IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
`
`Applicant:
`
`Horst OLSCHEWSKI et al.
`
`Title:
`
`TREPROSTINIL ADMINISTRATION BY
`INHALATION (as amended)
`
`Appl. No.:
`
`12/591,200
`
`Filing Date:
`
`11/12/2009
`
`Examiner:
`
`Sara Elizabeth Townsley
`
`Art Unit:
`
`1629
`
`Confirmation 4093
`Number:
`
`AMENDMENT AND REPLY ACCOMPANYING RCE
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`This paper responds to the Advisory Action mailed on June 4, 2013.
`
`The listing of claims begins on page 2 of this document.
`
`Remarks begin on page 4 of this document.
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`4825-4619-0356.1
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`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
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`Listing of Claims:
`
`1-17. (Canceled)
`
`18.
`
`(Currently Amended) A method of treating pulmonary hypertension
`
`comprising:
`
`administering by inhalation to a human in need thereof a therapeutically effective single event
`
`dose of an inhalable formulation with an a pulsed ultrasonic nebulizer, wherein said
`
`therapeutically effective single event dose comprises from 15 µg to 90 µg oftreprostinil or a
`
`pharmaceutically acceptable salt thereof and said therapeutically effective single event dose is
`
`inhaled in -1-0 ll_or less breaths by the human.
`
`19.-24. (Canceled)
`
`25.
`
`(Previously Presented) The method of claim 18, wherein the single event dose
`
`contains from 15 µg to 60 µg of treprostinil or a pharmaceutically acceptable salt thereof.
`
`26.
`
`(Canceled)
`
`27.
`
`(Previously Presented) The method of claim 18, wherein the ultrasonic
`
`nebulizer comprises an aerosolable solution having a concentration of said treprostinil or a
`
`pharmaceutically acceptable salt thereof from 500 µg/ml to 2500 µg/ml.
`
`28.
`
`(Previously Presented) The method of claim 18, wherein said administering
`
`does not significantly disrupt gas exchange in said human.
`
`29.
`
`(Previously Presented) The method of claim 18, wherein said administering
`
`does not significantly affect heart rate of said human.
`
`30.
`
`(Previously Presented) The method of claim 18, wherein said administering
`
`does not significantly affect systemic aiierial pressure and systemic arterial resistance of said
`
`human.
`
`31.
`
`(Canceled)
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`4825-4619-0356.1
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`32.
`
`(Previously Presented) The method of claim 18, wherein said administering of
`
`said therapeutically effective single event dose is performed in 5 or less breaths.
`
`33.
`
`(Previously Presented) The method of claim 18, wherein said human receives
`
`several therapeutically effective single event doses per day.
`
`34.
`
`(Previously Presented) The method of claim 27, wherein the concentration of
`
`said treprostinil or a pharmaceutically acceptable salt thereof in the aerosolable solution is
`
`600 µg/ml.
`
`35.
`
`(New) The method of claim 18, wherein the single event dose is administered
`
`in 5 minutes or less.
`
`36.
`
`(New) The method of claim 27, wherein the single event dose is administered
`
`in 5 minutes or less.
`
`37.
`
`(New) The method of claim 34, wherein the single event dose is administered
`
`in 5 minutes or less.
`
`38.
`
`(New) The method of claim 18, wherein said therapeutically effective single
`
`event dose is inhaled in 12 or less breaths by the human.
`
`39.
`
`(New) The method of claim 27, wherein said therapeutically effective single
`
`event dose is inhaled in 12 or less breaths by the human.
`
`40.
`
`(New) The method of claim 34, wherein said therapeutically effective single
`
`event dose is inhaled in 12 or less breaths by the human.
`
`4825-4619-0356.1
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`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
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`REMARKS
`
`Applicants respectfully request reconsideration and allowance of the present
`
`application.
`
`CLAIMS ST A TUS
`
`Claims 18, 25, 27-30 and 32-40 are pending. Claim 18 is amended to recite an upper
`
`limit of 18 breaths for the single event dose based upon paragraph 74 of the present
`
`specification as published. Claim 18 is further amended to specify that the ultrasonic
`
`nebulizer is a "pulsed" ultrasonic nebulizer based upon paragraph 0068 of the specification as
`
`published. Claims 35-37 are added to cover a preferred timing embodiment for the single
`
`event dose based upon paragraph 46 of the present specification. Claims 38-40 are added to
`
`cover an upper limit of 12 breaths for the single event dose based upon paragraphs 45 and 74
`
`of the present specification (paragraph 45 states that "20 breaths or less" may be used, while
`
`paragraph 74 specifically provides clinical results for a higher upper limit of 18 breaths and a
`
`lower upper limit of 9 breaths, thus supporting use of a number of breaths in between 9 and
`
`18, such as 12). No new matter has been introduced.
`
`CLAIM REJECTIONS UNDER 35 U.S.C. § 103(a)
`
`Claims 1-8, 10-23 and 25-31 stand rejected as obvious over Chaudry (US
`
`2004/0265238) in view of Sandifer et al. (J. Appl. Physiol. 99:2363-68 (2005)) and Cloutier
`
`(US patent no. 6,521,212). Reconsideration of the rejection is respectfully requested.
`
`The Accompanying Rule 131 Declaration Removes Sandifer As Prior Art
`
`Sandifer states that it was first published Sept. 1, 2005. Applicants submit herewith a
`
`Rule 131 Declaration to remove Sandifer as prior art. The Rule 131 Declaration is in
`
`accordance with MPEP 715.02, stating that "an affidavit or declaration under 37 CFR 1.131
`
`is required to show no more than the reference shows. Jn re Stryker, 435 F.2d 1340, 168
`
`USPQ 372 (CCPA 1971)." Also, the exhibit to the Rule 131 Declaration has the actual dates
`
`redacted, but the Declaration confirms the activity occurred before the reference's publication
`
`date. The accompanying Rule 131 Declaration establishes that the inventors possessed as
`
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`much or more than Sandifer shows prior to its publication date of Sept. I, 2005. Accordingly,
`
`Sandifer may not be cited in support of the rejection. For this reason alone, the rejection
`should be withdrawn. 1
`
`With Or Without Sandifer, No Teaching Of "Single Event Dose" Limitation
`
`Claim 18 requires a "'single event dose" of from 15 µg to 90 µg of treprostini I or a
`
`phannaceutically acceptable salt thereof~ which is inhaled in 18 breaths or less. All
`
`dependent claims require at least this limitation, though they are also further limited. The
`
`Advisory Action attempts to separate out a single, 1 minute increment of treatment from
`
`Sandifer to satisfy this limitation. While Applicants appreciate that the USPTO may give the
`
`claims their broadest reasonable interpretation during examination, such an interpretation of
`
`"single event dose" is beyond reasonable and completely eviscerates the words. The USPTO
`
`may not completely ignore a limitation in the claim.
`
`Sandifer teaches only 30-60 minutes events.
`
`Seep. 2364, left column, third full paragraph: "After each sheep was allowed to reach
`steady state for 30-60 min, treprostinil was infused at 250, 500, and 1,000 ng kg- 1 min- 1
`• Each
`
`infusion lasted 30-60 min. The experiment was repeated with the same dose of U-44069 but
`
`with the treprostinil delivered via aerosol at 0.28 ml/min in escalating doses of 250, 500, and
`
`
`1,000 ng kg- 1 min- 1." (underlining added)
`
`See also p. 2364, left column, last paragraph: "[t]o evaluate the duration of action of
`
`vasodilator aerosols, we delivered treprostinil for 30 minutes ... At the end of 30 minutes. the
`
`treprostinil was stopped ... " (emphasis supplied).
`
`Based on the above citations, it is clear to a person of ordinary skill in the art reading
`
`Sandifer that treprostinil was continuously administered for a 30-60 minute period in a single
`
`event and then stopped.
`
`1 Although the Advisory Action also cites Cloutier, which has overlapping disclosure with Sandifer, it
`appears that the rejection is significantly based upon a quote in Sandifer not found in Cloutier: "less total drug
`can be given on a daily basis by using intermittent inhalation compared with continuous infusion" (p. 2367, right
`
`4825-4619-0356.1
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`Furthermore, the amount of treprostinil administered by Sandifer's 30-minute single
`
`event dose is far outside the claimed range of 15 µg to 90 µgin claim 18. Without agreeing
`
`or disagreeing with the rationale provided in the Advisory Action, the rejection states that
`
`Sandifer administered 1 microgram/min/kg of body weight, or 21-3 7 micrograms per sheep
`
`per minute according to the rejection's analysis, during a single event dose lasting 30 minutes.
`
`That corresponds to 630 to 1, 110 micrograms per event. Even the lower amount of 250
`
`nanograms is well outside the claimed range when calculated with the Advisory Action's
`
`rationale (0.250 micrograms x 21 x 30
`
`157.5 micrograms). Sandifer's '"single event dose"
`
`is well outside the range of 15 µg to 90 µg in claim 18. For the record, Sandifer himself
`
`acknowledges that treprostinil doses used in his experiments on sheep are much higher than
`
`those for humans, see page 2367, left column, lines 12-14: "To achieve an effect in sheep, it
`
`was necessary to administer doses of treprostinil that were much higher than those used in
`
`treating patients, regardless of route of delivery." (underlining added)
`
`In addition, the number of breaths used to inhale Sandifer's 30-minute single event
`
`dose is far outside the claimed range of 18 breaths or less in claim 18. Even if one assumes
`
`that the Advisory Action's estimate of 10 breaths per minute applies to Sandifer' s sheep,
`
`Sandifer's shortest single administering event of 30 minutes will be performed in 300 breaths,
`
`which is much greater than 18 breaths or less recited in claim 18. For the record, "the
`
`respiration rate for sheep ... is about 12 to 15 breaths per minute (depending on
`
`environmental temperature)," see page 1, left column, last paragraph, Pezzanite et al, AS-595-
`
`W, Purdue Extension (enclosed).
`
`The PTO improperly disregards Applicants' surprising/unexpected results relying on
`
`Sandifer
`
`Applicants emphasize that the combination of a) the claimed dosing regimen of
`
`treprostinil and b) administration with a pulsed ultrasonic nebulizer recited in the pending
`
`claims represents surprising/unexpected results because it provides a significant improvement
`
`in quality of life for pulmonary hypertension patients due to its substantially greater
`
`column). This quote is mentioned several different places in the Advisory Action, including p. 3, paragraph 7
`and page 4, first paragraph.
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`convenience compared to the only other available inhaled prostacyclin on the market. This
`
`was shown previously in the Rule 132 Declarations of Drs. Rubin and Gotzkowsky filed on
`
`May 23, 2012 and August 10, 2012 respectively.
`
`Although Applicants provided similar comments on pages 11-12 of their response
`
`filed January 16, 2013, the PTO disregarded Applicants' surprising/unexpected results on
`
`pages 2-3 of the Advisory Action using the following comments to support its position:
`
`"Sandifer differs from the instant claims only in that the patient population is sheep
`rather than humans, and the type of aerosol delivery device is not identified. As
`discussed above, Sandifer discloses administration of inhaled aerosol treprostinil at a
`dose of 21-3 7 mcg/min, which falls within the range of 15-90 mcg/min as recited by
`instant claim 18 (again, assuming 10 human breaths is equivalent to approximately 1
`minute of inhalation), with the advantages of minimal effects on systemic
`hemodynamics, and reduced total amount of drug required, in turn reducing costs.
`Thus, the explicit disclosure of Sandifer would have given one of ordinary skill in the
`art a reasonable expectation of success in treating pulmonary hypertension with doses
`of intermittently inhaled aerosol treprostinil falling within the scope of the instant
`claims, e.g., 1 mcg/kg/min (equivalent to 70 mcg/min or 70 mcg per 10 breaths for a
`70 kg human)."
`
`First, the PTO is incorrect in its assertion that Sandifer differs from the instant claims
`
`only in that the patient population. Besides the PTO's acknowledged difference, Sandifer
`
`does not teach at least each of the following clements of claim 18: a) said therapeutically
`
`effective single event dose is inhaled in 18 or less breaths by the human; b) said
`
`therapeutically effective single event dose comprises from 15 µg to 90 µg of treprostinil or a
`
`pharmaceutically acceptable salt thereof. Applicants will explain below why one of ordinary
`
`skill in the art would not have arrived at elements a) and b ).
`
`Second, the PTO is incorrect that Sandifer does not identify the type of aerosol
`
`delivery system because Sandifer's first full paragraph in the left column on page 2364 clearly
`
`states that "[ d]rug aerosolization was performed with a Healthline Medical AM-601
`
`Medicator Aerosol Delivery System."
`
`Sandifer performs his experiments on sheep. To model pulmonary hypertension,
`
`Sandifer induces acute pulmonary vasoconstriction in his sheep by infusing U-44069 at 1000
`ngkg- 1min- 1 for180 min, see page 2364, left column. In his inhalation experiments, Sandifer
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`4825-4619-0356.1
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`continuously delivers treprostinil via aerosol for 30-60 min at 0.28ml/min in doses 250, 500
`and 1000 ngkg- 1min- 1
`
`• One of ordinary skill in the art would not be able to arrive, based on
`
`Sandifer, at the particular dosing regimen recited in claim 18, namely at administering to a
`
`human suffering from pulmonary hypertension a therapeutically effective single event
`
`dose of an inhalable formulation with a pulsed ultrasonic nebulizer, wherein said
`
`therapeutically effective single event dose comprises from 15 µg to 90 µg of treprostinil or a
`
`pharmaceutically acceptable salt thereof and said therapeutically effective single event dose is
`
`inhaled in 18 or less breaths by the human for the following reasons:
`
`1) Sandifer uses continuous aerosol delivery in a single administering event that lasts
`
`30-60 min. Sandifer's mode of administration is very different from the pulsed
`
`ultrasonic nebulizer recited in claim 18. Furthermore, as explained above, even
`
`the shortest of Sandifer's single administering events involves many more breaths
`
`than 18 or less breaths recited in claim 18. Sandifer does not teach or suggest the
`
`presently claimed methods.
`
`2) As Applicants explained before, see e.g. January 16th response, pages 7-8, not
`
`every compound that can be administered by inhalation can be administered in a
`
`pulsed ultrasonic nebulizer.
`
`In sum, contrary to the PTO's assertions on page 3 of the Advisory Action, Sandifer
`
`does not give one of ordinary skill in the art a reasonable expectation of success to arrive at
`
`the presently claimed method in claim 18. For the record, one of ordinary skill in the art
`
`would not be able to arrive at the surprising/unexpected results discussed above, nor predict
`
`the surprisingly robust patient benefits shown in the previously submitted Rule 132
`
`Declarations by making the changes in the inhalation method that are recited in claim 18.
`
`The PTO failed to establish a prima facie case of obviousness at least because it failed
`
`to make its obviousness analysis explicit.
`
`On pages 2, last paragraph, the PTO clarified that "the rejection relies upon two
`
`rationales: MPEP § 2143 (G) (some teaching, suggestion, or motivation in the prior art) and
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`4825-4619-0356.1
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`MPEP § 2143 (A) (combining prior art elements according to known methods to yield
`
`predictable results)."
`
`A) The PTO cannot rely on the rationale from MPEP § 2143 (A) at least because the
`
`PTO failed to articulate the required findings 1) and 3)
`
`MPEP § 2143 (A) states as follows:
`
`"To reject a claim based on this rationale, Office personnel must resolve the Graham
`
`factual inquiries. Then, Office personnel must articulate the following:
`
`•
`
`(1) a finding that the prior art included each element claimed, although not
`
`necessarily in a single prior art reference, with the only difference between the
`
`claimed invention and the prior art being the lack of actual combination of the
`
`elements in a single prior art reference;
`
`•
`
`(2) a finding that one of ordinary skill in the art could have combined the elements as
`
`claimed by known methods, and that in combination, each element merely performs
`
`the same function as it does separately;
`
`•
`
`(3) a finding that one of ordinary skill in the art would have recognized that the results
`
`of the combination were predictable; and
`
`•
`
`( 4) whatever additional findings based on the Graham factual inquiries may be
`
`necessary, in view of the facts of the case under consideration, to explain a conclusion
`
`of obviousness.
`
`The rationale to support a conclusion that the claim would have been obvious is that
`
`all the claimed elements were known in the prior art and one skilled in the art could have
`
`combined the elements as claimed by known methods with no change in their respective
`
`functions, and the combination yielded nothing more than predictable results to one of
`
`ordinary skill in the art. KSR, 550 U.S. at_, 82 USPQ2d at 1395; Sakraida v. AG Pro, Inc.,
`
`425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson's-Black Rock, Inc. v. Pavement
`
`Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v.
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`4825-4619-0356.1
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`Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). "[l]t can be
`
`important to identify a reason that would have prompted a person of ordinary skill in the
`
`relevant field to combine the elements in the way the claimed new invention does." KSR, 550
`
`U.S. at~' 82 USPQ2d at 1396. If any of these findings cannot be made, then this
`
`rationale cannot be used to support a conclusion that the claim would have been
`
`obvious to one of ordinary skill in the art." (emphasis added)
`
`Applicants respectfully submit that in the present rejection, the PTO failed to
`
`articulate at least findings 1) and 3) ofMPEP § 2143(A).
`
`With respect to finding 1 ), the PTO failed to articulate at least which reference teaches
`
`a therapeutically effective single event dose comprising from 15 µg to 90 µg of treprostinil or
`
`a pharmaceutically acceptable salt thereof, which dose is inhaled in 18 or less breaths by the
`
`human. As Applicants explained above, Sandifer does not teach this element of claim 18.
`
`With respect to finding 3), the PTO failed to articulate at least why selecting an
`
`ultrasonic nebulizer from Chaudry's list of inhalation devices in paragraphs 0052-0057, while
`
`selecting treprostinil from Chaudry's list of hypertension reducing agents in paragraphs 0022-
`
`0027 would be predictable to one of ordinary skill in the art especially in view of the evidence
`
`provided by Applicants demonstrating that not every hypertension reducing agent in
`
`Chaudry's paragraphs 0022-0027 can be administered by every inhalation device in
`
`Chaudry's paragraphs 0052-0057, see pages 7-8 of the response filed January 16, 2013, where
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`Applicants provide evidence that iloprost listed among hypertension reducing agents in
`
`Chaudry's paragraphs 0022-0027 cannot be administered by a metered dose inhaler, which is
`
`mentioned among possible inhalation devices in Chaudry's paragraph 0052-0057.
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`In sum, the PTO cannot rely on the obviousness rationale from MPEP § 2143 (A) for
`
`the reasons discussed above.
`
`B) The PTO cannot rely on the rationale from MPEP § 2143 (G) at least because the
`
`PTO failed to articulate the required finding (2)
`
`MPEP § 2143 (G) states as follows:
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`"To reject a claim based on this rationale, Office personnel must resolve the
`
`Graham factual inquiries. Then, Office personnel must articulate the following:
`
`•
`
`(1) a finding that there was some teaching, suggestion, or motivation, either in the
`
`references themselves or in the knowledge generally available to one of ordinary skill
`
`in the art, to modify the reference or to combine reference teachings;
`
`•
`
`•
`
`(2) a finding that there was reasonable expectation of success; and
`
`(3) whatever additional findings based on the Graham factual inquiries may be
`
`necessary, in view of the facts of the case under consideration, to explain a conclusion
`
`of obviousness.
`
`The rationale to support a conclusion that the claim would have been
`
`obvious is that "a person of ordinary skill in the art would have been motivated to
`
`combine the prior art to achieve the claimed invention and that there would have
`
`been a reasonable expectation of success. DyStar Textilfarben GmbH & Co.
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`Deutsch/and KG v. C.H Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641,
`
`1645 (Fed. Cir. 2006). If any of these findings cannot be made, then this
`
`rationale cannot be used to support a conclusion that the claim would have
`
`been obvious to one of ordinary skill in the art." (emphasis added)
`
`Applicants respectfully submit that the PTO failed to articulate the required finding 2) at least
`
`because the PTO failed to explain why one of ordinary skill in the art would have a
`
`reasonable expectation of success to arrive at the dosing regimen recited in claim 18, namely
`
`administering to a human suffering from pulmonary hypertension a therapeutically
`
`effective single event dose of an inhalable formulation with a pulsed ultrasonic nebulizer,
`
`wherein said therapeutically effective single event dose comprises from 15 µg to 90 µg of
`
`treprostinil or a pharmaceutically acceptable salt thereof and said therapeutically effective
`
`single event dose is inhaled in 18 or less breaths by the human. Applicants provided above a
`
`reasoned explanation on why one of ordinary skill would not have a reasonable expectation of
`
`success for arriving at such dosing regimen based Sandifer.
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`4825-4619-0356.1
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`In sum, the PTO cannot rely on the obviousness rationale from MPEP § 2143 (G) for
`
`the reasons discussed above.
`
`DOUBLE PA TENTING REJECTION
`
`Claims 18, 25, 27-30 and 32-34 stand provisionally rejected on the ground ofnon(cid:173)
`
`statutory obviousness-type double patenting over claims 1, 4-17 and 52-59 of co-pending
`
`Application No. 11/748,205 in view of Chaudry et al. (US Pub. No. 2004/0265328), Byron
`
`(Proc. Am. Thor. Soc. (1 ), pp. 321-328, 2004) and Cloutier et al. (USPN 6,521,212).
`
`Applicants will address this rejection at such time (if ever) that it becomes non-provisional.
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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 3 7 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
`
`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
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`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 authorizes payment
`
`of any such extensions fees to Deposit Account No. 19-0741.
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 672-5569
`Facsimile:
`(202) 672-5399
`
`&/
`Stephen B. Maebius
`Attorney for Applicants
`Registration No. 35,264
`
`4825-4619-0356.1
`
`-13-
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 13 of 23
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`

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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:
`
`11/12/2009
`
`Examiner:
`
`Sara Elizabeth Townsley
`
`Art Unit:
`
`Confirmation
`Number:
`
`1629
`
`4093
`
`DECLARATION UNDER 37 C.F.R. § 1.131 OF LEWIS RUBIN, M.D.
`
`I, Lewis Rubin, do hereby declare:
`
`1.
`
`I am 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 B.A. from Yeshiva University and an M.D. from Albert Einstein College
`
`of Medicine. My Curriculum Vitae submitted in this application with my prior Declaration
`
`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.
`
`4835-2628-0468.1
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 14 of 23
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`

`

`5.
`
`I am a paid consultant of United Therapeutics, the assignee of the above-identified
`
`patent application.
`
`6.
`
`I am familiar with the Advisory Action dated June 24, 2013 in U.S. patent
`
`application Ser. No. 12/591,200, which indicates how the rejection may be partially based upon a
`
`certain statement found in the Sandifer reference.
`
`7.
`
`Specifically, the Advisory Action stated that Sandifer would have given one of
`
`ordinary skill a reasonable expectation of success and would have provided an expectation of
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`certain benefits, quoting from Sandifer as follows: "less total drug can be given on a daily basis
`
`by using intermittent inhalation compared with continuous infusion" (p. 2367, right column,
`
`Sandifer, as quoted in the Advisory Action on page 3).
`
`8.
`
`Without agreeing or disagreeing with any conclusion drawn in the rejection about
`
`the teachings of Sandifer, I am providing this Declaration to establish that the co-inventors and I
`
`performed inhalation methods with pulmonary hypertension patients using treprostinil prior to
`
`Sept. 1, 2005, which is prior to the publication date of Sandifer. The methods we performed
`
`prior to Sept. 1, 2005 included at least as much of the disclosure found in Sandifer that is cited in
`
`the Advisory Action, except that our method used human pulmonary hypertension patients rather
`
`than a sheep model. Specifically, attached as Exhibit A to this Declaration is a redacted clinical
`
`trial report synopsis setting forth details of a clinical trial. The dates and certain other details
`
`have been redacted, but the explanation of how the trial was conducted and the results of that
`
`particular trial are retained. All results described in Exhibit A were obtained prior to Sept. I,
`
`2005.
`
`9.
`
`In Exhibit A, the reference to the "OptiNeb device, NEBU-TEC GmbH" is a
`
`reference to an ultrasonic nebulizer. The ultrasonic nebulizer was used to administer pulmonary
`
`hypertension patients the indicated amounts of treprostinil, including one single event dose of 2
`
`minutes providing about 40 micrograms of treprostinil. As indicated in Exhibit A, the results
`
`showed dose-dependent reduction of pulmonary vascular resistance and pulmonary arterial
`
`pressure in human pulmonary hypertension patients.
`
`4835-2628-0468.1
`
`2
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 15 of 23
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`

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`10.
`
`I further declare that all statements made herein of my own knowledge are true
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`and that all statements made on information and belief are believed to be true, and further, that
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`these statements were made with the knowledge that willful false statements and the like so made
`
`are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United
`
`States Code, and that such willful false statements may jeopardize the validity of the application
`
`or any patent issuing thereon.
`
`Signed this
`
`').(. r>t
`
`day of
`
`\Jc.vcu
`, 2013.
`~"~~'
`
`Lewis Rubin, M.D.
`
`48)5-2628-0468.1
`
`3
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 16 of 23
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`

`

`EXHIBIT A
`
`'
`
`'
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 17 of 23
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`

`

`CLINICAL TRIAL REPORT SYNOPSIS
`
`Investigation into efficacy, hacmodynamic effects and safety of
`Inhaled trcprostinil sodium and placebo
`in patients with pulmonary arterial hypertension
`
`Investigator Driven Study
`The study was performed according to Good Clinical Practice regulations
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 18 of 23
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`

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`SYNOPSIS
`
`l.Lmcil<x Corpor;1t1011
`
`lr1d1v1dual Stuoy Table f<cfernng
`to Part of the Dossier
`
`(F'or National /\ullwrity Use 011:v;
`
`Name of f'1nishcd FJroducts:
`Not
`
`Volume:
`
`~·Jamo of Active Ingredient
`1 rnproslinil sodium
`
`Title of Study:
`
`Investigation mto efficacy, haemodynamic effects and safety of Inhaled treprost1nil sod111111
`and pl;i,;et,o in put1onts with pulmon;iry ;irtunal hypertension
`
`Investigators
`
`Study center:
`
`Publication (reference): None at tho t1rnc of report
`
`Study period (years):
`
`Objectives:
`
`f'nrnm::f To assess t~1c
`1) Pulmonary vasculc.lr resistance (PVR, [dyn s cm-5]) following 1nh;1lod troprost1nil or
`placebo
`S e i:_QD_cl_cil}' T o assess
`2) Pulmonary arterial pressure (PAP, [rnrnHG])
`3) Cardiac output (CO, [Umin])
`4) Systemic arterial pressure (SAP, [mm HG]) and he;:irt rate (HR [beats/min])
`5) Systemic 3rten31 oxygen saturation (Sa02, [mm HG]) and venous cJxysicn saturcil1u11
`(Sv02, [mm HG])
`. ~) __ .!()!?_r~9-~1t_y of·~·~c-~~1d.i.r'_9-:'~r~g~~_cJ05-~s of inhale __ d·-·----
`Mcthodology: Mono-center, randornrzed. parallel groups, single-blind, single dose consecutive inhalation,
`assessment fur three hours folluwinq aorosolation. Inhalation with OptiNeb device, NEWJ·
`TEC GmbH, Elsenfcld, Germany
`f"AP, PVF<., CO, and Sv02 were measured with a Swan-C;;:mz thmmodilut1on pulmonary
`catheter and SAP besides Sa02 with a femoral artery catrwter.
`The study consists of throe study parts (D. E, F) to be d1ffcrent13tcd by thrc)() singlu cJosc:; of
`inhaled treprostin1I Tim same methods and design were applied for all three stuoy ports
`anc treatment groups For :ill troatments or study parts the same group of patients trealcd
`with PLA servecJ as control
`In a random orlJcJr, within study p;irt D pat10nts weru c1Hwr
`treated with H~F: Hi µ9/ml or PL.A 1nhalec for() rninutes
`
`Number of subjects (planned and analyzed):
`S1xtucn sub1ects (El subjects each with Tl~f.c or PU\) were pianr1ecJ and part1c1patrJ'.J 1n study
`part D Six pat1c;nts w1tl1 fl<.[ were 1rn:lu,Jed into study part [ <rnd f' as planncCI. nwre was
`nu drop out As fJLA was 3cJrrnn1stcred to one grcup of patients. a total of ?El c>UbJecls were
`enrolled and completed !lie study as planned. Data of all subjects were ariciiy;ccJ
`
`Diagnosis and main criteria for inclusion:
`Male and female patients with pulmonary hypertension (PH). either 1diopath1c/prrmary. or
`due to collagen vascular or con9enit3I heart disease, to HIV infoclion, to chronic
`thrornboembolic f)l1 or pulmonary fibrosis; NYHA function31 cl3sscs II-IV; no other severe
`pulmonary disease in tt10 medical history which could have interfered with tho inhalation
`procedure.
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1011, p. 19 of 23
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`

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`Individual Study Tabl