Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Horst OLSCHEWSKI et al.
`
`Title:
`
`TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`Appl. No.:
`
`13/469,854
`
`Filing Date:
`
`5/1112012
`
`Examiner:
`
`Art Unit:
`
`Sarah Elizabeth Townsley
`
`1629
`
`Confirmation Number:
`
`91 71
`
`AMENDMENT & REPLY UNDER 3 7 CFR § 1.111
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`This paper responds to the outstanding Non-Final Office Action dated October 3,
`
`2012. Applicants petition for extension of time to make this response timely.
`
`Amendments to the Specification begin on page 2 of this document.
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 3 of this document.
`
`Remarks begin on page 5 of this document.
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`4841-2970-8050.1
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`Amendments to the Specification:
`
`Please amend the specification as follows:
`
`Please replace paragraph 0072 with the following rewritten paragraph:
`
`All inhalations were performed with the OPTINEB® Optineb® ultrasonic nebulizer
`
`(Nebutec, Elsenfeld, Germany).
`
`Please replace paragraph 0078 with the following rewritten paragraph:
`
`Study iii) was a randomized, open-label, single blind study. The primary objective
`
`was to explore the shortest possible inhalation time for a 15µg dose of inhaled treprostinil. A
`
`total of 48 patients inhaled one dose of TRE during right heart catheter investigation. The
`
`drug was applied in 18, 9, 3, 2 or 1 breaths. The aerosol was generated by a pulsed ultrasonic
`
`nebulizer (VENT A-NEB®, Nebutec, Elsenfeld, Germany) in cycles consisting of 2 seconds
`
`aerosol production (pulse) and 4 seconds pause. The device included an opto-acoustical
`
`trigger for the patient to synchronize the inspiration to the end of the aerosol pulse, thereby
`
`providing exact dosage. The TRE dose of 15µg was either generated during 18 cycles
`
`(Optineb OPTINEB® filled with 1 OOµg/ml TRE, n=6), 9 cycles (200µg/ml TRE, n=6), 3
`
`cycles (600µg/ml TRE, n=21), 2 cycles (lOOOµg/ml TRE, n=7) or I cycle (2000µg/ml TRE,
`
`n=8). Hemodynamics and gas exchange were recorded for 120 - 180 minutes.
`
`Please replace paragraph 0085 with the following rewritten paragraph:
`
`Study iii) was performed with metacresol-free TRE solution, having no specific taste
`
`and smell. A total of 48 patients were enrolled. This study aimed at the reduction of
`
`inhalation time and aerosol volume needed for pulmonary drug delivery. A modified Optineb
`
`OPTINEB® inhalation device was programmed to produce a constant amount of aerosol
`
`during repeatable pulses of aerosol generation. With this device, treprostinil could be safely
`
`utilized up to a concentration of 2000µg/ml without considerable side effects. No
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`relationship of number or type of side effects to TRE concentration was observed. Reported
`
`side effects were mild transient cough (n=6), mild headache (n=2) and mild jaw pain (n= I).
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Listing of Claims:
`
`1. (original) A pharmaceutical formulation for inhalation comprising an aerosolable
`
`solution of treprostinil or a pharmaceutically acceptable salt thereof at a concentration from
`
`500 µg/ml to 2500 µg/ml adapted for use in an ultrasonic nebulizer, wherein the formulation
`
`is free of metacresol.
`
`2. (original) The pharmaceutical formulation for inhalation of claim 1, wherein the
`
`concentration of treprostinil or its pharmaceutically acceptable salt in the aerosolable solution
`
`is 600 µg/ml.
`
`3. (original) The pharmaceutical formulation for inhalation of claim 1, wherein the
`
`aerosolable solution has a volume that provides at least one aerosolized dose from 15 µg to
`
`90 µg of treprostinil or a pharmaceutically acceptable salt thereof.
`
`4. (original) The pharmaceutical formulation for inhalation of claim 1, wherein the
`
`aerosolable solution has a volume that provides several aerosolized doses sufficient to treat a
`
`patient for one day, wherein each dose is from 15 µg to 90 µg of treprostinil or a
`
`pharmaceutically acceptable salt thereof.
`
`5. (original) The pharmaceutical formulation for inhalation of claim 4, wherein the
`
`concentration of treprostinil or its pharmaceutically acceptable salt in the aerosolable solution
`
`is 600 µg/ml.
`
`6. (original) A component for an ultrasonic nebulizer comprising the formulation of
`
`claim 1.
`
`7. (original) A component for an ultrasonic nebulizer comprising the formulation of
`
`claim 2.
`
`8. (original) A component for an ultrasonic nebulizer comprising the formulation of
`
`claim 5.
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`9. (original) A kit for treating a patient, comprising
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`Atty. Dkt. No. 080618-1 156
`Appl. No. 13/469,854
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`(i) an ultrasonic nebulizer (a) adapted to receive a pharmaceutical formulation for
`
`inhalation comprising an aerosol able solution of treprostinil or a pharmaceutically acceptable
`
`salt thereof at a concentration from 500 µg/ml to 2500 µg/ml, wherein the formulation is free
`
`of metacresol and (b) adapted to administer a therapeutically effective single event dose of
`
`the formulation comprising from 15 µg to 90 µg of treprostinil or a pharmaceutically
`
`acceptable salt thereof by inhalation in 10 or less breaths;
`
`(ii) a pharmaceutical formulation for inhalation comprising an aerosolable solution of
`
`treprostinil or a pharmaceutically acceptable salt thereof at a concentration from 500 µg/ml to
`
`2500 µg/ml, wherein the formulation is free of metacresol; and
`
`(iii) instructions for a patient to use the kit to by administering a therapeutically
`
`effective single event dose of the formulation comprising from 15 µg to 90 µg of treprostinil
`
`or a pharmaceutically acceptable salt thereof by inhalation in 10 or less breaths.
`
`10. (original) The kit of claim 9, wherein the concentration oftreprostinil or its
`
`pharmaceutically acceptable salt in the aerosolable solution is 600 µg/ml.
`
`11. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
`
`administer a therapeutically effective single event dose of the formulation comprising from
`
`15 µg to 90 µg of treprostinil or a pharmaceutically acceptable salt thereof by inhalation in 3
`
`or less breaths.
`
`12. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
`
`administer a therapeutically effective single event dose of the formulation comprising from
`
`15 µg to 90 µg of treprostinil or a pharmaceutically acceptable salt thereof by inhalation in
`
`one breath.
`
`13. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
`
`administer the therapeutically effective single event dose of the formulation as droplets with
`
`a diameter less than about 5 microns.
`
`14. (original) The kit of claim 9, wherein the ultrasonic nebulizer is a pulsed
`
`ultrasonic nebulizer comprising an opto-acoustical trigger for the patient to synchronize
`
`inspiration with an aerosol pulse.
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`4841-2970-8050.1
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`REMARKS
`
`Applicants respectfully request reconsideration and allowance of the present
`
`application.
`
`Claims 1-14 are pending.
`
`CLAIMS ST A TUS
`
`SPECIFICATION
`
`Applicants have amended paragraphs 0072, 0078 and 0085 to address the issue
`
`regarding the use of trademarks raised by the PTO on pages 2-3 of the Office Action. No
`
`new matter has been added.
`
`CLAIM REJECTIONS UNDER 35 U.S.C. § 103(a)
`
`Claims 1-8 stand rejected as obvious over Chaudry (US Publication no.
`
`2004/0265238). Applicants respectfully traverse.
`
`The PTO failed establish a prima facie case of obviousness at least for each of the
`
`following independent reasons. Moreover, the unexpected results of a formulation having the
`
`particular claimed drug concentration range, which is adapted for use in an ultrasonic
`
`nebulizer and which lacks metacresol, would more than rebut any possible case of prima
`
`facie obviousness.
`
`1) At the time of filing of the presently claimed invention, one of ordinary skill in the
`
`art would have been motivated to include metacresol in a treprostinil formulation
`
`(notwithstanding that it is not mentioned in Chaudry) because the only FDA-approved and
`
`commercially available formulation of treprostinil at that time (for parenteral use) included
`metacresol (see http://remodulin.com/pdfs/remodulin-prescribinginformation.pdf); 1
`
`1 As explained in paragraphs 77-81 of the 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
`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
`
`aerosolable solution of treprostinil or a pharmaceutically acceptable salt thereof at a
`
`concentration from 500 µg/ml to 2500 µg/ml"; and
`
`3) One of ordinary skill in the art would not have arrived, based on Chaudry, at "an
`
`aerosolable solution of treprostinil or a pharmaceutically acceptable salt thereof at a
`
`concentration from 500 µg/ml to 2500 µg/ml adapted for use in an ultrasonic nebulizer."
`
`Applicants provide a more detailed discussion of each of these reasons below.
`
`1) As explained in the present specification, the present inventors performed two out
`
`of three initial clinical studies of inhalation formulations in an ultrasonic nebulizer with
`
`metacresol (see paragraphs 77-81 of the present specification). After patients twice reported
`
`foul taste (paragraph 80), they also tested solutions at the claimed concentration of
`
`treprostinil without metacresol. They found that, when treprostinil was formulated as
`
`claimed at a concentration range of 500 µg/ml to 2500 µg/ml for use in an ultrasonic
`
`nebulizer, the metacresol could be eliminated and a pharmaceutically stable and acceptable
`
`formulation for ultrasonic nebulization resulted. This is shown in the data in the present
`
`specification and further demonstrated by the FD A's approval of Tyvaso®, the first inhaled
`
`treprostinil product (see www.tyvaso.com). An invention based on the discovery of a
`
`hitherto unrecognized problem in the prior art (such as foul taste of the originally developed
`
`treprostinil formulation) may be unobvious, even though the solution to the problem, once
`
`recognized, is obvious. In re Sponnoble, 160 USPQ 23 7 (CCPA 1969).
`
`Furthermore, the present inventors unexpectedly discovered that removal of
`
`metacresol improved the arterial oxygen saturation in pulmonary hypertension patients
`
`receiving the inhalation formulation. As stated in paragraph 79, discussing the results of the
`
`second study which included metacresol, ''oxygen saturation was significantly decreased at a
`
`dose of 120 µg TRE in all 3 patients." By contrast, when metacresol was removed from the
`
`formulation in the third study, paragraph 80 states that the drop in oxygen saturation (Sa02)
`
`no longer occurred. Paragraph 80 further states that the present inventors attributed the drop
`
`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
`
`as follows:
`
`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`Treprostinil sodium
`
`0.1-10.0 mg/ml
`
`Sodium Chloride
`
`2.0-10.0 mg/ml
`
`Citric Hydroxide
`
`Citric Oxide
`
`Water
`
`q.s.
`
`q.s.
`
`q.s.
`
`Although Chaudry's range for treprostinil encompasses "500 µg/ml to 2500 µg/ml" recited in
`
`claim I, Chaudry does not teach or suggest the particular treprostinil concentration range of
`
`claim 1. To remedy the deficiencies of Chaudry, the PTO provides the following comments
`
`on page 4 of the Office Action:
`
`"As recognized by MPEP § 2144.05, where the claimed ranges "overlap or lie inside
`ranges disclosed by the prior art" a prima facie case of obviousness exists. In re
`Wertheim, 541F.2d257,191USPQ90 (CCPA 1976); In re Woodruff, 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 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)."
`
`The treprostinil concentration range recited in claim I is non-obvious over Chaudry's range
`
`at least because this particular range is critical for providing a dose of 15 to 90 µg in a few
`
`breaths, e.g., in 10 breaths or less, in a single inhalation event. In this regard, Applicants
`
`quote from the PTO's citation of In re Aller: "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." (Bold
`
`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
`
`Example 2, paragraphs 0068-0095. This range of concentration enables the patient to receive
`
`an effective dose for treating pulmonary hypertension in a smaller number of breaths
`
`compared to the only other available inhaled prostacyclin that was available at the time of
`
`filing, which resulted in enhanced quality of life for the patients. As evidence supporting this
`
`point, Applicants attach a copy of the Rule 132 Declaration of Dr. Rubin submitted in related
`
`application Ser. No. 12/591,200.
`
`One of ordinary skill in the art would not be able to arrive at the treprostinil
`
`concentration range recited in claim 1 based on Chaudry at least for the following reasons:
`
`A) although Chaudry relates to inhalation formulations, Chaudry does not provide any
`
`evidence that any of compounds disclosed in his paragraphs 0022-0027 can in fact be
`
`administered by inhalation. All of Chaudry's working examples, including the one for
`
`treprostinil, are prophetic.
`
`B) Chaudry does not provide any guidance regarding relationship between dosages
`
`and drug concentrations for any of his inhalation formulations. In other words, one of
`
`ordinary skill in the art would not know based on Chaudry what particular drug concentration
`
`to use to deliver a particular drug dose. More specifically, one of ordinary skill in the art
`
`would not know based on Chaudry what particular treprostinil concentration to use to deliver
`
`a particular dose of treprostinil. As shown in the present specification's clinical studies, it is
`
`the local effect of drug amount deposited in the lungs, rather than plasma concentration
`
`resulting from inhalation, which appears primarily responsible for the efficacy in pulmonary
`
`hypertension patients.
`
`C) Based on Chaudry, one of ordinary skill in the art would not conclude that
`
`treprostinil can be administered in a dose of 15 to 90 µg in a few breaths, e.g. in 10 breaths
`
`or less, in a single inhalation event because according to Chaudry, the smallest time for an
`
`individual inhalation event or session is 3 minutes, see e.g. paragraph 0067, which
`
`corresponds to 30-42 breaths taking into account that a normal respiratory rate for an adult
`
`human at rest is 10-14 breaths per minute. Thus, one of ordinary skill in the art would have
`
`no reason to optimize Chaudry's range of 0.1-10.0 mg/ml in order to arrive at the particular
`
`treprostinil range recited in claim 1.
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`In sum, the PTO failed to establish a prima facie case of obviousness for the reasons
`
`discussed above. Accordingly, Applicants request withdrawal of the rejection.
`
`3) Although Chaudry states in paragraph 0057 that nebulizers for use with his
`
`inhalable formulations "are not limited to, jet nebulizers (optionally sold with compressors),
`
`ultrasonic nebulizers, and others," one of ordinary skill in the art would not have concluded
`
`based on Chaudry that the treprostinil formulation of his prophetic example 4 is adapted for
`
`use in an ultrasonic nebulizer as claim I recites. Chaudry does not provide any documentary
`
`evidence that any of his formulations, including the treprostinil formulation of his prophetic
`
`example 4, can be used with any type of nebulizer, including an ultrasonic nebulizer. At the
`
`same time, it is known that not every drug can be adapted for use in an ultrasonic nebulizer
`
`because "[u]ltrasonic nebulizers ... may cause drug degradation," see the abstract of the
`
`enclosed reference, Rau, Respiratory Care, 2002, 47, 1257-1278. In view of the
`
`unpredictability of drug administration via ultrasonic nebulizers, Example 2 of the
`
`specification represents a surprising result because it provides experimental evidence that a
`
`treprostinil solution can be successfully administered with an ultrasonic nebulizer.
`
`Applicants emphasize that the combination of (a) the claimed concentration of
`
`treprostinil, (b) in a formulation adapted for an ultrasonic nebulizer, and (c) which is free of
`
`metacresol, resulted in a pharmaceutically acceptable solution that could be used to deliver a
`
`dosage of treprostinil by inhalation that was substantially more convenient to patients than
`
`the only other available inhaled prostacyclin on the market (i.e., iloprost) at the time of filing.
`
`This is shown in the enclosed copy of the Rule 132 Declaration of Dr. Rubin (submitted in
`
`related application Ser. No. 12/591,200).
`
`In sum, the PTO failed to establish a prima facie case of obviousness at least for the
`
`reasons discussed in this section. Accordingly, Applicants request withdrawal of the
`
`rejection.
`
`Claims 1-14 stand rejected as obvious over Chaudry (US Publication no.
`
`2004/0265238) and further in view of Nebu-Tec (VENT A-NEB Operating Instructions
`
`(2005)). Applicants respectfully traverse.
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`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
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`Nebu-Tec does not remedy the discussed above deficiencies of Chaudry. In
`
`particular, Nebu-Tec does not provide any reason for selecting the particular treprostinil
`
`concentration range of claim 1. Furthermore, Nebu-Tec does not provide any evidence that a
`
`treprostinil solution can be administered via an ultrasonic nebulizer without treprostinil
`
`degradation. Moreover, the cited references do not suggest the advantages reported by
`
`patients in quality of life surveys as shown in the accompanying copy of Dr. Rubin's Rule
`
`132 Declaration. In sum, because the PTO failed to establish a prima facie case of
`
`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
`
`Applicants believe that the present application is in condition for allowance.
`
`Favorable reconsideration of the application is respectfully requested. The Examiner is
`
`invited to contact the undersigned by telephone if it is felt that a telephone interview would
`
`advance the prosecution of the present application.
`
`The Commissioner is hereby authorized to charge any additional fees which may be
`
`required regarding this application under 37 C.F.R. §§ 1.16-1.17, or credit any overpayment,
`
`to Deposit Account No. 19-0741. Should no proper payment be enclosed herewith, as by a
`
`check being in the wrong amount, unsigned, post-dated, otherwise improper or informal or
`
`even entirely missing or a credit card payment form being unsigned, providing incorrect
`
`information resulting in a rejected credit card transaction, or even entirely missing, the
`
`Commissioner is authorized to charge the unpaid amount to Deposit Account No. 19-0741.
`
`If any extensions of time are needed for timely acceptance of papers submitted herewith,
`
`Applicants hereby petition for such extension under 37 C.F.R. § 1.136 and authorize payment
`
`of any such extensions fees to Deposit Account No. 19-0741.
`
`Respectfully submitted,
`
`Date January 4, 2013
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`( 415) 984-9810
`Facsimile:
`(415) 434-4507
`
`By~~~=-~~z::::.::::z:::::_~
`Alexey V. Sap~n
`
`Agent for Applicants
`Registration No. 56,439
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`4841-2970-8050 .1
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`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Horst OLSCHEWSKI et al.
`
`Title:
`
`TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Appl. No.:
`
`12/591,200
`
`Filing Date:
`
`11112/2009
`
`Examiner:
`
`Sara Elizabeth Townsley
`
`Art Unit:
`
`Confirmation
`Number:
`
`1629
`
`4093
`
`DECLARATION UNDER 37 C.F.R. § 1.132 OF LEWIS RUBIN, M.D.
`
`L Lewis Rubin, do hereby declare:
`
`1.
`
`I am the Emeritus Professor of Medicine and the Emeritus Director of the
`
`Pulmonary and Critical Care Division of the University of California, San Diego School of
`
`Medicine.
`
`2.
`
`I have extensive experience and background in the field of treating pulmonary
`
`hypertension, including a 8.A. from Yeshiva University and an M.D. from Albert Einstein College
`
`of Medicine. My Curriculum Vitae attached as Appendix A provides additional details on my
`
`qualifications and experience.
`
`3.
`
`4.
`
`I am a citizen of the United States of America.
`
`I am a co-inventor of the subject matter claimed in U.S. patent application Ser.
`
`No. 12/591,200.
`
`4836-5125-4287. l
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`5.
`
`I am a paid consultant of United Therapeutics. the assignee of the above-identified
`
`patent application.
`
`The Cited References
`
`6.
`
`I am familiar with the Office Action dated Dec. 22. 2011 in U.S. patent
`
`application Ser. No. 12/591,200 and the references cited therein.
`
`7.
`
`I have reviewed US 2004/0265238 (Chaudry), including prophetic Ex. 4, cited by
`
`the Office Action for teaching inhalation of treprostinil. Prophetic Ex. 4, in its entirety, reads as
`
`follows:
`
`"Example 4
`
`[0097]
`
`Treprostinil sodium 0.1-10.0 mg/ml Sodium Chloride 2.0-10.0 mg/ml Sodium Hydroxide
`
`q.s. Citric Acid q.s. Water q.s.
`
`[0098] Example 4 is a prophetic example of a formulation comprising the vasodilator
`
`epoprostenol [sic: treprostinil]. Sodium chloride may be added to the solution to adjust
`
`tonicity, and sodium hydroxide and citric acid are added to adjust the pH of the solution.
`
`The solution of Example 4 may be made by methods known to those of ordinary skill in
`
`the art."
`
`8.
`
`This prophetic example of Chaudry merely provides a possible pre-inhalation
`
`solution oftreprostinil with a drug concentration range of 0.1 to 10.0 mg/ml treprostinl.
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`Providing a pre-inhalation solution with a broad concentration range does not enable one to
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`determine what dosage of drug should be given to a patient with a particular disease. Dosage is
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`determined by how much of the solution is converted to aerosol. as well as how much of the
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`aerosol is then inspired by the patient if a nebulizer is used. In addition, the type of nebulizer
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`used, together with other factors, such as whether the solution is further diluted with propellant in
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`the formation of aerosol, and the length of time or number of breaths per event, would further
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`impact the dosage of drug that a patient is given.
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`9.
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`Not only is there no dosage information, but there is no data in Chaudry that
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`would provide any reasonable expectation that one could treat a patient suffering from
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`pulmonary hypertension with the proposed treprostinil solution.
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`10.
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`I have also reviewed U.S. Patent No. 6,521,212 (Cloutier). which shows that
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`treprostinil was administered to sheep in a model of pulmonary hypertension with a continuous
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`nebulizer over a period of 30 to 60 minutes. This patent states that '·aerosolized UT-15
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`[treprostinilJ can be given in high doses without significant non-lung effects". See Exhibit B.
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`However, Cloutier does not suggest that a pulmonary hypertension patient can be dosed with
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`treprostinil or a salt thereof using an ultrasonic nebulizer at a dose of 15 to 90 micrograms in one
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`single event dose of 10 breaths or less.
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`11.
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`I have also reviewed Byron, Proc. Am. Thorac. Socy., (1), pp. 321-328 (2004),
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`cited by the Office Action for teaching certain types of inhalers. Byron is a reference discussing
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`various devices for delivery of drugs by inhalation, including metered dose inhalers. Byron fails
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`to provide any dosage information that would address the deficiencies noted above in Chaudry
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`and Cloutier.
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`12.
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`I have also reviewed U.S. Patent No. 6,357,671 (Cewers), cited by the Office
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`Action for teaching ultrasonic nebulizers. Cewers discusses an improved type of ultrasonic
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`nebulizer. As with the other cited references discussed above, Cewers also fails to provide any
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`dosage information that would address the deficiencies of the other references in relation to the
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`present invention.
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`Prior literature taught away from present inventi9_r!
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`13.
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`In my opinion, a person in the pulmonary hypertension field would be led away
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`from the present invention by the prior literature. At the time of filing our patent application, the
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`only FDA-approved prostacyclin-type drug that could be given in an inhalable form was iloprost,
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`marketed as Ventavis®. The following excerpt from the FDA approved label for inhaled iloprost
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`shows an event dose of up to only 5 micrograms and 6 to 9 events per day:
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`DOSAGE A:"D .-\D:.\Il:"ISTR.-\ TIO~
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`'i entaYis 1s mtended to be inhaled using either of two pulmonary drug deliYery de\·ices:
`rhe I-nebt AADt Svstem or the Prodose~ AADt Svr,,tem. The first inhaled dose :;houlcl
`.
`.
`be 2.5 mcg (a-. defo·ere-d ;1t the mouthpiece> If rlus dose 1s well tol.:-nted. do<>ing :;hould
`be mcrea<,ed to 5.0 mcg ::md mamr::uned ar that dose: otherw1<>e mamtam tlle dose ar 2.5
`mcg Ventans should be f<lken 6 to 9 times per cby (no more than once en•ry 2 hours)
`dunng waking hours. according ro iudn-idual need :md toler;ib1hty. The maximum daily
`dose evahrnted m clmical 5tud1es wa.:, -l5 mcg (5 mcg 9 times per day).
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`I 4.
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`The side effects caused by prostacyclin-type drugs would suggest that it is better
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`to have smaller per event dosing and more events per day, as in the case of iloprost. In other
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`words, due to the risk of side effects at higher doses, the pathway suggested by iloprost was to
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`reduce dosage per event and increase number of events per day.
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`15.
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`As explained in the present specification (paragraph 90), we performed a clinical
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`trial using a relatively high single event aerosolized dose of 15 micrograms of treprostinil in one
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`breath. This drug administration with a single breath induced pulmonary vasodilation for longer
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`than 3 hours compared to placebo inhalation. Side effects were minor, of low frequency and not
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`related to drug concentration. The fact that one breath of 15 micrograms of treprostinil could
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`provide such a long duration of action in a pulmonary hypertension patient was unexpected.
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`Because of the duration of action, as explained below, there was a measurable benefit in patient
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`quality of life based on the reduced number of events needed to treat pulmonary hypertension
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`patients using an ultrasonic nebulizer to deliver a relatively high dose of treprostinil compared to
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`iloprost in one event.
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`16. We also performed clinical testing at a dose of up to 90 micrograms treprostinil
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`per event in less than 10 breaths per event. which the pulmonary hypertension patients could also
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`tolerate with minimal side effects as shown in the present specification (paragraph 89). I was
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`surprised that such high concentrations of treprostinil were so well tolerated by pulmonary
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`hypertension patients, especially in light of the prior literature and experience with iloprost
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`discussed above.
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`17.
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`These surprising findings led to an FDA-approved label for inhaled treprostinil,
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`showing administration with a target dose of up to 54 micrograms per event and only 4 events
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`(versus 6 to 9 for iloprost) per day:
`
`---------DOSAGE . .\.. 'D .U>~Il="lS TR\ TIO:"-------(cid:173)
`C ;;e onh-w:ith tlie T.,-,_·a;o ~a:a:1011 Svs:en:.. (2.:)
`Admmi~ter undrlu:ed ~1~ 'iu-ppl..ted.. . .:... ~iugle brea:h of T)YJ':iO idiw:·s
`appro:-n:n.·m~ly 6 :neg o: rr~pros!!::.iL ._::.: ·1
`Admimster ill~ s.cpa:rare trea::u:en; ~e'. ~1om eJ ~h day appr~x.i.irutdy :ou:
`hou:~ apar~ dunng wab.Gg hour; 1 ::'.I'•
`::niual dos.1ge: 3 brea:h~ [18 m.::g] per ::-ea:n:.en: se~;ior:. :: : breatbs are
`nor rolerated reduce re 1 or::' brea:k. C. l)
`Dosage iliculd be :.r:::re;!sed by JL addir~on.a.I 3 brea:h~ at apprcxin:.it~iy
`1-::' we.el: in:eP:al;. tf wle:a:ed C.: ·'
`Titrate tc target n:nlltenaue do; age of~ b:e:r.h~ ~r ~ ~ u::.:: g pe:
`trea:meu: ".e>.siot: a; to~era:t-1. C.1)
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`18.
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`I also am aware of a clinical trial in which pulmonary hypertension patients were
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`switched from inhaled iloprost to inhaled treprostinil, which is also discussed in the present
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`specification at paragraph 87:
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`·'[0087) In study i) it was shown that the inhalation of treprostinil and iloprost in similar
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`doses resulted in a comparable maximum pulmonary vasodilatory effect. However, marked
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`differences in the response profile were noted. The onset of the pulmonary vasodilatory effect of
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`inhaled treprostinil was delayed compared to iloprost, but lasted considerably longer, with the
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`PVR decrease continuing beyond the one-hour observation period. Although the average dose of
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`treprostinil was higher than the iloprost dose, no systemic effects were noted after treprostinil
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`inhalation, whereas flush and transient SAP decrease, accompanied by more prominent cardiac
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`output increase, occurred after iloprost inhalation. Such side effects were more prominent than
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`in previous studies with inhaled iloprost. This may have been caused by the fact that the iloprost
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`dose used in this study was 50% higher than the recommended single inhalation dose (5 µg) and
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`that the preceding treprostinil inhalation may have added to the systemic side effects caused by
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`the iloprost inhalation. Surprisingly. with TRE there was no such systemic side effect, although
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`the average effect on PVR was as potent as with iloprost.'"
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`19.
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`In addition, some patients were asked to answer the following question as part of
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`a quality of life questionnaire: "'how easy or difficult is it to plan when you will use the
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`medication each time?'\ and each patient in the study responded with a grade of I (extremely
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`difficult), 2 (very difficult), 3 (difficult), 4 (somewhat easy), 5 (easy), 6 (very easy), and 7
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`(extremely easy). The 71 subjects who answered this question both while taking inhaled iloprost
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`and then again after switching to inhaled treprostinil responded with an average score of 3.6
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`(between difficult and some