stability and the amount of active ingredient is a results effective parameter. The optimization of a result effective parameter is considered within the skill of the artisan. See, In re Boesch and Slaney (CCPA) 204 USPQ 215. This is what research chemists do, optimization of result-effective variables through routine experimentation (MPEP 2144.05 IIA and B). Thus, it would have been obvious for one of ordinary skill in the art to optimize the storage stability in order to reach a formulation that maintains its stability and meets the limitation of claim 81.
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). Voswinckel also teaches that typical iloprost inhalation sessions consume considerable time every day. Thus, it would have been obvious to provides a method that administers the combined iloprost and treprostinil formulation in one minute or less as taught for the treprostinil administration method by Voswinckel. 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 that currently exists for iloprost inhalation. 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. As such, it would have been obvious administer the combined iloprost and treprostinil formulation above in at least two or three administering events per day since at least 6 or 4 times a day is known and routine for treating pulmonary hypertension with iloprost and treprostinil independently. 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 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. 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 to 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 mg/ml concentration of the nebulizer solution and the time of inhalation as taught by Voswinckel.
Regarding claim 92, Voswinckel delivers a total inhaled doses of 7.5 or 15 μg treprostinil. 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 above 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. 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 for 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 using iloprost trometamol and the FDA teaches treprostinil in their respective nebulizer formulations. 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 which are stored in ampules.
Claims 1, 75, 81, 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, 81, 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 (PTO-892), 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 Voswinckel, the EMA, nor the FDA explicitly teach a formulation comprising both iloprost, treprostinil, and the various 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 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 formulate the combined iloprost and treprostinil formulation above with sodium chloride since NaCl is a known and routine excipients in nebulizer solutions for pulmonary drug delivery as taught by the EMA, FDA, and Pilcer. It would have been further obvious to one of ordinary skill in the art to adjust the amount of sodium chloride in the formulation to reach the desired osmolarity as taught by Pilcer. As such, one of ordinary skill in the art would have 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 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 range of claims 99 and 101.
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 using the methods described above 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.
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, 81, 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 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. 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, it would have been prima facie obvious to one of ordinary skill in the art to combine the method of the copending claims with the method of Voswinckel 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, 81, 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 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. 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, it would have been prima facie obvious to one of ordinary skill in the art to combine the method of the copending claims with the method of Voswinckel 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, 81, 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 obvious to modify the method of the US’728 claims with the teachings of Voswinckel to administer the treprostinil of the US’728 claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation. The US’728 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, it would have been prima facie obvious to one of ordinary skill in the art to combine the method of the US’728 claims with the method of Voswinckel 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, 81, 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 obvious to modify the method of the US’327 claims with the teachings of Voswinckel to administer the treprostinil of the US’327 claims with the iloprost of Voswinckel in a single liquid pharmaceutical formulation. The US’327claims 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, it would have been prima facie obvious to one of ordinary skill in the art to combine the method of the US’327 claims with the method of Voswinckel 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 Arguments
1. Applicant's arguments filed 11/17/2025 have been fully considered but they are not persuasive:
Applicant argues that the prima facie case of obviousness to combine iloprost and treprostinil is overcome by the unexpected results provided in Examples 2-4 of the instant specification which show that iloprost is surprisingly more stable in the treprostinil-containing formulations 1 and 2 of Examples 3 and 4 as compared to the formulation of Example 2, which does not contain treprostinil (p. 6 of Remarks). Applicant further cites the EMA label for Ventavis as evidence of the stability problems associated with iloprost (p. 6-7 of Remarks).
In response to applicant’s argument of unexpected results, an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). Furthermore, Applicants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness. Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). In this case, Applicant has not provided a comparison to the closest prior art or explained the data in a way that sufficiently shows unexpected results. First, if the applicant means to show an unexpected increase in the stability of iloprost, the closest prior art for such a comparison would be the commercially available Ventavis solution. As taught above by the EMA, the Ventavis solution comprises: iloprost, trometamol, ethanol 96%; sodium chloride; hydrochloric acid; and water. It is not clear from the instant specification if the formulation of Example 2 (i.e., Applicants comparative example) comprises the same excipients. Additionally, these examples employ glass vials or LDPE ampules, which could also have a significant effect on storage stability. As such, there could be other variables accounting for the change in stability which may have to do with the excipients or storage vessel rather than the inclusion of treprostinil. Secondly, Examples 2-4 of the instant specification, which applicant broadly points to, comprise several stability tests at various temperatures and RH levels. Additionally, the examples measure various parameters such as visual appearance, %LC of iloprost, and individual impurities. Thus, it is unclear what parameter is being used to define “improved stability” since Applicant has not provided a detailed explanation. If the differentiating factor is that the amount of iloprost after one month of storing is at least 90% as instantly claimed (claim 81), it appears that the comparative formulation of example 2 (i.e., iloprost only) actually retains 92.7% of iloprost at the 1 month mark (table 7), which meets this limitation.
Regarding the stability problems associated with Iloprost as taught by the EMA, as pointed out by the Applicant, the claims do not define what entails as “storage”. Applicant points to the stability of Ventavis following opening the ampoule and the solution remaining in the nebulizer after use. Such a storage condition is not reasonably defined in the claims. The EMA label for Ventavis teaches that the formulation has a shelf life of 2 years when contained in the storage ampoules. The “storing” period as recited in instant claims 75 and 81 reads on storing the formulation in ampoules, which would have more than adequate storage stability (i.e., 2 years) as taught by the EMA.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616