Doxycycline - USA

On Oct 04, 2019 (unsealed opinion), Delaware court found infringement of formulation patents & rejected Sun’s argument that the patents were obvious.

Galderma sued Sun pharma over Oracea® Capsules patents, US 8,206,740; US 8,394,405; US 8,470,364 and US 7,749,532. Sun seeks to bring to market a new drug (NDA) which is bioequivalent to Galderma's Oracea Capsules, a once-daily 40mg administration of doxycycline for the treatment of the papules and pustules of acne rosacea. In December 2018, the Court held a three-day bench trial. At trial, Galderma asserted infringement of claim 1 of the '740 patent, claims 1 and 3 of the '405 patent, and claims 1 and 2 of the '364 patent.

Claim 1 of the '740 patent recites:

An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum ofO.l ~g/ml and a maximum of 1.0 ~g/ml, the composition consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline; (ii) a delayed release (DR) portion comprising 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Claim 1 of the '405 patent recites:

An oral pharmaceutical composition comprising about 40 mg of total doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 J.Lg/ml and a maximum of 1.0 J.Lg/ml, wherein the composition consists of 70 to 80 percent of the doxycycline formulated as an immediate release (IR) formulation and 20 to 30 percent of the doxycycline formulated as a delayed release (DR) formulation.

Claim 1 of the '364 patent recites:

An oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Claim 2 of the '3 64 patent recites:

An oral pharmaceutical composition comprising doxycycline, which at a once-daily dosage will give blood levels of the doxycycline of a minimum of 0.1 J.Lg/ml and a maximum of 1.0 J.Lg/ml, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; as [sic] a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Sun's NDA Product is a once-daily doxycycline bilayer tablet consisting of two distinct layers as an immediate release ("IR") layer and a modified release ("MR") layer, each of which contains doxycycline. IR layer contains 26.4 mg of doxycycline & releases all 26.4 mg of its doxycycline immediately upon administration without any enhanced, delayed, or extended effect. MR layer contains 13.6 mg of doxycycline out of which 3.6 mg doxycycline get released in the first 30 minutes after administration, and remaining 10 mg doxycycline releases later than 30 minutes after administration. This dual release from MR layer is because of use of two hypromellose polymers.

Main dispute was regarding "IR Portion" and "DR Portion". The parties agreed at trial that "immediate release" (IR ), as defined in the patents, is "a dosage form that is intended to release substantially all of the active ingredient on administration with no enhanced, delayed, or extended release effect." Court construed "delayed release" (DR) to mean "release of a drug at a time other than immediately following oral administration." The case was tried without any specific construction of "portion" as the parties agreed throughout trial (and even for some time after trial) that the term would be given its "plain and ordinary meaning."

Galderma contends that the "immediate release portion" limitations are met by the combination of: (1) the Sun NDA Product's IR layer; and (2) the part of the Sun NDA Product's MR layer that dissolves in the first 30 minutes after administration. Under Galderma's theory, the Sun NDA Product's IR portion, therefore, has about 30 mg of doxycycline, consisting of: (1) the entire 26.4 mg of doxycycline in the IR layer, and (2) the about 3.6 mg of doxycycline that is released from the MR layer in the first 30 minutes after administration. Similarly, on Galderma's view, the "delayed release" portion of Sun's NDA Product is the remaining 10 mg of doxycycline- all from the MR layer- which is released following the first 30 minutes after administration.

Sun counters that its NDA Product's "immediate release portion" includes only the 26.4 mg of doxycycline in the IR layer. Thus, because the IR layer has less than the about 30 mg of doxycycline claimed by the patents, Sun's view is that its NDA Product does not meet the IR portion limitations. Sun contends that its NDA Product also does not meet the "delayed release portion" limitations, for two reasons: (1) the MR layer is not "delayed release" because it releases doxycycline starting immediately after administration and the amount of doxycycline released "continuously increases over time, with no plateau or stoppage of release" and (2) even if the MR layer were a "delayed release portion," the MR layer has 13.6 mg of doxycycline, which is greater than the about 10 mg of doxycycline required by the claims.

After careful review, the Court concluded that the parties' dispute over whether the IR portion and DR portion limitations are met by Sun's NDA Product turns on the meaning of "portion." If "portion" is a functional term - such that the "IR portion" limitation is satisfied if a formulation dissolves in a manner in which 30 mg (or about 30 mg) of doxycycline is released immediately after oral administration, regardless of where in the product that doxycycline comes from- then the Sun NDA Product infringes. If, alternatively, "portion" is a structural term - such that each part of an accused product must be analyzed for its structure and then characterized as either an IR or DR structure - then the Sun NDA Product does not infringe.

In this case parties never asked the Court to construe the disputed claim term, “potion”. This is because in previous Amneal case, court issued claim construction where "portion" had its "plain and ordinary meaning”.  In present case it became apparent when Court reviewed the parties' post-trial briefs.  It was only during closing argument, which the Court heard on the last day of trial, that it began to appear as if Sun was, in fact, seeking additional claim construction. Throughout the case the understanding of portion was like plain and ordinary meaning.  Court said that it is now clear, has always been Sun- that has desired for the Court to modify its understanding of what constitutes a DR portion (as well as an IR portion). Therefore, it was incumbent on Sun somehow to have asked the Court to alter its understanding of the scope of the asserted claims by construing the portion terms. Sun has now done so, but it is far too late.

Nevertheless, court said that it will,  address the claim construction dispute and apply this construction to the evidence presented at trial. With respect to claim language, court said that it supports Galderma’s position. The absence of an explicit structural requirement in the asserted claims suggests that the inventors intended "portion" by itself not to impose a structural requirement. With respect to specification, court said that it too does not provide strong support for either side's proposed construction. The term "portion" is used four times in the specification and none of those uses indicates that the term is being used in a restrictive or narrowing manner. Nothing in this usage of "portion" indicates that the patent is using the term to refer to a physically or structurally discrete part of the composition. Prosecution History and Amneal IPR supports Sun's proposed construction. But court said that for purposes of determining the proper construction of the "portion" terms to apply in the instant litigation, the IPR provides some limited- but not dispositive, and, ultimately, not sufficiently persuasive- support for Sun's proposed construction. Court also looked into extrinsic evidences & said that the definitions provide support for Galderma's proposed constructions and none for Sun's, as they do not suggest that "portion," in general usage, is narrowly limited to structurally discrete parts. Hence, court concluded that that a POSA would understand the "portion" terms to have a broad, functional meaning, rather than a narrow, structural meaning.

Court therefore held that under this construction Sun's NDA Product satisfies immediate release & delayed release portion limitations of claim. Moreover, Sun has not proven by clear and convincing evidence that the asserted claims of the patents are invalid due to obviousness.