Estradiol - USA

 

On Sep 02, 2020, Delaware Court found estrogen transdermal patents invalid under lack of enablement & lack of written description support.

Noven pharmaceuticals (Plaintiff) sued Amneal pharmaceuticals (Defendant) under Hatch-Waxman Act as Defendant filed ANDA to market generic version of Minivelle®. Noven markets Minivelle® transdermal film in USA for the treatment of moderate to severe vasomotor symptoms due to menopause.  Noven sued Amneal for the infringement of US 9,833,419; US 9,730,900 and US 9,724,310 patents which are expiring in July 2028. Amneal countered with non-infringement, invalidity based on enablement, written description support & on-sale bar defenses. Court held bench trial in Nov. 2019 & Jan. 2020.

Claim 1 of US’419 is representative:

1. A monolithic transdermal drug delivery system for estradiol, consisting of (i) a backing layer, (ii) a single adhesive polymer matrix layer defining an active surface area and, optionally, (iii) a release liner, wherein the single adhesive polymer matrix layer comprises an adhesive polymer matrix comprising estradiol as the only drug, wherein the adhesive polymer matrix layer has a coat weight of greater than 10 mg/cm² and includes greater than 0.156 mg/cm² estradiol, and the system achieves an estradiol flux of from 0.0125 to about 0.05 mg/cm²/day, based on the active surface area.

Claim 1 of US’900 is representative for US’900 & US’310 evaluation :

1. A method for administering estradiol, comprising applying to the skin or mucosa of a subject in need thereof a monolithic transdermal drug delivery system consisting of (i) a backing layer and (ii) a single adhesive polymer matrix layer defining an active surface area and comprising an adhesive polymer matrix comprising estradiol as the only drug, wherein the polymer matrix has a coat weight of greater than about 10 mg/ cm² and includes greater than 0.156 mg/ cm² estradiol, and the system achieves an estradiol flux of from about 0.0125 to about 0.05 mg/ cm² /day, based on the active surface area.

 

Infringement:

Infringement of US’419 patent:

Noven contented that Amneal infringed claims of US’419 patent under literal infringement. Specifically Noven argued that Amneal’s ANDA product meet the limitation of “coat weight of greater than 10 mg/cm^2".” During claim construction court construed this limitation as having plain & ordinary meaning. Amneal ANDA product have inprocess coat weights above 10 mg/cm². Specifically, the upper limits of the coat weight in the tentatively-approved product are 10.75 mg/cm² for any individual coat weight value and 10.5 mg/cm² for the average coat weight value. Similarly, the upper limits under Anmeal's proposed amended ANDA for individual and average coat weights are 10.45 and 10.40 mg/cm2, respectively (Amneal amended its ANDA after tentative approval to tighten the limits). Court, thus held that Anmeal's product infringes the asserted claims of the '419 patent.

Infringement of US’900 & US’310 patents:

Noven contented that Amneal infringed claims of US’900 & US’310 patents under Doctrine of Equivalents (DOE). Specifically Noven argued that Amneal’s ANDA product meet the limitation of “coat weight of greater than about 10 mg/cm^2".” During claim construction court construed this limitation as - "having a coat weight which weighs more than 110% of 10 mg/cm²"; that is, a coat weight of more than 11 mg/cm². Because the claim mentions “about” term which is defined in the specification as plus or minus 10%. Court sided with Amneal during claim construction which proposed claim construction as - 9 mg/cm² to 11 mg/cm^2.  Amneal argued that lower limit is excluded since specification mentions this lower limit with respect to the prior formulation of Noven, Vivelle-Dot®. Therefore, infringement would be found only if Amneal’s ANDA contains coat weight of greater than 11 mg/cm². As seen in infringement of US’419 patent, Amneal product contains coat weight less than 11 mg/cm². Thus, Amneal does not infringe under literal infringement.

Noven argued that Amneal product infringes claims under DOE. Amneal counterargued that DOE theory is barred because of prosecution history estoppel (PHE). Specifically, Amneal argued that during prosecution Noven added this coat weight limitation & thus there is an estoppel. The Court agreed with Amneal & said that the amendments to add the coat weight limitations were narrowing. Secondly, the reason for the amendment is "a substantial one relating to patentability ." The purpose of the amendment was to avoid an obviousness rejection based on prior arts and highlight the "unexpected results based on the coat weight of the polymer to achieve the claimed flux of drug delivery." Third, Noven has not rebutted the presumption that estoppel applies, because it has failed to show that the coat weight amendment is "tangential to the asserted equivalent in the Amneal ANDA Product." Court did not find Noven’s argument persuasive. Noven argued that prior art references disclosed a coat weight range of 9 to 11 mg/cm² , so the Examiner could not have relied on the coat weight amendment to overcome rejection. Noven further argued that the Examiner had initially rejected all claims, including claim 27, which included the limitation "a coat weight of greater than about 10 mg/cm²”. Noven said that it later added this limitation into claim 1 & thus this limitation is not distinguishing feature that is responsible for allowance of claims. But court agreed with Amneal instead & said that without the coat weight limitation in the claims, Noven "would not have been able to argue that the claimed invention embodied the 'unexpected result' of higher coat weight causing higher flux rates, to overcome the obviousness rejection."

Court, therefore held that, Noven failed to prove that Amneal's ANDA product infringes the asserted claims of the '900 or '310 patents under the doctrine of equivalents.

 

Invalidity:

Specification defines “transdermal” as delivery, administration or application of a drug by means of direct contact with skin or mucosa. As used herein, "dermal" includes skin and mucosa, which includes oral, buccal, nasal, rectal and vaginal mucosa.

Lack of enablement:

With respect to Lack of enablement, Amneal argued that asserted patents fail to enable the claimed transmucosal estradiol patch systems. The specification only teaches about transdermal system containing skin & not mucosa. The asserted claims are broad; they cover not just estradiol patch systems for application to the skin but also estradiol patches to be applied to any mucosal tissue, including oral, buccal, nasal, rectal, and vaginal tissue. Specification fails as to how to make or use an estradiol patch system on any mucosa (let alone all mucosae ). The specification is silent as to how much estradiol to include, or what coat weight should be used. The specification fails to identify which excipients or ingredients would be useful for making any (let alone all) of the claimed transmucosal systems. Moreover, there is no mention in the specification of whether or how the central discovery of the patents - increasing coat weight to increase flux - would apply to the various mucosae. This is perhaps not surprising, since the relationship was discovered by testing flux across skin, not mucosa! tissue. The specification's example with respect to the flux achieved with various formulations pertained only to skin, not mucosae. A POSA seeking to make a claimed transmucosal embodiment would have faced the added challenge of obtaining the claimed flux values while keeping the estradiol concentration in the claimed range and the coat weight in the claimed range above 10 or 11 mg/cm².

Dr. Lobo (Defendant expert) explained that the physiology and drug release characteristics of oral, buccal, nasal, rectal, and vaginal mucosa could vary greatly - not only from skin, but from one another. This is primarily because the skin has an impervious barrier due to a protective outer layer, known as the "stratum comeum," which is lacking in mucosae. Drug delivery across the skin is, therefore, constant and prolonged over days, while estradiol delivery across the mucosae was known to be rapid, sometimes exhibiting a burst effect. The patents provide a POSA no guidance about how to achieve the claimed daily flux when the drug is so rapidly absorbed over mucosa.

Court said that the patents and publications Noven relied on in an effort to show that the state of the art was sufficiently advanced that a POSA would somehow have found in the specification of the Patents-in-Suit sufficient guidance to make and use a transmucosal embodiment of the claims (let alone embodiments with respect to each mucosa covered by the claims) do not suffice. Turning to the quantity of experimentation, the "nature and predictability of the field," and the level of ordinary skill, the Court found that the development and use of transmucosal patch systems constituted novel, highly unpredictable endeavors at the pertinent time. Noven's remaining arguments for enablement are unavailing. Court therefore concluded that the Asserted Claims of the Patents-inSuit are invalid for lack of enablement.

Lack of written description support:

As argued above for enablement, Court said that the specification lacks any description or example of a transmucosal estradiol system, including any description or example of any oral, buccal, nasal, rectal, or vaginal patch systems, even though such systems are within the scope of the claims. Aside from the specification's definition of"flux" and "transdermal" the words "oral," "buccal," "nasal," "rectal," or "vaginal" mucosa do not appear in the specification. The specification fails to convey to a POSA the inventor's possession or invention of the claimed transmucosal estradiol patch systems. Transmucosal delivery and formulation is a separate and distinct scientific field from transdermal formulation, each with separate bodies of specialized knowledge and separate technical literature and treatises. Court thus held that a POSA reading the specification would not have understood the inventor of the patents-in-suit to be in possession of the transmucosal embodiments. Therefore, the Asserted Claims are invalid under lack of written description support.