Recently Anubha had blogged about the IPAB decision revoking Allergan’s patent for Combigan. Combigan refers to a combination eye-drop product used for treating glaucoma comprising combination of Brimonidine tartarate and Timolol maleate. Media reports termed this decision as the latest in a series of intellectual property setbacks suffered by Western drugmakers. These skewed reports also portray this revocation decision as one of many tactics by India to remove an inconvenient patent out of the way to introduce affordable generic versions. What these reports failed to highlight was that several claims of patents covering Combigan were invalidated as being obvious even in major jurisdictions like US and EU. Also it wasn’t as though the Indian patent was invalidated by applying one of those sections (eg. Section 3) which is unique to Indian patent law. An analysis of US CAFC decisions and IPAB decision for Combigan is presented below. Longish post, but hope to make it worth your while.
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Combigan US patents: Background
The patents in question are 4 OB listed patents related to Combigan viz: the ’463 patent, the ’258 patent, the ’976 patent and the’149 patent. The claims of '463, ‘258, and '976 patents with the exception of claim 4 of ‘149 patent were generally treated as a single group.
Claim 1 of ‘463 patent was considered representative and it states: 1. A composition comprising about 0.2% timolol by weight and about 0.5% brimonidine by weight as the sole active agents, in a single composition.
Sandoz sought to market a generic version of Combigan thus triggering litigation under Hatch Waxman framework. The district court rejected allegations that claim 1 of ‘463 patent was invalid as obvious over prior art. On appeal, the Fed circuit reversed the district court's finding that the claims of the '463 patent were non-obvious.The CAFC decision can be found here
Sandoz sought to market a generic version of Combigan thus triggering litigation under Hatch Waxman framework. The district court rejected allegations that claim 1 of ‘463 patent was invalid as obvious over prior art. On appeal, the Fed circuit reversed the district court's finding that the claims of the '463 patent were non-obvious.The CAFC decision can be found here
Prior art: what was known at the time of invention?
Both timolol and brimonidine were commercially available drugs in their claimed concentrations used for ophthalmic conditions at the time of the invention. At the time of the invention, it was known that the serial administration of brimonidine and timolol reduced intraocular pressure greater than either timolol or brimonidine alone. Moreover, DeSantis (US 5502052), the primary prior art reference, expressly provided a motivation to formulate fixed combinations of alpha2-agonists and beta blockers, including timolol, in order to increase patient compliance.
District court findings:Summary
- The court found that there would be no motivation to create the combination product because the FDA did not view patient compliance as a factor for approval.
- Second, the court found that the formulation arts are unpredictable.
- There were some teachings in the prior art that taught away from the claimed invention.
- Finally, the court observed that there were secondary considerations that support the finding of non-obviousness including long-felt need and unexpected results.
Federal circuit: Do secondary considerations outweigh motivation to combine?
The CAFC addressed each of the findings of district court as follows:
- Fed circuit opined that there is no requirement in the patent law that the person skilled in the art should be motivated to combine based on the rationale that forms basis for FDA approval. Motivation to combine may be found in many different places and forms; it cannot be limited to those reasons the FDA sees fit to consider in approving drug applications.
- While agreeing that formulation sciences inherently contain a certain degree of unpredictability, the opinion stated that “obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.”
- It also agreed that the prior art as a whole taught away from the invention.
- Previous attempts to treat patients twice per day with brimonidine resulted in a loss of efficacy eight to nine hours post administration. This loss of efficacy is referred to as the “afternoon trough.” The court found that a twice per day dosage regimen of Combigan® unexpectedly did not suffer from the afternoon trough issue. The Fed circuit concurred with district courts findings that that this result was unexpected. However the CAFC maintained that there was a motivation to achieve better patient compliance. Whether or not that combination also solved problems associated with the afternoon trough, we find the motivation to make the combination was real.
Thus the CAFC opined that unexpected results and prior art teaching away were NOT sufficient to outweigh the other evidence of obviousness with respect to these formulation claims.
Claim 4 of ‘149 patent: A different conclusion?
As mentioned above, claim 4 of ‘149 patent was analyzed separately by Federal Circuit. Claim 4 of the ’149 patent is directed to reducing the daily number of doses of brimonidine without loss of efficacy by administering fixed combination and reads as follows:
4. A method of reducing the number of daily topical ophthalmic doses of brimonidine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy, wherein the concentration of brimonidine is 0.2% by weight, said method comprising administering said 0.2% brimonidine by weight and 0.5% timolol by weight in a single composition
While the federal circuit held that the formulation of 0.2%wt brimonidine and 0.5%wt timolol was obvious, it came to a different conclusion with respect to claim 4 of the '149 patent. The CAFC reasoned that although the prior art shows concomitant administration of brimonidine and timolol, it does not establish that switching from 3 times a day to 2 times a day does not result in loss of efficacy. Hence it concluded that claim 4 was NOT obvious in light of prior art.
Avoiding loss of efficacy an inherent result of the formulation?: Judge Dyk’s dissent
Dissenting from the majority’s opinion holding that claim 4 of the ’149 patent is not invalid as obvious Judge Dyk observed that avoiding loss of efficacy is an inherent result of the claimed method. Since the formulation was held obvious, inherent result /property of the formulation is also obvious. Judge Dyk reasoned a newly-discovered result or property of an existing (or obvious) method of use is not patentable.
The majority differed and observed that the prior art evidence does not conclusively establish that dose reduction “from 3 to 2 times a day without loss of efficacy” limitation is an inherent property or a necessary result of the administration.
IPAB decision:
The IPAB concluded “We too are of the opinion like the Federal Court that there was a reasonable expectation of success in view of the DeSantis. Therefore for the above reason, we find that the invention is obvious."
With regard to non-compliance of Section 8, the IPAB noted that the applicant had failed to inform the Controller regarding refusal of corresponding EU patent and various stages of prosecution in the US counterpart patents (non-final rejections etc.). Curiously, Allergan tried to argue that Therasense like inequitable conduct standards should be set for Section 8. In Therasense, Inc. vs. Becton, Dickinson and Co (Fed. Cir. 2011) an en banc decision, the Federal Circuit held that inequitable conduct must be shown with clear and convincing evidence and that there was intent to withhold or misrepresent information and that the information was material. However, the IPAB reasoned that our law does not make any qualification regarding the failure to disclose nor does it say that the failure to furnish the S.8 details must be deliberate and willful. The IPAB opined that even if it was to assume Therasense like standards for the present case but for that the fact that the EP office action and/or US office action were kept away from the Controller, the patent may not have been granted. The IPAB decision itself can be found here and Anubha’s post on the same can be accessed here.
What was different in the Indian decision?
In India, Combigan was protected by only one patent viz IN219504. Since method of treatment claims are precluded from patentability in India, claim 4 of ‘149 wasn’t patented. Since the claims of IN219504 were invalidated by IPAB, it paved way for generic entry (read Ajanta pharma).
On the other hand in US, as discussed earlier Combigan was protected by several patents (patent thicket). Even though Sandoz succeeded in establishing that claims of ‘463 patent were invalid as obvious, the Fed circuit ruled that claim 4 of 149 as not obvious. Thus market entry for generics (Sandoz) in US is barred until expiry of ‘149 patent i.e. April 19, 2022.
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