[author: Courtenay C. Brinckerhoff]

In a decision issued November 2, 2012, the Intellectual Property Appellate Board of India (IPAB) determined in a post-grant opposition proceeding that Roche’s patent covering its Pegasys® (pegylated interferon alfa-2a) product for the treatment of Hepatitis C, is invalid as obvious. The IPAB determined that an NGO had standing to challenge the patent, and cited U.S. case law, including KSR, in support of its decision.

The Patent at Issue

The patent at issue was India Patent No.198952, which claimed priority to a U.S. patent application filed in 1996. Claim 1 (as reproduced in the PTAB decision) recites:

1. A physiologically active branched PEG IFNα conjugate having the formula … , wherein R and R’ are independently lower alkyl; X is NH or O; n and n’ are integers having a sum of from 600 to 1500; and the average molecular weight of the polyethylene glycol units in said conjugate is from 26,000 daltons to about 66,000 daltons.

Standing for an NGO

Roche challenged the standing of an NGO to oppose the patent in a post-grant proceeding. The PTAB refused to read a requirement for a “commercial interest” into the difference between “any person” (who may challenge a patent prior to grant) and “any interested person” (who may challenge a patent after grant). The PTAB stated:

The continuance of an unworthy patent on the Register is not only against the interest of other persons carrying on the same business but also against the public interest. For the protection of valid patents, we have no doubt to prevent the busybodies and unnecessary interferences. But, it is as much against the public interest to allow unworthy patents to be on the Register, as it is to prevent third parties having no interest from attacking a deserving patent. … The interest should not be a fanciful interest. … In the present case, the appellant claims that it is a society which works for the community of HCV and HIV sufferers. This is not challenged. The invention is admittedly for the use in the case of hepatitis-C. The continuance or removal of the patent will definitely affect the interest of the community for whom the appellant claims to work. … We therefore hold that the appellant who works for a community which needs the medicine is definitely a "person interested."

Obviousness

The PTAB noted that the Patents Act does not provide a presumption of validity to granted patents:

Due to the purely non-adversarial nature of the grant of patent where there is no pre-grant opposition, we cannot exclude the possibility of an unjustifiable invention getting a grant. It is only because the filters may be porous at the IPO, that even after the two tier oppositions, revocation is provided.

As summarized by PTAB, the patent describes the invention as a “new PEG interferon conjugate” that “has surprising properties.” In particular, the invention is said to relate to “a new class of PEG derivative interferon alpha” where, “instead of having two linear PEG molecules at two different sites, it achieves the same effect by attachment of two linear PEG molecules at a single site.” The patent “states that this conjugate, when compared to other PEG interferon alpha conjugates has (i) a much greater antiproliferative activity, (ii) disproportionate to the enhancement or reduction that occurs in its other characteristics and (iii) virtually no immunogenicity.”

The controller (who had upheld the patent) had summarized the prior art as showing as follows:

1. Interferons are known and known to be bifunctional.
2. Preparation of PEG conjugates is known.
3. Effects of conjugation are known.
4. Variation of tissue uptake and distribution with variance in molecular weight is known.

(Still, the controller had sustained patentability based on his reading of the references.)

The IPAB cited this evidence in support of its determination of obviousness:

From Annexure B we see that pegylation was first developed by Davis, Abuchowski and colleagues in the 1970s. Their goal was to enhance the delivery of therapeutic molecules; perhaps more importantly, pegylation has also been shown to change the pharmacokinetics and thus, the pharmacodynamics of the therapeutic molecule without the limitations of classical liposomes. … Using pegylation to increase the size and molecular weight of a therapeutic protein alters the immunological, pharmacokinetic and pharmacodynamic properties of the protein in ways that can extend its potential uses. Large proteins generally have more attachment sites and, therefore, are commonly multipegylated. Attachment at multiple sites, however, increases the likelihood of steric interference at the active site of the native protein, resulting in a possible inhibition or reduction of activity. The attachment of branched PEG moieties can increase the size of the moiety (and net total molecular weight of the conjugated protein) without a resultant increase in the number of attachment sites. In addition, branched chain PEG conjugates have been shown to have increased pH and thermal stability and increased resistance to proteolytic digestion compared with linear PEG conjugates. The authors cited from Monfardini to show the advantage of branched chain PEG conjugates. They also said that pegylation may decrease the cellular protein clearance.

The IPAB then cited the Federal Circuit’s 2007 decision in Pfizer, Inc. v. Apotex, Inc., where the court found that claims directed to a specific pharmaceutical salt were obvious, despite some advantageous properties that were associated with the claimed salt. As summarized by the IPAB:

The Court held that “obviousness cannot be avoided simply by showing of some degree of unpredictability in the art so long as there was a reasonable probability of success. The Court held that indeed, a rule of law equating unpredictability to patentability, applied in this case, would mean that any new salt – including those specifically listed in the ‘909 patent itself – would be separately patentable, simply because the formation and properties of each salt must be verified through testing. This cannot be the proper standard “since the expectation of success need only be reasonable, not absolute. …

This conclusion on obviousness appears to be almost tailor-made for this case. Here too, the prior arts while not experimenting with interferon specifically did not exclude it, the success of Ex-C and Ex-E would have given the person skilled in the art a reasonable hope of success. All the claim paradigms were mentioned in the prior arts. The unpredictability of success cannot rule out obviousness. So even if different proteins may display different properties, the expectation of success was reasonable especially since it was known that linear pegylation improved the activity of Interferon.

The IPAB also cited the Supreme Court decision in KSR:

In KSR International Co. v. Teleflex Inc. … the United States Court of Appeals for the Federal Circuit [sic!] refixed the bar on patentability. That case revolved around the question of obviousness and stated that the Court must ask whether the improvement is more than the predictable use of prior art elements according to their established functions. It stated that the question is not as to the combination of obviousness of the patent but as to the combination of obviousness of a person of ordinary skill in the art.

The IPAB determined that the claimed invention was obvious, noting:

It was known that PEG conjugated biomolecules have (i) better physical and thermal stability, (ii) protection against susceptibility to enzymatic degradation, (iii) increased solubility, (iv) longer in vivo circulating half-life, (v) decreased clearance and (vi) enhancing potency. It was also known at the time of invention that branched PEG conjugates had increased pH and thermal stability and greater stability than linear PEG conjugates and reduced immunogenicity and antigenicity and reduced toxicity. It was also known that pegylation of some proteins may result in reduction of in vitro activity along with the enhanced in vivo activity and that the pegylation of interferon reduces in vitro antiviral activity but increases antiproliferative activity in human tumor cells.

With regard to unexpected results, the IPAB did not give weight to unsupported assertions in the patent or data submitted during the proceeding “without the supporting affidavits of the authors,” which was further criticized for being “published after the priority date.”

Thus, “the invention [was] held to be obvious” and “the grant of Patent No.198952 [was] set aside.”

Too Many Firsts?

According to an article at IP Watch, this patent was “the first product patent on a medicine in India after the country switched to a product patent regime for medicines” under TRIPS, and now is “India’s first successful post-grant opposition case.”

The NGO’s persistent efforts to invalidate the patent are interesting, particularly as we prepare for post grant review challenges under the America Invents Act. Well-funded organizations opposed to pharmaceutical or biotechnology patents could launch targeted attacks against key patents. While the immediate effect of such successful challenges might be to make the specific patented products more widely available through generic products, the long-term effects on research and development could have a negative impact on public health. As it is, I imagine that this decision will have pharmaceutical and biotechnology companies revisiting their plans to pursue patent protection and product development in India.