Predicting Synergy

Many US practitioners were shaken by the Supreme Court’s establishment of an “obvious to try” rationale for obviousness in KSR v Teleflex:

“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.” (Emphases added)

On June 18, 2013 the Court of Appeals of the Federal circuit (CAFC) decided NOVO NORDISKA/S INC. V CARACO PHARMACEUTICAL LABORATORIES LTD. [Opinion]

The case was an appeal to the CAFC by NOVO following a finding of obviousness by the district court for the Eastern District of Michigan which held that claim 4 of U.S. Patent No. 6,677,358 was obvious in litigation stemming from an ANDA (abbreviated new drug application)  filed by Caraco. At issue was whether secondary considerations relating to unexpected results render a claim non-obvious. (The case also dealt with inequitable conduct using the standards established in Therasense, but this posting will relate only to the obviousness issues)

Claim 4 of US 6,677,358, is directed towards a combination therapy for diabetes:

A method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin.

The claim recites two active ingredients repaglinide and metformin, used in combination. Each of these active ingredients was previously known as an anti-diabetic medication and the issue to be resolved was whether the combination is obvious in the sense of § 103.

Repaglinide is an insulin secretagogue of the meglitinide class.  Insulin secretagogues stimulate insulin release from the pancreas.  Insulin secretagogues include sulfonylureas as well as meglitinides. At the filing date of US 6,677,358 there were fifteen known secretagogues of which five were in the meglitinide class. Repaglinide is a rapid and short-acting insulin secretagogue that is quickly eliminated from the body.

Metformin is an insulin sensitizer which acts on the liver to reduce glucose production, thereby improving insulin sensitivity in muscle and fat tissues. At the relevant time, metformin was the main insulin sensitizer in use.

 Novo initiated a study in Australia, conducted by Dr. Moses, in which patients that did not respond well to metformin monotherapy were given a repaglinide/metformin combination. The Moses study indicated that this combination reduced glycosylated hemoglobin 1.41%, roughly double the effect observed with either drug administered separately. The Moses study also measured fasting plasma glucose (FPG) and revealed that the repaglinide/metformin combination reduced FPG to levels eight times lower than those typically observed with metformin alone.  This was surprising because repaglinide is known to be short acting, and was not previously believed to affect FPG.

Based upon the results of the Moses study, Novo filed a patent application. Claims in that application were rejected by the Examiner who reasoned that “…it was obvious to try combining repaglinide with metformin, and it was also predictable that the combination would yield, at a minimum, a benefit equal to the drugs taken separately, i.e., an “additive” effect.”

No progress was made in prosecution until Novo presented a declaration from Dr. Sturis which contained results of an additional study.

Dr. Sturis’s study tested the effects of metformin and repaglinide on the glucose levels of “Zucker obese rats,” which are rats bred specifically for use in pharmaceutical studies as models for obesity, diabetes and heart disease. Dr. Sturis divided twenty rats into four groups:

the first group was given a placebo;

the second was given only metformin;

the third was given only repaglinide; and

the fourth was given the repaglinide/metformin 

combination therapy. 

Dr. Sturis measured the blood glucose levels of these rats at 30, 60, and 120 minutes,  and  then calculated the combination’s “hypothetical additive effect” by adding the glucose reduction found in the metformin-only rats to that of the repaglinide-only rats. 

Dr. Sturis then compared the “hypothetical additive effect” to the actual glucose reduction found in the repaglinide/metformin group to calculate the probability (as a “p-value”) that any glucose reduction caused by the combination therapy might be attributable to synergistic rather than additive effects.

He reported the results in two ways. First, he plotted a chart showing glucose levels across time and then calculated the “area under the curve” for each line, thus expressing the average glucose reduction found across the entire study for each group of rats. According to this calculation, the rats who received the repaglinide/metformin treatment experienced a greater average reduction in blood glucose levels than the other three groups, and the combination therapy also proved more effective than the “hypothetical additive effect” of the two drugs. The p-value for this finding was 0.061.  Second, Dr. Sturis analyzed the glucose measurements at 120 minutes mark and found the largest disparity between repaglinide/metformin and the other three groups. Using the 120 minute data alone, he calculated a p-value of 0.02.

In his declaration, Dr. Sturis opined that the 0.061 p-value “indicate[d]”  that repaglinide/metformin had a synergistic effect upon blood glucose levels over the entire two-hour span, and that the 0.02 p-value at the 120-minute mark in particular demonstrated “significant synergy.” His conclusion was that repaglinide/metformin combination therapy had synergistic effects in Zucker obese rats, and that his study, together with the Moses Study “strongly suggest[ed] that the combination of repaglinide and metformin has synergistic properties in type 2 diabetic [human] patients.”

In submitting this evidence, Novo’s counsel asserted that the declaration provided “clear evidence of synergy…in the treatment of type II diabetes.”  In the opinion of Novo’s counsel, any prima facie case of obviousness was “rebutted by the evidence of synergistic and surprising results achieved by the claimed combined therapy in humans.”

The Examiner withdrew the obviousness rejection based upon these submissions.

To this point, this posting has been a summary of the facts presented in the first few pages of the court decision.

Now let’s look at these facts in the context of the KSR “obvious to try” rationale.

Was there “market pressure to solve a problem”?  Yes, some patients did not respond well to metformin monothereapy.

Were there a finite number of identified… solutions? Yes, there were fifteen known secretagogues of which five were in the meglitinide class and 10 were sulfonylureas.

Now comes the hard question, were these solutions “predictable”?  The answer here depends on what is meant by predictable.

One of ordinary skill would probably have predicted that each of the fifteen known secretagogues, including each of the five meglitinides, would have at least an additive effect when combined with metformin. That assertion seems consistent with the way that Dr. Sturis calculated his “hypothetical additive effect”.

However, one of ordinary skill might not have predicted that any of the fifteen known secretagogues would produce an eightfold reduction in FPG as repaglinide did in the Moses study.

Now we return to the CAFC decision and its analysis of the lower court finding of obviousness.

In the initial trial, both parties agreed that Caraco established a prima facie case that it was obvious to try combination therapy using metformin and repaglinide to treat Type II diabetes. This is because it was well known that two drugs having different mechanisms for treating diabetes can be more effective than one, and so drugs were often tested in combination therapy after demonstrating effectiveness in monotherapy. In fact, combination therapy using insulin sensitizers and insulin secretagogues was common at the time, and metformin was the most widely-used insulin sensitizer at the relevant date.

The district court viewed this as a prima facie case for obviousness and then went about analyzing “the evidence and assertions of unexpected and surprising results, as well as synergistic results.”  The lower court focused on the question of whether the reported synergy was unexpected.

Caraco submitted new prior art as well as testimony from expert witnesses and Novo scientists. Upon review of Caraco’s evidence, the district court determined that one of ordinary skill would have expected some synergy from the repaglinide/metformin combination. The district court did not find that the two studies proffered by Novo were sufficient to establish an unexpected or superior level of synergy. Instead the lower court found that the results presented by Novo were entirely expected based upon the state of the art. The district court finally concluded that Caraco had provided “clear and convincing” evidence of obviousness of claim 4.

The CAFC reviews all of the arguments and, in the end, upholds the district court ruling of obviousness. In this specific case, that is not surprising (despite a well reasoned and thorough dissent from Judge Newman).

What is surprising, is the implication that if an extraordinary amount of synergy is observed, a combination may be patentable, even if there were only a finite number of solutions which might have been predicted to work in a less dramatic fashion. Perhaps this makes the “obvious to try” rationale established by KSR less troubling.