One challenge in prosecuting formulation patent applications is convincing Examiners at the U.S. Patent and Trademark Office (USPTO) that changes to formulations of previously known compounds are not only novel under 35 U.S.C. § 102, but also non-obvious under 35 U.S.C. § 103. Examiners are often skeptical in reviewing formulation applications since changes to known formulations are viewed as routine optimizations of ingredients that produce a predictable result. In Horizon Pharma Ireland Ltd. v. Actavis Laboratories, UT, Inc., No. 14-7992 (NLH/AMD) (D.N.J. May 12, 2017), the court, however, sided with the patent holder finding that the patented claims cleared the obviousness hurdle. This represents a win for pharmaceutical companies seeking to rebut obviousness rejections during patent prosecution and a cautionary tale for competitors seeking to invalidate formulation patents.
The drug at the center of the dispute was Horizon’s Pennsaid® 2% (diclofenac sodium topical solution), which is a gel formulation that can be used for the topical treatment of knee pain, such as in osteoarthritis. Actavis filed an Abbreviated New Drug Application No. 207238 ("ANDA") for its generic copy of PENNSAID® 2% and argued that claim 12 of the '913 patent is not patentable because it is "obvious." Claim 12 of U.S. Patent No. 9,066,913 (“the ’913 patent”), which depends indirectly from independent claim 1 via claims 8 and 9, also provided below, reads:
12. A method for treating pain due to osteoarthritis of a knee of a patient in need thereof, said method comprising:
administering to the knee a topical formulation of claim 9,
wherein the administration of the formulation is twice daily.
9. The topical formulation of claim 8, wherein the hydroxypropyl cellulose is present at 2.5% w/w
8. The topical formulation of claim 1, wherein the DMSO is present at 45.5% w/w.
1. A topical formulation comprising:
diclofenac sodium present at 2% w/w;
DMSO present at about 40 to about 50% w/w;
ethanol present at 23-29% w/w;
propylene glycol present at 10-12% w/w;
hydroxypropyl cellulose; and
water to make 100% w/w,
wherein the formulation has a viscosity of 500-5000 centipoise.
The question presented to the Court is whether the ’913 patent was obvious in light of the prior art Pennsaid® 1.5% and other references. Pennsaid® 2% has thickening agents (propylene glycol and hydroxypropyl cellulose) making it more viscous than Pennsaid® 1.5%. In addition, Pennsaid® 2% differs from Pennsaid® 1.5% in that three ingredients are changed while two are unchanged.
Defendants argued that the changes to Pennsaid® 1.5% were obvious optimizations of result-effective variables that produced a predictable result. To support their assertion, defendants presented an expert who compared adjusting levels of ingredients in a formulation to adjusting the tone of a stereo receiver:
[The expert] testified that drug formulation is like adjusting a stereo receiver, and the formulation of Pennsaid 2% from the Pennsaid 1.5% chassis was simply like turning the knobs to adjust the bass and treble to achieve the desired result, in this case the delivery of the active agreement to the desired spot under the skin and at the knee at a reduced dosing regimen…. [The expert] explained that a POSA would have used her own knowledge about drug formulations and the available literature to perform a routine optimization of Pennsaid 1.5% by turning up the dial for a little more diclofenac sodium, turning up the dial for ethanol by double, turning off the dial for glycerin, turning on the dial for HPC, leaving the dials for DMSO and propylene glycol at their current setting, and turning the dial for water to sufficiently fill in the remainder.
The court, however, disagreed and upheld the ’913 patent as being non-obvious. The court found the asserted claim was not a result of routine optimization of Pennsaid® 1.5%, as “general principles and ranges of permissible concentrations would not have predicted the exact formulation and dosing frequency that resulted in Pennsaid® 2%.”
In its decision, the court criticized the defendants’ expert testimony for three reasons. First, the court found that the expert failed to explain the difference between the analogy, where the stereo knobs are independently adjustable, and the claimed formulation, where the totals must add up to one-hundred percent. This is an important concept because it highlights an important distinction between applications in the biotech and pharma spaces and those in more mechanical setting.
Second, the court criticized the analogy as failing to consider the need for the drug to pass through many layers of human tissue before reaching its target. Again, the difference between applications that are intended for human use, ingestion, absorption, etc. and those that are not are important to the courts holding.
And finally, the court found insufficient evidence to support the defendant’s argument that the changes to the Pennsaid® 1.5% formulation would produce a predictable result, particularly as to the formulation's absorption, thickness, and drying time. This appears to be the most significant of the three reasons, at least in my opinion, and emphasizes the importance of providing adequate support for a claim arguing that a change to a formulation yields a predictable result.
Overall, this holding is a victory for drug manufacturers whose formulations are modifications to existing formulations as this holding seems to place a higher burden on the party challenging the obviousness of the patent. Companies wanting to challenge formulation patents in post-grant proceedings need to provide sufficient support when they challenge a formulation claim as being a product of a mere routine optimization. Conversely, pharmaceutical or biologics companies should consider this holding during patent prosecution when seeking to rebut rejections of formulation claims based on obviousness, especially when Examiners allege that such formulations are merely the result of routine optimization of result-effective variables that produced a predictable result. Applicants may wish to highlight for the Examiner any unusual properties of the formula as support that the claim is non-obvious in light of this holding.
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