Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`IN THE UNITED STA TES PA TENTAND TRADEMARK OFFICE
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`Applicant:
`
`Horst OLSCHEWSKI et a1.
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`Title:
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`TREPROSTINIL ADMINISTRATION BY
`INHALATION
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`Appl. No.:
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`13/469,854
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`Filing Date:
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`5/11/2012
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`Examiner:
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`Sarah Elizabeth Townsley
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`Art Unit:
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`1629
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`Confirmation Number:
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`9171
`
`
`AMENDMENT & REPLY UNDER 37 CFR_§_1.1 l l
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`Mail Stop Amendment
`Commissioner for Patents
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`PO. Box 1450
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`Alexandria, VA 22313- 1450
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`Commissioner:
`
`This paper responds to the outstanding Non—Final Office Action dated October 3,
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`2012. Applicants petition for extension of time to make this response timely.
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`Amendments to the Specification begin on page 2 ofthis document.
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`Amendments to the Claims are reflected in the listing of claims which begins on
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`page 3 of this document.
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`Remarks begin on page 5 ofthis document.
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`Atty. Dkt. No. 080618—1 l56
`Appl. No. l3/469,854
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`Amendments to the Specification:
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`Please amend the specification as follows:
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`Please replace paragraph 0072 with the following rewritten paragraph:
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`All inhalations were performed with the OPTINEB® thifieb® ultrasonic nebulizer
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`(Nebutec, Elsenfeld, Germany).
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`Please replace paragraph 0078 with the following rewritten paragraph:
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`Study iii) was a randomized, open—label, single blind study. The primary objective
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`was to explore the shortest possible inhalation time for a 15 ug dose of inhaled treprostinil. A
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`total of 48 patients inhaled one dose of TRE during right heart catheter investigation. The
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`drug was applied in 18, 9, 3, 2 or 1 breaths. The aerosol was generated by a pulsed ultrasonic
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`nebulizer (VENTA—NEB®, Nebutec, Elsenfeld, Germany) in cycles consisting of2 seconds
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`aerosol production (pulse) and 4 seconds pause. The device included an opto—acoustical
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`trigger for the patient to synchronize the inspiration to the end of the aerosol pulse, thereby
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`providing exact dosage. The TRE dose of 15ug was either generated during l8 cycles
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`(thineb OPTINEB® filled with IOOug/ml TRE, n=6), 9 cycles (200ug/ml TRE, n=6), 3
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`cycles (600ug/ml TRE, n=21), 2 cycles (lOOOug/ml TRE, n=7) or l cycle (2000ug/ml TRE,
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`n=8). Hemodynamics and gas exchange were recorded for 120 — l80 minutes.
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`Please replace paragraph 0085 with the following rewritten paragraph:
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`Study iii) was performed with metacresol—free TRE solution, having no specific taste
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`and smell. A total of 48 patients were enrolled. This study aimed at the reduction of
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`inhalation time and aerosol volume needed for pulmonary drug delivery. A modified thineb
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`OPTINEB® inhalation device was programmed to produce a constant amount of aerosol
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`during repeatable pulses of aerosol generation. With this device, treprostinil could be safely
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`utilized up to a concentration of 2000ug/ml without considerable side effects. No
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`relationship of number or type of side effects to TRE concentration was observed. Reported
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`side effects were mild transient cough (n=6), mild headache (n=2‘) and mild jaw pain (n=l).
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`Atty. Dkt. No. 080618—1156
`Appl. No. 13/469,854
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`Amendments to the Claims:
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`This listing of claims will replace all prior versions, and listings, of claims in the application:
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`Listing of Claims:
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`1. (original) A pharmaceutical formulation for inhalation comprising an aerosolable
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`solution of treprostinil or a pharmaceutically acceptable salt thereof at a concentration from
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`500 ug/ml to 2500 ug/ml adapted for use in an ultrasonic nebulizer, wherein the formulation
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`is free of metacresol.
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`2. (original) The pharmaceutical formulation for inhalation of claim I, wherein the
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`concentration of treprostinil or its pharmaceutically acceptable salt in the aerosolable solution
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`is 600 ug/ml.
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`3. (original) The pharmaceutical formulation for inhalation of claim 1, wherein the
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`aerosolable solution has a volume that provides at least one aerosolized dose from 15 ug to
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`90 ug oftreprostinil or a pharmaceutically acceptable salt thereof.
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`4. (original) The pharmaceutical formulation for inhalation of claim 1, wherein the
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`aerosolable solution has a volume that provides several aerosolized doses sufficient to treat a
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`patient for one day, wherein each dose is from 15 ug to 90 ug of treprostinil or a
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`pharmaceutically acceptable salt thereof.
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`5. (original) The pharmaceutical formulation for inhalation of claim 4, wherein the
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`concentration of treprostinil or its pharmaceutically acceptable salt in the aerosolable solution
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`is 600 ug/ml.
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`6. (original) A component for an ultrasonic nebulizer comprising the formulation of
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`claim 1.
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`7. (original) A component for an ultrasonic nebulizer comprising the formulation of
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`claim 2.
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`8. (original) A component for an ultrasonic nebulizer comprising the formulation of
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`claim 5.
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`9. (original) A kit for treating a patient, comprising
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`Atty. Dkt.No.080618—1156
`Appl. No. 13/469,854
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`(i) an ultrasonic nebulizer (a) adapted to receive a pharmaceutical formulation for
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`inhalation comprising an aerosolable solution of treprostinil or a pharmaceutically acceptable
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`salt thereof at a concentration from 500 ug/ml to 2500 ug/ml, wherein the formulation is free
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`of metacresol and (b) adapted to administer a therapeutically effective single event dose of
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`the formulation comprising from 15 ug to 90 ug of treprostinil or a pharmaceutically
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`acceptable salt thereof by inhalation in 10 or less breaths;
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`(ii) a pharmaceutical formulation for inhalation comprising an aerosolable solution of
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`treprostinil or a pharmaceutically acceptable salt thereof at a concentration from 500 ug/ml to
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`2500 ug/ml, wherein the formulation is free of metacresol; and
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`(iii) instructions for a patient to use the kit to by administering a therapeutically
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`effective single event dose ofthe formulation comprising from 15 ug to 90 ug of treprostinil
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`or a pharmaceutically acceptable salt thereof by inhalation in 10 or less breaths.
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`10. (original) The kit of claim 9, wherein the concentration of treprostinil or its
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`pharmaceutically acceptable salt in the aerosolable solution is 600 ug/ml.
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`11. (original) The kit ofclaim 9, wherein the ultrasonic nebulizer is adapted to
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`administer a therapeutically effective single event dose of the formulation comprising from
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`15 ug to 90 ug of treprostinil or a pharmaceutically acceptable salt thereof by inhalation in 3
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`or less breaths.
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`12. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
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`administer a therapeutically effective single event dose of the formulation comprising from
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`15 ug to 90 ug of treprostinil or a pharmaceutically acceptable salt thereofby inhalation in
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`one breath.
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`13. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
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`administer the therapeutically effective single event dose of the formulation as droplets with
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`a diameter less than about 5 microns.
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`14.
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`(original) The kit of claim 9, wherein the ultrasonic nebulizer is a pulsed
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`ultrasonic nebulizer comprising an opto—acoustical trigger for the patient to synchronize
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`inspiration with an aerosol pulse.
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`Atty. Dkt. No. 080618-1156
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`Appl. No. 13/469,854
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`REMARKS
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`Applicants respectfully request reconsideration and allowance of the present
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`application.
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`Claims 1-14 are pending.
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`CLAIMS STATUS
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`SPECIFICATION
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`Applicants have amended paragraphs 0072, 0078 and 0085 to address the issue
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`regarding the use of trademarks raised by the PTO on pages 2-3 of the Office Action. No
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`new matter has been added.
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`CLAIM REJECTIONS UNDER 35 U.S.C. § 103(a)
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`Claims 1-8 stand rejected as obvious over Chaudry (US Publication no.
`
`2004/0265 23 8). Applicants respectfully traverse.
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`The PTO failed establish aprimafacie case of obviousness at least for each of the
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`following independent reasons. Moreover, the unexpected results ofa formulation having the
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`particular claimed drug concentration range, which is adapted for use in an ultrasonic
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`nebulizer and which lacks metacresol, would more than rebut any possible case ofprima
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`facz'e obviousness.
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`1) At the time of filing of the presently claimed invention, one of ordinary skill in the
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`art would have been motivated to include metacresol in a treprostinil formulation
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`(notwithstanding that it is not mentioned in Chaudry) because the only FDA-approved and
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`commercially available formulation of treprostinil at that time (for parenteral use) included
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`metacresol (see http://remodulin.com/pdfs/remodulin-prescribinginformation.pdf);l
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`
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`1 As explained in paragraphs 77—81 ofthe present specification, the inventors performed two ofthree
`initial clinical studies on pulmonary hypertension human patients with a formulation containing metacresol
`before deciding to conduct a third study in which it was omitted.
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`Atty. Dkt. No. 080618—1156
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`Appl. No. 13/469,854
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`2) One of ordinary skill in the art would not have arrived, based on Chaudry, at “an
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`aerosolable solution of treprostinil or a pharmaceutically acceptable salt thereof at a
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`concentration from 500 [pg/ml to 2500 Egg/ml”; and
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`3) One of ordinary skill in the art would not have arrived, based on Chaudry, at “an
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`aerosolable solution of treprostinil or a pharmaceutically acceptable salt thereof at a
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`concentration from 500 ug/ml to 2500 ug/ml adapted for use in an ultrasonic nebulizer.“
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`Applicants provide a more detailed discussion of each of these reasons below.
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`1) As explained in the present specification, the present inventors performed two out
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`ofthree initial clinical studies ofinhalation formulations in an ultrasonic nebulizer with
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`metacresol (see paragraphs 77—81 of the present specification). After patients twice reported
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`foul taste (paragraph 80), they also tested solutions at the claimed concentration of
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`treprostinil without metacresol. They found that, when treprostinil was formulated as
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`claimed at a concentration range of 500 ug/ml to 2500 ug/ml for use in an ultrasonic
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`nebulizer, the metacresol could be eliminated and a pharmaceutically stable and acceptable
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`formulation for ultrasonic nebulization resulted. This is shown in the data in the present
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`specification and further demonstrated by the FDA’s approval of Tyvaso®, the first inhaled
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`treprostinil product (see www.tyvaso.com). An invention based on the discovery ofa
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`hitherto unrecognized problem in the prior art (such as foul taste of the originally developed
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`treprostinil formulation) may be unobvious, even though the solution to the problem, once
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`recognized, is obvious. In re Sponnoble, 160 USPQ 237 (CCPA 1969).
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`Furthermore, the present inventors unexpectedly discovered that removal of
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`metacresol improved the arterial oxygen saturation in pulmonary hypertension patients
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`receiving the inhalation formulation. As stated in paragraph 79, discussing the results ofthe
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`second study which included metacresol, “oxygen saturation was significantly decreased at a
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`dose of 120 ug TRE in all 3 patients.” By contrast, when metacresol was removed from the
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`formulation in the third study, paragraph 80 states that the drop in oxygen saturation (8803)
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`no longer occurred. Paragraph 80 further states that the present inventors attributed the drop
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`in oxygen saturation to the presence of metacresol in the earlier study.
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`2) Chaudry discloses a formulation comprising treprostinil in his prophetic example 4
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`as follows:
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`Atty. Dkt. No. 080618-1156
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`Appl. No. 13/469,854
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`Treprostinil sodium
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`0.1-10.0 mg/ml
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`Sodium Chloride
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`2.0-10.0 mg/ml
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`Citric Hydroxide
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`Citric Oxide
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`Water
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`q.s.
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`q.s.
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`q.s.
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`Although Chaudry’s range for treprostinil encompasses “500 ug/ml to 2500 ug/ml” recited in
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`claim 1, Chaudry does not teach or suggest the particular treprostinil concentration range of
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`claim 1. To remedy the deficiencies of Chaudry, the PTO provides the following comments
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`on page 4 ofthe Office Action:
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`“As recognized by MPEP § 2144.05, where the claimed ranges "overlap or lie inside
`ranges disclosed by the prior art" aprimafacie case of obviousness exists. In re
`Wertheim, 541 F.2d 257,191 USPQ 90 (CCPA 1976); In re Woodrufi’, 919 F.2d
`1575,16 USPQ2d 1934 (Fed. Cir. 1990).
`
`In addition, it would have been within the capabilities of one of ordinary skill in the
`art to adjust and optimize the treprostinil concentration in the inhalable formulations
`within the ranges disclosed by Chaudry. As recognized by MPEP § 2144.05,
`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 ofa claim are disclosed in the prior art, it is not inventive to discover the
`optimum or workable ranges by routine experimentation." In re AIIer, 220 F.2d
`454,456, 105 USPQ 233,235 (CCPA 1955).”
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`The treprostinil concentration range recited in claim 1 is non—obvious over Chaudry’s range
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`at least because this particular range is critical for providing a dose of l 5 to 90 ug in a few
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`breaths, e.g., in 10 breaths or less, in a single inhalation event.
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`In this regard, Applicants
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`quote from the PTO’s citation of In re Aller: “Generally, differences in concentration or
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`temperature will not support the patentability of subject matter encompassed by the prior art
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`unless there is evidence indicating such concentration or temperature is critical‘” (Bold
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`underlining added) Applicants respectfully submit that the specification as filed provides the
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`Atty. Dkt.No. 080618-1156
`Appl. No. 13/469,854
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`evidence supporting the criticality of the treprostinil concentration range recited in claim 1 in
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`Example 2, paragraphs 0068-0095. This range of concentration enables the patient to receive
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`an effective dose for treating pulmonary hypertension in a smaller number of breaths
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`compared to the only other available inhaled prostacyclin that was available at the time of
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`filing, which resulted in enhanced quality of life for the patients. As evidence supporting this
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`point, Applicants attach a copy of the Rule 132 Declaration of Dr. Rubin submitted in related
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`application Ser. No. 12/591,200.
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`One of ordinary skill in the art would not be able to arrive at the treprostinil
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`concentration range recited in claim 1 based on Chaudry at least for the following reasons:’
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`A) although Chaudry relates to inhalation formulations, Chaudry does not provide any
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`evidence that any of compounds disclosed in his paragraphs 0022-0027 can in fact be
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`administered by inhalation. All of Chaudry’s working examples, including the one for
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`treprostinil, are prophetic.
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`B) Chaudry does not provide any guidance regarding relationship between dosages
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`and drug concentrations for any of his inhalation formulations.
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`In other words, one of
`
`ordinary skill in the art would not know based on Chaudry what particular drug concentration
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`to use to deliver a particular drug dose. More specifically, one of ordinary skill in the art
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`would not know based on Chaudry what particular treprostinil concentration to use to deliver
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`a particular dose of treprostinil. As shown in the present specification’s clinical studiesLit is
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`the local effect of drug amount deposited in the lungs, rather than plasma concentration
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`resulting from inhalation, which appears primarily responsible for the efficacy in pulmonary
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`hypertension patients.
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`C) Based on Chaudry, one of ordinary skill in the art would not conclude that
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`treprostinil can be administered in a dose of 15 to 90 ug in a few breaths, e.g. in 10 breaths
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`or less, in a single inhalation event because according to Chaudry, the smallest time for an
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`individual inhalation event or session is 3 minutes, see e.g. paragraph 0067, which
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`corresponds to 30-42 breaths taking into account that a normal respiratory rate for an adult
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`human at rest is 10-14 breaths per minute. Thus, one of ordinary skill in the art would have
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`no reason to optimize Chaudry’s range of0. l-10.0 mg/ml in order to arrive at the particular
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`treprostinil range recited in claim 1.
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`Atty. Dkt. No. 080618—1 156
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`App]. No. 13/469,854
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`In sum, the PTO failed to establish aprimafacz'e case of obviousness for the reasons
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`discussed above. Accordingly, Applicants request withdrawal of the rejection.
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`3) Although Chaudry states in paragraph 0057 that nebulizers for use with his
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`inhalable formulations “are not limited to, jet nebulizers (optionally sold with compressors),
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`ultrasonic nebulizers, and others,” one of ordinary skill in the art would not have concluded
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`based on Chaudry that the treprostinil formulation of his prophetic example 4 is adapted for
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`use in an ultrasonic nebulizer as claim 1 recites. Chaudry does not provide any documentary
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`evidence that any of his formulations, including the treprostinil formulation of his prophetic
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`example 4, can be used with any type of nebulizer, including an ultrasonic nebulizer. At the
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`same time, it is known that not every drug can be adapted for use in an ultrasonic nebulizer
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`because “[u]ltrasonic nebulizers ...may cause drug degradation,” see the abstract of the
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`enclosed reference, Rau, Respiratory Care, 2002, 47, 1257—1278. In view of the
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`unpredictability of drug administration via ultrasonic nebulizers, Example 2 of the
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`specification represents a surprising result because it provides experimental evidence that a
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`treprostinil solution can be successfully administered with an ultrasonic nebulizer.
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`Applicants emphasize that the combination of (a)_the claimed concentration of
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`treprostinilb) in a formulation adapted for an ultrasonic nebulizer, and c) which is free of
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`metacre_io_l_, resulted i_n_a_pharmaceuticallv acceptafie solution that could be used to deliver a
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`dosage_oftremstinil_by inhalation that was substantially more convenient to p_a_tients than
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`the only other available inhaledprostwclin on the market (i._e_., ilop_r_ost) at the time of f1]_ing.
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`This is shown in the enclosed copy of the Rule 132 Declaration of Dr. Rubin (submitted in
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`related application Ser. No. 12/591,200).
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`In sum, the PTO failed to establish aprimafacie case of obviousness at least for the
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`reasons discussed in this section. Accordingly, Applicants request withdrawal ofthe
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`rejection.
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`Claims 1—14 stand rejected as obvious over Chaudry (US Publication no.
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`2004/0265238) and further in view of Nebu—Tec (VENTA—NEB Operating Instructions
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`(2005)). Applicants respectfully traverse.
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`Atty. Dkt. No. 080618-1156
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`Appl. No. 13/469,854
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`Nebu-Tec does not remedy the discussed above deficiencies of Chaudry.
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`In
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`particular, Nebu-Tec does not provide any reason for selecting the particular treprostinil
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`concentration range of claim 1. Furthermore, Nebu-Tec does not provide any evidence that a
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`treprostinil solution can be administered via an ultrasonic nebulizer without treprostinil
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`degradation. Moreover, the cited references do not suggest the advantages reported by
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`patients in quality of life surveys as shown in the accompanying copy of Dr. Rubin’s Rule
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`132 Declaration.
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`In sum, because the PTO failed to establish aprimafacie case of
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`obviousness, Applicants request withdrawal of the rejection.
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`CONCLUSION
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`Applicants believe that the present application is in condition for allowance.
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`Favorable reconsideration ofthe application is respectfully requested. The Examiner is
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`invited to contact the undersigned by telephone if it is felt that a telephone interview would
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`advance the prosecution ofthe present application.
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`The Commissioner is hereby authorized to charge any additional fees which may be
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`required regarding this application under 37 C.F.R. §§ 1.16-1.17, or credit any overpayment,
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`to Deposit Account No. 19-0741. Should no proper payment be enclosed herewith, as by a
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`check being in the wrong amount, unsigned, post-dated, otherwise improper or informal or
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`even entirely missing or a credit card payment form being unsigned, providing incorrect
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`information resulting in a rejected credit card transaction, or even entirely missing, the
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`Commissioner is authorized to charge the unpaid amount to Deposit Account No. 19-0741.
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`If any extensions of time are needed for timely acceptance of papers submitted herewith,
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`Applicants hereby petition for such extension under 37 C.F.R. §1.136 and authorize payment
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`of any such extensions fees to Deposit Account No. 19-0741.
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`Respectfully submitted,
`
`By
`
`,
`
` Date January 4, 2013
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(415) 984-9810
`Facsimile:
`(415) 434-4507
`
`Alexey V. Saprién
`Agent for Applicants
`Registration No. 56,439
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