Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
`
`lN THE UNlTE'J) STATES PATENT AND TRAlJEMARK 0Ffi1CE
`
`Applicant:
`
`Horst OLSCHEWSKI et al.
`
`Title:
`
`TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`Appl. No.:
`
`13/469,854
`
`Filing Date:
`
`5/11/2012
`
`Examiner:
`
`Art Unit
`
`Sarah Elizabeth Townsley
`
`1629
`
`Confirmation Number:
`
`9171
`
`REPLY UNDER 37 CFR § 1.116
`
`Mail Stop AF
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`This paper responds to the outstanding Final Office Action dated March 13, 2014 and
`
`a telephonic interview that Applicants' representative, Alexey Saprigin (Reg.# 56,439) and
`
`Examiner Townsley conducted on May 21, 2014.
`
`Amendments to the Specification begin on page 2 of this document.
`
`Amendments to the Claims are reflected in the listing of claims \vhich begins on
`
`page 3 of this document.
`
`Remarks begin on page 5 of this document
`
`4836-9773-59631
`
`-1-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 1 of 11
`
`

`

`Atty. Dkt No. 080618-1156
`Appl. No. 13/469,854
`
`Amendments to the Specification:
`
`Please amend the specification as follows:
`
`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 15 µg dose of inhaled treprostiniL A
`
`total of 48 patients inhaled one dose of TRE during right heart catheter investigation. The
`
`drng was applied in 18, 9, 3, 2 or 1 breaths. The aerosol was generated by a pulsed ultrasonic
`
`nebuliz.er (Optineb® VENTA NEB®, Nebutec, Elsenfold, Germany) in cycles consisting of2
`
`seconds aerosol production (pulse) and 4 seconds pause. The device included an opto(cid:173)
`
`acoustical trigger for the patient to synchronize the inspiration to the end of the aerosol pulse,
`
`thereby providing exact dosage. The TRE dose of 15 µg was either generated during 18 cycles
`
`(Optineb filled with lOOµg/mI 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 l cycle (2000µg/ml TRE, ff''8).
`
`Hemodynamics and gas exchange were recorded for 120 - 180 minutes.
`
`4836-9773-5963.'
`
`-2-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 2 of 11
`
`

`

`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
`
`Listing of Claims:
`
`l-8. (Canceled)
`
`9. (currently amended) A kit fix treating a patient, comprising
`
`(i) an ultrasonic nebulizer (a} adapted to receive a pharmaceutical formulation fiJr
`
`inhalation comprising an aerosolable solution of treprostinil or a phmmaceutically acceptable
`
`salt thereof at a concentration from 500 µg/ml to 2500 µg/ml, wherein the fommlation is fre.e
`
`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 -l-0 £(Lor less breaths;
`
`(ii) a pharmaceutical formulation for inhalation comprising an aerosolable solution of
`
`treprostinii 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
`
`effoctive single event dose of the fonnulation comprising from 15 µg to 90 µg oftreprostinil
`
`or a pharmaceutically acceptable salt thereof by inhalation in ..f-0 ~.Q __ or less breaths.
`
`10. (original) The kit ofclaim 9, wherein the concentration oftreprostinii or its
`
`pharmaceutically acceptable salt in the aerosolabk solution is 600 µg/m L
`
`11. (original) The kit of claim 9, wherein the ultrasonic nebulizer is adapted to
`
`administer a therapeutically effective single event dose of the fonnulation comprising from 15
`
`µg to 90 µg of treprostinil or a phammceutically 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 phammceuticaHy acceptable salt thereof by inhalation in one
`
`breath.
`
`4836-·9773--5963.1
`
`-3-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 3 of 11
`
`

`

`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
`
`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 nebuHzer comprising an opto-acoustical trigger for the patient to synchronize
`
`inspiration with an aerosol pulse.
`
`4836-9773-5963.1
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 4 of 11
`
`

`

`Atty. Dkt No. 080618-1156
`Appl. No. 13/469,854
`
`REMARKS
`
`Applicants respectfully request reconsideration and allowance of the present
`
`application.
`
`CLAIMS STATUS
`
`Applicants have canceled claims t -8, to present the claimed invention in a clearer
`
`manner. Applicants reserve the right to file one or more continuing applications directed to
`
`the subject matter of the canceled claims. Claim 9 is amended to recite that each event is
`
`administered in 20 or less breaths, support for which can be found in paragraph 45. No new
`
`matter has been added.
`
`After the amendment, claims 9-14 are pending.
`
`The PTO should enter the present amendment because it merely cancels claims and
`
`raises no new issues.
`
`SPECIFICATION AMEND.1\.1ENT
`
`Applicants have amended paragraph 0078 to correct an inadvertent typographical
`
`error. Support for the amendment may be fi.mnd in paragraph 0072 and in the remaining text
`
`of paragraph 0078. In particular, paragraph 0072 teaches that in Example 2, to which
`
`paragraph 0078 belongs, "AH inhalations were perfonned with the Optineb® ultrasonic
`
`nebulizer (Nebutec, Elsenfeld, Germany)." Furthermore, paragraph 0078 states as follows:
`
`"The TRE dose of 15 ~ig was either generated during 18 cycles (Optineb filled with 1 OOµg/m I
`
`TRE, n=6), 9 cycles (200µg/mI TRE, n=6), 3 cycles (600µg/m1 TRE, n=21), 2 cycles
`
`(1 OOOµg/ml TRE, n=7) or 1 cycle (2000µg/ml TRE, n=8)."
`
`wiA Y 21 ST INTERVIEW
`
`Applicants thank the Examiner for the interview. During the interview, among other
`
`things, Applicants' representative explained the Examiner that Nebu-Tec nebulizer is not
`
`compatible with treprostiniL This argument in a greater detail may be found below.
`
`4836-9773-5963. i
`
`-5-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 5 of 11
`
`

`

`Atty. Dkt No. 080618-1156
`Appl. No, 13/469,854
`
`CLAIM REJECTIONS UNDER 35 U.S.C. § l03(a)
`
`Claims 1-8 stand rejected as obvious over Chaudry (US Publication no.
`
`2004/0265238). Applicants respectfully traverse.
`
`Applicants believe that the revised claim set obviates the rejection.
`
`Claims l- l 4 stand rejected as obvious over Chaudry (US Publication no.
`
`2004/0265238) and further in view of Ne bu-Tee (VENTA-NEB Operating Instructions
`
`(2005)). Applicants respectfully traverse.
`
`As for claims 1-8, Applicants believe that the revised claim set obviates the rejection.
`
`As fiJr claims 9-14, the PTO failed to establish aprimafacie case of obviousness at
`
`least because one of ordinary skill in the art would not have arrived at "'(i) an ultrasonic
`
`nebulizer (a) adapted to receive a phannaceJJtl.9-5±.Lformulation for inhalation compr!_~fag __ ~n
`
`aerosolable solution of treQIQ_~tiniLm a pharmaceutically accept~Jdj_!',? __ §J~J_t_thereof at a
`
`concentrationJr.Qm __ ~OO µg/ml to 2500 µg/ml, ... (b) 5±.Q_~pted to administer a therapey_tjs_~J_ly
`
`~ff.~_9-ih:'.~ single event dose of the fofl't!_i,!l5:!:.HQ.D- comprising from 15 µg to ~QJJ,g _ _gJtreprostinil
`
`or a pham1aceutic_~Hy_acceptable salt thereof by inhalation in 20 or less breaths" based on the
`
`cited references.
`
`The VENT A-NEB document teaches a nebulizer adapted for VENTA VIS® (iloprost)
`
`inhalation, see e.g. the front page of the VENTA-NEB document VENTAVIS® is an
`
`inhalation solution of iloprost (see the enclosed documents: a) "Highlights of Prescribing
`
`lnfonnation" (US prescription information for VEN TA VIS® and b) "Annex L Summary of
`
`Product Characteristics (European prescribing infomiation for VENT A VIS®). According to
`
`these prescribing documents, \lENTA VIS® is available only in ampules with 10 mcg/mL and
`
`20 mcg/mL ln the US and in ampules with 10 mcg/mL in Europe. This means that the
`
`highest drug concentration for which the nebulizer from the VENTA-NEB document may
`
`have been adapted is 20 mcg/mL Applicants respectfully submit that the pending claims
`
`recite "a concentration from 500 µg/ml to 2500 p.g/ml" for treprostinil. Thus, the lowest
`concentration for treprostinU recited in the pending claims is ;&~jmS'.§ __ l;t.l.gbS'.r than the highest
`
`-6-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 6 of 11
`
`

`

`Atty. Dkt. No. 080618-1156
`AppL No. 13/469,854
`
`concentration for which the nebulizer from the VENTA-NEB document may be used. One of
`
`ordinary skill in the art would not have predicted or concluded with a reasonable expectation
`
`of success that the nebulizer from the VENT A-NEB document could be successfully used for
`
`administering treprostinil solution having "a concentration from 500 µg/ml to 2500 µg/ml"
`
`recited in the pending claims because very high drug concentrations, such as "a concentration
`
`from 500 µg/ml to 2500 µg/mi" for treprostinil recited in the pending claims, may make
`
`aerosolization for ultrasonic nebulizers inefficient or even impossible due to physical
`
`properties resulting from high drug concentration, such as foaming. See e.g. p. 601 right
`
`column, first full paragraph of the enclosed reference, Labiris and Dolovich, Br. J. Clin.
`
`Pharmacol, 56, 600-612: "high drug concentrations may decrease the drug output with some
`nebulizers; colomycin at concentrations > 75 :mg mr1 foams in all nebulizers, especially
`ultrasonic ones, making aerosolization of the drug ven: inefficient if not im.11ossible [8]."
`
`(emphasis added)
`
`Thus, in view of the teachings of Lab iris, one of ordinary skill in the art would not be
`
`able to make the required finding regarding a reasonable degree of success/predictability of
`
`the PTO's proposed combination, even assuming there was a motivation to incorporate the
`
`other limitations of the present claims. And that is just one of several unpredictable variables
`
`relating to the question of whether the nebulizer could even generate an aerosol based on such
`
`a high concentration of an acidic drug. Further complicating variables that would have
`
`prevented a reasonable expectation of success include whether or not the patients would have
`
`been able to tolerate the taste and acidity of a higher concentration of drug in the aerosol, as
`
`well as how the aerosol would have distributed within the patient's lung. 1n fact, the
`
`inventors had to ultimately remove one ingredient, metacresol, in order to obtain a nebulizer
`
`system that could be tolerated by patients.
`
`For the record, in view of the teachings ofLabiris, one of ordinary skill in the art
`
`would not have had a motivation to combine Chaudry and the VENTA-NEB document
`
`because in Example 4, Chaudry teaches a concentration of treprostinil sodium to be 0.1-10.0
`
`rng/m l ( l 00-10000 µg/ml), while the highest drug concentration for which the nebulizer from
`
`the VENT A-NEB document may have been adapted is only 20 mcg/mL
`
`Thus, one of ordinary skill in the art would not have arrived at "(i) an ultrasonic
`
`nebulizer (a) adapted to receive a pharmaceutical formulation for inhalation comprising an
`
`4836-9773-5963.1
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 7 of 11
`
`

`

`Atty. Dkt No. 080618-1156
`Appl. No. 13/469,854
`
`!'!~rn~_Q1'!.bJ£_~_QJJJti@ __ Qf1!:~P-rn~tlnH __ QL1LP!:rn,rm!'!9-£1lti~;1Uy_;19-~~P-11!bJ£ __ ~_~JUh~.r_~QL?1J!
`concentration from 500 µg/ml to 2500 µg/mL ... (b) adapted to administer a therapeutically
`
`effective single event dose of the formulation comprising from 15 µg to 90 µg of treprostinil
`
`or a pharmaceuticallv acceptable salt thereof by inhalation in 20 or less breaths" based on the
`
`cited references.
`
`Applicants respectfully submit that the fact that the data in the specification's
`Example 2 demonstrating that a solution having a concentration oftreprostinil within the
`
`range from 500 t1g/ml to 2500 µg/m1, such as 600 µg/ml, l 000 µg/ml and 2000 µg/ml, can be
`
`efficiently aerosolized by an ultrasonic nebuiizer represents surprising results that could not
`
`be expected based on Chaudry and the VENTA-NEB document.
`
`In addition to the unexpected results, the PTO should consider other objective indicia
`
`of non~obviousness, such as commercial success of the presently claimed invention. In this
`
`regard, Applicants bring the PTO's attention to Leo Pharmaceutical Products, Ltd. v. Teresa
`
`Stanek Rea (Fed. Cir. 2013), ·which says as follows (emphasis supplied):
`
`In addition to evidence of unexpected results, Leo Pharmaceuticals provided other
`objective indicia of non- obviousness. For example, the commercial success of Leo
`Pharmaceutical's Tadonex® ointment is a testament to the improved properties of the
`'013 patent's claimed invention. Taclonex® is the first FDA-approved drng to
`combine vitamin D and corticosteroids into a single for- mulation for topical
`application. While FDA approv~Ul'.J!.Qt~~S'.l~!.ITI_inative of nonobviousness, it can be
`relevant in evaluating th~ __ Q_pj£9-1is_~_ indicia of nonobviousness. See Knoll PhqnzL:3:;_Q,_,.
`Lnr:,_J:~,]j~_m, __ fharm. USA, Inc., 367 F.3d 1381, 1385 (Fed. Cir. ___ :fQQ1}, __ H£re, FDA
`approval highlights that Leo Pharmaceutical~~--fQ!I.tHtl!'J.tion is trulv storage stable,
`something that the prior '!.It __ fmnrnl§!)gns did not achieve.
`
`ln this regard, Applicants submit a plot obtained from an independent tracking
`
`organization that compares US inhaled prostacyclin market shares for Ventavis®, which is an
`
`inhalation solution containing iloprost fommlated for inhalation via I-neb® AAD® (Adaptive
`
`Aerosol Delivery) System, and Tyvaso®, which is a fbrmulation oftreprostinil intended for
`
`administration by oral inhalation using the Optineb-ir device,
`
`4836-9773-5963.1
`
`-8-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 8 of 11
`
`

`

`Atty. Dkt. No. 080618-1156
`Appl. No. 13i469,854
`
`US Inhaled Prostacyclin Market Share
`100
`
`80
`
`60
`
`QJ
`&... ro
`..c
`V')
`tj
`~
`!I... 40
`ffl
`:E
`'#. 20
`
`l
`
`I
`
`-Ventavis
`-Tyvaso
`
`0
`
`Sept. Sept. Sept. Sept. Sept.
`2009 2010 2011 2012 2013
`
`Tyvaso was approved in the US around July 30, 2009, whereas Ventavis was
`
`approved in the US around Dec. 29, 2005. Despite Ventavis' long presence on the US market
`
`before the launch ofTyvaso, Tyvaso immediately took away the majority of the US market
`
`for inhaled prostacyclins from Ventavis in a single year. During the time period of Sept. 2009
`
`to Sept 20 l 0 when the majority of this rapid sales growth occurred for Tyvaso, the assignee
`
`of the present application (who markets Tyvaso) had an average 25.0% share of sales
`
`representative contacts in the pulmonary hypertension market compared to 30.7% share of
`
`sales representative contacts for Actelion, who markets Ventavis. IhlJ~_,__I)YJ!§O enjoyed
`
`trem~ndQ.Y..$.._.9-Qff1mercial success during this period despite Q.~ing_.mr!d<eted with a
`
`substantially lower share of pulmon(!r.yJJ.YP-~ITS(rn~ion sales representatives. This represents a
`
`dramatic case of commercial success that is attributable directly to the differences of the
`
`claimed invention over the prior art
`
`As previously explained in the Rule 132 Declaration of Dr. Rubin submitted in the
`
`child Application no. 12/591,200 on May 23, 2012, patients who used both Ventavis and
`
`4836-·9773-·5983.1
`
`-9-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 9 of 11
`
`

`

`Atty. Dkt. No. 080618-1156
`Appl. No. 13/469,854
`
`Tyvaso reported statistically significant higher satisfaction based on Tyvaso's ease of use in
`
`quality of life questionnaires, which results directly from the more convenient dosing
`
`reflected in the Tyvaso label and recited in the instant claims. Thus, there is a clear nexus
`
`between the commercial success of Tyvaso and the present claims, confirmed by the above
`
`market share data and the patient satisfaction data reported by Dr. Rubin in his Rule 132
`
`Declaration.
`
`As stated in Lea Pharmaceuticals v. Rea (Fed. Cir. 2013), in which the Federal Circuit
`
`reversed the Board for finding a combination pharmaceutical invention obvious:
`
`Whether before the Board or a court, this court has emphasized that consideration of
`the objective indicia is part of the whole obviousness analysis, not just an
`afte11hought. See Cyclobenzaprine, 676 F.3d at 1075-76 (A fact finder "may not defer
`examination of the objective considerations until after the fact finder makes an
`obviousness finding." (quoting Stratojlex, Inc. v. Aeroquip Corp., 713 F.2d 1530 (Fed.
`Cir. 1983))).
`
`More specifically, the court found:
`
`While FDA approval is not determinative of nonobviousness, it can be relevant in
`evaluating the objective indicia of nonobviousness. See Knoll Pharrn. Co., inc. v.
`Teva. Pharm. USA, Inc., 367 F.3d 1381, 1385 (Fed. Cir. 2004). Here, FDA approval
`highlights that Leo Pharmaceutical's fonnulation is truly storage stable, something
`that the prior art fonnulations did not achieve.
`
`As in Leo, the FDA approval ofTyvaso's more convenient dosing regimen is
`
`probative evidence of unobviousness, showing "something that the prior art formulations did
`
`not achieve." Iloprost (Ventavis), while it achieved FDA approval, has been far less
`
`successful because of the more convenient dosing regimen that was surprisingly possible for
`
`treprostinil (Tyvaso). As Dr. Rubin explained in his Rule 132 Declaration, which has not
`
`been rebutted by the PTO, one of ordinary skill in the art would not have expected to be
`
`successful at achieving the approved dosage regimen ofTyvaso based on a variety of factors,
`
`including unknown effocts of high treprostinil concentration in the solution to be aerosolized,
`
`number of breaths per event, and potential side effects resulting from higher drug doses.
`
`Given the negative results ofiloprost, these results are unexpected in Dr. Rubin's opinion.
`
`4836-9773-5963.1
`
`-10-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 10 of 11
`
`

`

`ln sum, because of the reasons discussed above, Applicants request withdrawal of the
`
`rejection.
`
`Atty. Dkt No. 080618-1156
`Appl. No. 13/469,854
`
`CONCLUSION
`
`Applicants believe that the present application is in condition fix allowance.
`
`Favorable reconsideration of the application is respectfolly requested. The Examiner is
`
`invited to contact the undersigned by telephone if it is folt 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. 19-07 41. lf
`
`any extensions of time are needed fbr 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 foes to Deposit Account No. 19-0741.
`
`Date June 13, 2.Q1:±
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(415) 984-9810
`facsimile:
`(415) 434-4507
`
`Respectfully submitted,
`
`Alexey V. Saprigin
`Agent for Applicants
`Registration No. 56,439
`
`4836-9773-5963.1
`
`-11-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1161, p. 11 of 11
`
`