Diclofenac - USA

On Oct 10, 2019, Federal Circuit affirmed district court’s decision which prohibited Actavis from marketing generic version of PENNSAID 2% till Oct 2027.

Horizon is the assignee of U.S. Patent Nos. 8,217,078; 9,132,110; 8,618,164; 8,546,450 (method of use patents); and US 9,168,304; 9,168,305; 9,101,591; 8,563,613; 9,220,784; 8,871,809; 8,252,838; 9,066,913 (formulation patents). These patents are listed in orange book for PEENSAID 2% (diclofenac topical solution). It is used for trating knee pain. Actavis sought to market a generic version of PENNSAID 2% and filed ANDA.Horizon then sued Actavis in New Jersey court.

Claim 10 of the ’450 patent is illustrative of the asserted claims of the method-of-use patents:

10. A method for applying topical agents to a knee of a patient with pain, said method comprising: applying a first medication consisting of a topical diclofenac preparation to an area of the knee of said patient to treat osteoarthritis of the knee of said patient, wherein the topical diclofenac preparation comprises a therapeutically effective amount of a diclofenac salt and 40–50% w/w dimethyl sulfoxide; waiting for the treated area to dry; subsequently applying a sunscreen, or an insect repellant to said treated area after said treated area is dry, wherein said step of applying a first medication does not enhance the systemic absorption of the subsequently applied sunscreen, or insect repellant; and wherein said subsequent application occurs during a course of treatment of said patient with said topical diclofenac preparation.

Claim 49 of the ’838 patent is illustrative of the asserted claims of the formulation patents:

49. A topical formulation consisting essentially of: 1–2% w/w diclofenac sodium; 40–50% w/w DMSO; 23–29% w/w ethanol; 10–12% w/w propylene glycol; hydroxypropyl cellulose; and water to make 100% w/w, wherein the topical formulation has a viscosity of 500–5000 centipoise.

New Jersey court in its deciosn found certain terms indefinite, noninfingement with respect to ANDA label & finally nonobviouness of particular claim. Horizon appealed and Actavis cross-appealed the district court’s final judgment.

I Claim construction:

During claim construction, the district court found that the term “the topical formulation produces less than 0.1% “impurity A” after 6 months at 25°C and 60% humidity” was indefinite the identity of “impurity A” is unknowable to a person of ordinary skill in the art (“POSITA”). Second, the district court found that the term “the formulation “degrades” by less than 1% over 6 months” was indefinite because neither the claims nor the specification disclose the means to evaluate degradation. Third, the district court found that the term “consisting essentially of” was indefinite.

Upon appeal, Federal Circuit with respect to term “impurity A” agreed with district coiurt & said that POSITA would not know, with reasonable certainty, the identity of the substance as claimed. The term “impurity A” only appears in claim 4 and Example 6 of the ’913 patent. Court daid that Horizon does not cite to any part of the specification, the claims, or the prosecution history that defines or directly connects “impurity A” to USP Compound A which Horizon attemped to connect. Because the specification omits the details of the HPLC experiment—such as the column, the mobile phase, and the flow rate—a POSITA faced with this specification would not reasonably presume that Example 6 was undertaken using a pharmacopoeia chromatographic system. This outcome undermines Horizon’s reliance on the pharmacopoeias to extrapolate meaning into “impurity A.”

With respect to “degrades” term, federal circuit said that district court’s finding that the claims reciting the “degrades” term are indefinite follows from the indefiniteness determination about “impurity A.” Since “impurity A” is indefinite, it logically follows that another term, such as the “degrades” term, which relies on “impurity A” for its construction, must also be indefinite.

With respect to “Consisting Essentially Of” term, federal circuit said that district court properly considered this term in accordance with legal meaning: “consisting of only the specified materials and those that do not materially affect the basic and novel properties of the claimed invention.” Parties’ dispute focuses on the basic and novel properties of the formulation patents. Court said that the specification of the formulation patents identified five basic and novel properties: (1) better drying time; (2) higher viscosity; (3) increased transdermal flux; (4) greater pharmacokinetic absorption; and (5) favorable stability.

Horizon argues that the Nautilus definiteness standard focuses on the claims and therefore does not apply to the basic and novel properties of the invention. Court further said that Supreme court’s Nautilus definiteness standard applies to the basic and novel properties of an invention. Because by using the phrase “consisting essentially of” in the claims, the inventor in this case incorporated into the scope of the claims an evaluation of the basic and novel properties. Having determined that the basic and novel properties of an invention are part of the scope of the claims in this case, it follows that those basic and novel properties, “when read in light of the specification and the prosecution history, must provide objective boundaries for those of skill in the art.” Now with respect to drying time, court found that the two different methods for evaluating “better drying time” do not provide consistent results at consistent times. Court also found persuasive the testimony of Actavis’s expert that a POSITA would not know under what standard to evaluate the drying rate. Therefore, court concluded that the phrase “consisting essentially of” was indefinite based on its finding that the basic and novel property of “better drying time” was indefinite on this record.

II. Summary Judgment of non-infringement:

On January 27, 2017, after the district court reaffirmed its claim constructions and related indefiniteness determinations, Actavis filed a motion for summary judgment of noninfringement. Actavis argued that there was no dispute that Actavis did not directly infringe the patents-atissue, and that, while Horizon premised its allegations of induced infringement upon the labeling of Actavis’s ANDA product.

Court said that Actavis’s ANDA product, diclofenac sodium topical solution 2%, is a generic version of Horizon’s PENNSAID®2%. Both products are directed to the treatment of osteoarthritis pain on the knees.

Main disputed part of the label was following warning portion which states:

“Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution”.

Court evaluated Actavis’s label vis-à-vis the claims of the method-of-use patents and noted that the dispute between the parties centered around the warning in Actavis’s label to wait until the treated area is dry before covering it or applying another substance.  Although Horizon recognizes that not every user will need to apply sunscreen, insect repellant, or another topical medication, it contends that, when such need arises, Actavis’s instruction will lead to an infringing use.  Actavis argues that its proposed label does not induce infringement because, unlike the method-of-use patents, its label does not promote the application of a second topical agent after application of the diclofenac sodium gel. Actavis maintains that its label never affirmatively instructs the patient to apply anything after the diclofenac sodium gel; the label merely permits applying a second topical agent after the patient waits for the diclofenac sodium to dry. Its label, therefore, does not contain any instruction that induces infringement.

Court said that the patented method here requires three distinct steps. The user must: (1) apply the inventive formulation, (2) wait for the area to dry, and (3) apply sunscreen, insect repellant, or a second topical medication. The instructions in Actavis’s label, however, only require the first step of this method, nothing else. The warning, then, operates in an “if/then” manner: if the user wants to cover the treated area with clothing or apply another substance over it, then the patient should wait until the area is dry. This does not encourage infringement, particularly where the label does not require subsequent application of sunscreen, insect repellant, or a second medication. Court thus held that “Actavis’s proposed label does [no] more than simply permit, rather than require or direct, the post-product application of sunscreen, insect repellant, or a second topical medication.”  The fact that Actavis’s label does not require subsequent application of other products reflects that the product has “substantial noninfringing uses, [and] intent to induce infringement cannot be inferred even [if Actavis] has actual knowledge that some users of its product may be infringing the patent.”

III. Trial on obviousness:

The district court’s Markman and summary-judgment orders disposed of most of the asserted claims of the patents-at-issue. At trial, only one claim remained—claim 12 of the ’913 patent. Actavis maintained that claim 12 of the ’913 patent was invalid as obvious. Actavis stipulated that if the claim was found not invalid at trial, its ANDA product would infringe the claim. On May 12, 2017, the district court found that Actavis had not shown, by clear and convincing evidence, that claim 12 of the ’913 patent is invalid for obviousness.

During appeal, Actavis argued that the district court erred by requiring that the prior art predict the exact formulation of the asserted claim. For obviousness arguments Actavis relied on previous formulation i.e. PENNSAID 1.5% which differes qualitatively with respect to HPC & quantitatively  with respect to certain excipients when compared to PENNSAID 2%. Federal Circuit sided with district court which credited Horizon’s expert’s (Dr. Bunge’s) testimony that the inventive formulation was complex and that a POSITA would be challenged to predict relative ratios in order to achieve the desired goal of PENNSAID® 2%. Court also found that the combination of changes to the PENNSAID® 1.5% formulation were not obvious optimizations of result-effective “variables that would produce a predictable result, particularly as to the formulation’s absorption, thickness, and drying time.” Court also found that the variables involved in this case, including the components of the inventive formulation, interact in an unpredictable or unexpected way, such that the results emanating into PENNSAID® 2% were not obvious. Court found that nothing in the prior art allowed a POSITA to find “the schematic or roadmap to a diclofenac gel effective at two doses a day compared to prior art’s four doses a day.” Court thus held that claim 12 of the ’913 patent was nonobvious.