Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Horst OLSCHEWSKI et al.
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`TREPROSTINIL ADMINISTRATION BY
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`INHALATION
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`12/591,200
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`11/12/2009
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`Sarah Elizabeth Townsley
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`1629
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`Applicant:
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`Title:
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`Appl. No.:
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`Filing Date:
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`Examiner:
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`Art Unit:
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`Confirmation Number: 4093
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`PRE-APPEAL BRIEF CONFERENCE REQUEST FOR REVIEW
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`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Sir:
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`Applicants file this Pre-Appeal Brief Conference Request together with a Notice of
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`Appeal.
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`REMARKS
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`The sole remaining rejection- a rejection of claims 18, 25, 27-30 and 32-40 under 35
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`U.S.C. § 103(a) over Chaudry (US 2004/0265238) in view of Cewers (USPN 6,357,671)(cid:173)
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`should be withdrawn. The Office has not established a reason to combine the references as
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`relied upon in the rejection, and even if the references were combined as proposed, the
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`combination does not teach or suggest several elements of the claims. In addition, objective
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`indicia of non-obviousness, including unexpected results and commercial success, further
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`undermine any hint of obviousness.
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`Chaudry generally relates to inhaled drugs for treating pulmonary hypertension and
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`lists at least five categories of drugs encompassing a litany of specific compounds.
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`(paragraphs 22-26). The rejection focuses on one element of this expansive disclosure:
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`"[ v ]asodilators for use herein also include prostaglandins (Eicosanoids), including
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`prostacydin (Epoprostenol) and prostacydin analogs, including Iloprost and Treprostinil"
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`(paragraph 26). Importantly, Chaudry teaches that not only are these diverse categories of
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`drugs interchangeable, but that "any other compound capable of treating pulmonary
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`hypertension" can be used (paragraph 27 (emphasis added)). Chaudry's disclosure regarding
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`methods of administration is equally broad and, in fact, covers "any [] conventionally known
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`method of administering inhalable medicaments,'' but does disclose nebulization as a
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`preferred approach (paragraph 52). Thus, Chaudry discloses administering "any" compound
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`that can treat pulmonary hypertension using "any" known method of administering the drug
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`by inhalation.
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`Despite this broad disclosure, Chaudry does not teach a "pulsed ultrasonic nebulizer,''
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`as required by the claims, and Cewers is cited to remedy this deficiency. Yet, the rejection
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`offers no particular reason why one would combine Cewers with Chaudry as proposed,
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`including a reason to select a pulsed ultrasonic nebulizer from among the many types of
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`known nebulizers. This is reason enough to withdraw the rejection.
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`Even if Chaudry and Cewers were combined from among the many different
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`permutations of drug-device combinations to arrive at a pulsed ultrasonic nebulizer and
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`treprostinil combination, the combination would fail to teach at least two features of the
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`claims: (1) the number of breaths per single event dose (all claims require 18 or less breaths
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`per event); and (2) the amount of drug delivered to the patient per single event dose (all
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`claims require 15 to 90 micrograms per event) (collectively, "Event Dose Features"). This is
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`another independent reason to withdraw the rejection.
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`Any hint of obviousness is overshadowed by the surprising and unexpected
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`advantages of the claimed invention. Chaudry teaches the interchangeability of the drugs and
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`devices as discussed above. Thus, one of ordinary skill in the art would not have predicted
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`the dramatic advantages that result from selecting treprostinil over iloprost, for example, for
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`use in a pulsed ultrasonic nebulizer when adjusted to achieve delivery of the drug according
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`to the Event Dose Features. For example, treprostinil, but not iloprost, can be administered
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`with a pulsed ultrasonic nebulizer so that its therapeutically effective single event dose is
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`inhaled in 18 or less breaths by a human. This could not be predicted based on Chaudry and
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`Cewers. See Advisory Action at 2 ("One of ordinary skill in the pharmaceutical arts
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`appreciates that clinical results for a given compound cannot be predicted in advance .... ").
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`And FDA has approved a product, Tyvaso ®, for such an administration regimen. See Leo
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`Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013) ("While FDA approval is
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`Appl. No. 12/591,200
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`not determinative of nonobviousness, it can be relevant in evaluating the objective indicia of
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`nonobviousness."). These unexpected advantages are described in Rule 132 declarations
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`from Dr. Rubin (filed May 23, 2012) and Dr. Gotzkowsky (filed Aug. 10, 2012). In addition,
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`these advantages are directly connected to the Event Dose Features, which are absent in the
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`combined disclosures of Chaudry and Cewers.
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`The Office asserts that one of ordinary skill in the art would somehow arrive at the
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`therapeutically effective single event treprostinil dose "from 15 µg to 90 µg ... inhaled in 18
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`or less breaths by the human" recited in the present claims from a treprostinil sodium
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`concentration of0.1-10 mg/ml in Chaudry's prophetic example 4. Advisory Action at p. 2.
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`Yet, the Office does not explain how treprostinil sodium concentration in a solution prior to
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`nebulization not associated with any particular type of nebulizer would permit one of
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`ordinary skill in the art to achieve a therapeutically effective single event treprostinil dose
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`that is (a) inhaled in 18 or less breaths by the human (b) such that 15 to 90 micrograms of
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`treprostinil is delivered to the patient.
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`In fact, Voswinckel 2009 (submitted with the reply filed April 28, 2014) provides
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`comparative experimental evidence that iloprost (disclosed in Chaudry' s paragraph [0026]
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`next to treprostinil) is not useful for treating pulmonary hypertension when administered by
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`inhalation in less than 3 minutes (high dose, low breath regimen) because iloprost induces
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`unacceptable side effects. This side-by-side experimental evidence represents an unexpected
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`result based on selecting treprostinil for use with a pulsed ultrasonic nebulizer in a high dose,
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`low breath regimen, which would not have been predicted or expected based upon Chaudry' s
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`teaching of interchangeability. See e.g., Voswinckel (2009), p. 54, sentence bridging left and
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`right columns: "A dose of more than 5 µg iloprost per inhalation or a reduction of inhalation
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`time to less than 3 min induces in most patients caused considerable systemic prostanoid side
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`effects like hypotension, dizziness, headache, jaw pain, nausea or [diarrhea]." Thus, one of
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`ordinary skill in the art would not have expected to be able to reduce the number of breaths
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`down to "18 or less breaths by the human" for any of the compounds disclosed in Chaudry's
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`paragraphs 0022-0027, including treprostinil.
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`The PTO admits (Final Office Action, p. 16) that "treprostinil has certain advantages
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`over iloprost, such as reduced or no side effects at higher doses." Despite this admission, the
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`PTO did not find these advantages of treprostinil over iloprost to be surprising or unexpected.
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`Appl. No. 12/591,200
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`Yet, a person of ordinary skill in the art would not have had any way of knowing that this
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`result would have been possible for treprostinil using a pulsed ultrasonic nebulizer, which
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`had never before been tried in humans. Indeed, based on Chaudry, one of ordinary skill in
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`the art would have expected (at best) that iloprost and treprostinil would be interchangeable
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`and yield similar results. The PTO's disregard of treprostinil's documented advantages over
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`iloprost because they are not unexpected in the PTO's view demonstrates that, contrary to In
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`re Piasecki, 745 F.2d 1468 (Fed. Cir. 2012), the PTO is evaluating Applicants' rebuttal
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`evidence against its obviousness conclusion, instead of evaluating the facts of the rebuttal
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`evidence together with the facts upon which the initial obviousness conclusion was made,
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`while restarting the evaluation of obviousness.
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`The rejection also overlooks other objective indicia of non-obviousness, such as
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`commercial success of the presently claimed invention. Applicants submitted in the reply
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`filed April 28, 2014 the following plot obtained from an independent tracking organization
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`that compares the market share for two inhaled prostacyclin products: (1) Ventavis®, which is
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`an inhalation solution containing iloprost formulated for inhalation via I-neb® AAD®
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`(Adaptive Aerosol Delivery) System; and (2) Tyvaso®, which is a formulation of treprostinil
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`intended for administration by oral inhalation using the Optineb-ir device. Both Ventavis®
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`and Tyvaso ® are prostacyclin analog products delivered by inhalation.
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`Tyvaso® was approved by FDA on or about July 30, 2009, whereas Ventavis® was
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`approved in the U.S. on or about December 29, 2005. Despite the fact that Ventavis® was on
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`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
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`the market around 3.5 years before Tyvaso®, Tyvaso® took away the majority of the U.S.
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`market for inhaled prostacyclins from Ventavis® in a single year. During the time period
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`from September 2009 to September 2010 when the majority of this rapid sales growth
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`occurred for Tyvaso®, the assignee of the present application, which markets Tyvaso®, had an
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`average 25.0% share of sales representative contacts in the pulmonary hypertension market
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`compared to 30.7% share of sales representative contacts for the company marketing
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`Ventavis® according to the data in the independent tracking service. Thus, Tyvaso® enjoyed
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`tremendous commercial success during this period despite being supported by a substantially
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`lower share of pulmonary hypertension sales representatives. This represents a strong case of
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`commercial success that is attributable directly to the differences of the claimed invention
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`over the prior art.
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`As previously explained by Dr. Rubin, one of the world's preeminent experts in
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`treating pulmonary hypertension, patients who used both inhaled iloprost and the presently
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`claimed invention reported statistically significant higher satisfaction based on the presently
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`claimed invention's ease of use (Rubin Rule 132 Declaration at paragraphs 18-19). This ease
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`of use results directly from the more convenient dosing reflected in the Tyvaso® label and
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`recited in the instant claims. Thus, there is a clear nexus between the commercial success of
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`Tyvaso and the present claims, confirmed by the above market share data and the patient
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`satisfaction data reported by Dr. Rubin.
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`In view of the above remarks, the PTO should withdraw the sole remaining
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`obviousness rejection.
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`Date March 9, 2015
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`Respectfully submitted,
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`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 672-5569
`Facsimile:
`(202) 672-5399
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`By /Stephen B. Maebius/
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`Stephen B. Maebius
`Attorney for Applicants
`Registration No. 35,264
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