Estradiol – USA

Estradiol – USA

On Dec 22, 2017, District court of Delaware held that a patent related to Estradiol (Minivelle®) ER film is valid but not infringed because of prosecution history estoppel.

Noven is the holder of New Drug Application (“NDA”) No. 203752, for the manufacture and sale of an estradiol transdermal delivery system (Minivelle®),with dosages of 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day and 0.1 mg/day. Minivelle® is indicated for treatment of moderate to severe vasomotor symptoms (also known as “hot flashes”) due to menopause and for the prevention of post-menopausal osteoporosis. On March 20, 2015, Plaintiff Noven Pharmaceuticals, Inc. (“Noven” or “Plaintiff’) filed suit against Defendant Actavis Laboratories UT, Inc. (“Actavis” or “Defendant”) alleging infringement of U.S. Patent No. 8,231,906 (the “‘906 patent”), which is directed to a transdermal product for the delivery of the hormone estradiol. The Court held a claim construction hearing on May 3, 2016 and issued a claim construction opinion on July 5, 2016. The Court conducted a three-day bench trial in January and February of 2017 and heard closing arguments on May 8, 2017. At trial and in its post-trial briefing, Noven claimed that Actavis infringed the asserted claims of the ‘906 patent literally and under the doctrine of equivalents. Actavis, in turn, claimed that prosecution history estoppel barred Noven from asserting infringement under the doctrine of equivalents and that the asserted claims of the ‘906 patent were invalid as obvious.
Infringement under DOE & prosecution history estoppel:
Noven asserted that Actavis’s proposed generic product and/or manufacturing process infringe claims 1-14 of the ‘906 patent. Claim 1 reads:
1. A monolithic transdermal drug delivery system for estradiol, comprising a single polymer matrix layer defining an active surface area and comprising a polymer matrix comprising estradiol as the only drug, wherein the polymer matrix layer has a coat weight selected from the group consisting of 12.5 mg/cm2 and 15 mg/cm2 , includes greater than 0.156 mg/cm2 estradiol, and achieves an estradiol flux that is greater than 0.01 mg/cm2 /day, based on the active surface area.

On May 29, 2012 during prosecution, claim 1 did not contain a quantitative coat weight limitation. On May 29, 2012, the PTO issued a Final Office Action, rejecting certain claims under 35 U.S.C. § 103 over certain prior arts such as Kanios, Nuwayser & Rovati. With respect to the rejections, the Examiner stated that although Rovati “does not teach that the system achieves an estradiol flux that is greater than 0.01 mg/cm2 /day,” “[i]t would have been obvious to one of ordinary skill in the art at the time that the invention was made to utilize the matrix taught by Kanios II in the monolithic patch of Rovati … to achieve the instantly claimed estradiol flux.” On May 30, 2012, in response to the May 29, 2012 Final Office Action, Applicant amended claim 1 & argued that amended claim 1 was patentable over Rovati in view of Kanios II because both prior art references did not “teach or suggest a polymer matrix coat weight as recited in the instant claims.” Applicant also argued that “Rovati does not recognize any criticality of the coat weight of the polymer matrix” and that “Rovati’s example appears to have a coat weight of about 9.8 mg/cm2 which is significantly lower than the 12.5 or 15 mg/cm2 recited in the claims.”
Actavis contended that prosecution history estoppel bars Noven from asserting infringement of claim 1 under the doctrine of equivalents. Actavis’s arguments focused on the “coat weight” limitation of claim 1. In Actavis’s view, the Applicant “added the ‘coat weight’ limitation to distinguish the claims from” Rovati. Actavis further contended that Noven cannot establish “the narrow tangential relation exception to prosecution history estoppel,” “[b]ecause both the reason for the amendment and the asserted equivalent relate to [the coat weight of the polymer matrix layer].” Noven asserted that the “coat weight” amendment “was not made for reasons of patentability or to narrow the claims in view of the prior art” but, instead, was made “to claim two specific embodiments.” Moreover, even if estoppel would presumptively apply, Noven contends that the coat weight amendment “was only tangentially related to the equivalent in question” because “[t]he amendment rewrote the limitation into the independent claim.”
Court said that the ‘906 patent’s prosecution history demonstrates that the Applicant added the coat weight limitation to overcome a § 103 rejection based on Rovati in view of Kanios II. For example, in its response to the PTO’s rejection, the Applicant stated that “Rovati does not recognize any criticality of the coat weight of the polymer matrix” and that “Rovati’ s example appears to have a coat weight of about 9 .8 mg/cm2 [,] which is significantly lower than the 12.5 or 15 mg/cm2 recited in the claims.” The Applicant further stated that Rovati “does not teach or suggest a polymer matrix coat weight as recited in the instant claims” and that “Kanios II does not provide any teachings regarding the coat weight of its polymer matrix.” From these statements (and the entirety of the prosecution history), the Court concludes that the Applicant used the coat weight amendment to distinguish the amended claim over Rovati, making the coat weight amendment substantially related to patentability.
For the reasons explained above, the Court concluded that the coat weight amendment was a narrowing amendment made to distinguish the claim over prior art and further concluded that the reason for the amendment was not tangentially related to the equivalent in question. Consequently, prosecution history estoppel bars Noven from asserting infringement of the coat weight limitation under the doctrine of equivalents.
Invalidity:

Actavis argued that the asserted claims are obvious over the prior art because: (1) a POSA would have been motivated to make a smaller estradiol transdermal delivery system; (2) the specific size reduction in making a smaller transdermal estradiol delivery system would have been a design choice; (3) a POSA attempting to modify Vivelle-Dot® would have been motivated to keep the polymer matrix weight ofVivelle-Dot® the same and would, therefore, arrive at the claimed coat weight limitation; (4) a POSA attempting to modify Vivelle-Dot® would have been motivated to use the same amount of estradiol as Vivelle-Dot®, thereby increasing the amount of estradiol per unit area; and (5) a POSA attempting to modify VivelleDot® would have been motivated to increase flux.
Court after hearing both the parties held that the Court is not persuaded that a POSA would have been motivated by the prior art to develop a transdermal estradiol system smaller than Vivelle-Dot®. Although Actavis correctly observed that its cited “prior art [references] … disclose[] that patients preferred smaller estradiol transdermal drug delivery systems,” none of the references indicates that patients preferred a transdermal estradiol patch smaller than Vive/le-Dot® Further the Court agrees with Noven that “a POSA would not have had a reasonable expectation of success in implementing any chosen size reduction” because a “POSA would have had to test numerous combinations … to determine if flux could be increased enough” to allow for that size reduction. Additionally, although certain techniques were known to be beneficial in increasing flux, a POSA would recognize that those same techniques could also deleteriously impact other aspects of the drug’s profile. Accordingly, the Court concluded that the specific size reduction in designing a smaller patch would not have been “an obvious design choice.” Given this conclusion and the evidence cited above, Actavis has failed to prove that the claimed size limitations would have been obvious to a POSA in July 2008.
Accordingly, again, Actavis has failed to prove that the polymer matrix weight limitation, estradiol limitation, flux limitation would have been obvious to a POSA at the priority date of the ‘906 patent. Also there is a nexus between Minivelle®’s commercial success and the invention claimed in the ‘906 patent. Minivelle®’s size – a feature claimed by the ‘906 patent – has been a central theme of promotion since Minivelle®’ s launch and is crucial to its success. Accordingly, Noven has proven a causal nexus. The secondary consideration of commercial success further demonstrates the nonobviousness of the asserted claims of the ‘906 patent.
CONCLUSION:
Pursuant to Federal Rule of Civil Procedure 52(a), and having considered the entire record with respect to prosecution history estoppel and invalidity, the Court concluded that:
(1) Prosecution history estoppel bars Noven from asserting infringement of the coat weight limitation of the ‘906 patent under the doctrine of equivalents; and

(2) Actavis has failed to prove, by clear and convincing evidence, that the asserted claims of the ‘906 patent are invalid as obvious.
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