Wednesday, September 29, 2010

Glaxo Fires Latest Shot in Patent Battle with Genentech over Therapeutic Molecule Antibodies

On September 20, Glaxo Smith Kline (Glaxo) sued Genentech for infringement of US patent numbers RE40,070 and RE41,555 in the District of Delaware. The patents claim methods of purifying monomeric IgG antibody using hydrophobic interaction chromatography. GSK alleges in its complaint that Genentech's production of therapeutic monoclonal antibody products, specifically Herceptin, infringes the patents. Herceptin is an important monoclonal antibody therapeutic used to treat HER2 positive breast cancer. The complaint is available here.

The lawsuit is the latest volley in an ongoing patent war between GSK and Genentech over recombinant monoclonal antibody technology. Most of the patents that have been asserted are directed towards general methodologies used in the production and formulation of monoclonal antibody therapeutics.

For example, in 1999 Glaxo sued Genentech for allegedly infringing US patent numbers 5,545,403 and 5,545,405 (both generally claiming methods of treatment using recombinant antibody glycosylated by Chinese hamster ovary (CHO) cells), and US patent numbers 5,654,403 and 5,792,838 (both directed towards methods of stabilizing antibody formulations using copper chelators). Glaxo alleged that the patents were infringed by Genentech's production of Herceptin and Rituxan, two cancer drugs that target breast cancer whose tumors over express the HER2 protein and CD20 positive, B-cell non-Hodgkin's lymphoma, respectively. A district court held for Genentech, finding all of the asserted Glaxo claims invalid and/or not infringed. The case settled while on appeal to the Federal Circuit.

In 2000, Glaxo sued Genentech for allegedly infringing US patent number 5,633,162, which claims methods of growing CHO cells in a serum-free medium. While the complaint does not specifically identify the allegedly infringing Genentech products, Genentech reported in a filing to SEC that it assumed that the lawsuit was directed towards Herceptin and Rituxan. This case settled early in the litigation.

In 2009, Glaxo received FDA approval to market Arzerra, an anti-CD20 approved for the same indication as Genentech's Rituxan (chronic lymphocytic leukemia). Thus, the two products can be viewed as direct market competitors, perhaps biosimilars (we are still awaiting guidance from FDA as to criteria for biosimilarity under the new biosimilarity legislation passed by Congress as part of healthcare reform).

In 2009, Glaxo filed a declaratory judgment action in the Southern District of Florida seeking a judgment of invalidity, unenforceability and noninfringement with respect to Genentech's patent number 6,331,415. This patent is widely referred to as the “Cabilly II” patent, and came out of a highly publicized interference between Genentech and Celltech. The patent broadly covers the co-expression of immunoglobulin heavy and light genes in a single host cell. Genentech has been quoted as stating that the patent is "the backbone of recombinant antibody production in the biotech industry." Genentech has already asserted the patent against MedImmune and Centocor, alleging that those companies’ production of monoclonal antibodies products Synagis, ReoPro and Remicade infringe the patent. The litigation between Genentech and MedImmune resulted in a Supreme Court decision on standing of a patent licensee to bring a declaratory judgment action action challenging the patent. Genentech successfully moved to have the litigation transfer to the Central District of California, where the Centocor and MedImmune litigations are located.

In 2010, Genentech (along with Biogen Idec, its partner in the marketing of Rituxan) sued Glaxo in the Southern District of California for allegedly infringing US patent number 7,682,612. The patent claims methods of treating chronic lymphocytic leukemia using an anti-CD20 antibody, and thus invalid would appear on its face to be infringed by Arzerra. This case is somewhat noteworthy, since it is the only one in which the patent is specifically directed towards an antibody recognizing a specific antigen (CD20), as opposed to the other patents all relating to general methods of antibody production and formulation.

Tuesday, September 28, 2010

Jury Finds Scruggs Willfully Infringed Monsanto Patents, Award at Least $9 Million in Damages

10 years ago Monsanto sued farmers Mitchell and Eddie Scruggs (collectively referred to as "Scruggs") for infringing patents relating to genetically modified Roundup Ready soybean seeds and Bollgard-containing cotton seeds. The case has resulted in numerous judicial decisions, including three Federal Circuit decisions, most notably Monsanto v. Scruggs, 459 F.3d 1328 (Fed. Cir. 2006). Scruggs raised numerous arguments against Monsanto, including first sale/patent exhaustion, implied license, lack of sufficient written description and enablement, as well as allegations of patent misuse and antitrust violations.

Nonetheless, Monsanto has prevailed, and on September 21 a jury in the Northern District of Mississippi found that Monsanto is entitled to $2.6 million for Scruggs unauthorized planting of saved crop seeds contain the patented genes, and $6.3 million for their sale of saved soybean seeds containing the Roundup Ready gene (a practice referred to as "brown bagging"). Not only that, the jury found that the infringement was willful, which means that the court can enhance the damages up to triple the amount found by the jury, or close to $30 million. Based on history, I would not be surprised if Scruggs continues to appeal, perhaps stretching this out a few more years.

District Court Denies Novozymes Motion for Preliminary Injunction in Battle for Control of the Alpha-Amylase Market

On September 24, 2010, a federal district court in the Western District of Wisconsin denied a motion for preliminary injunction in a patent lawsuit between two of the leading companies in the field of genetically engineered industrial enzymes, Novozymes and Genencor (a division of Danisco). The two companies are essentially the only competitors in the market for alpha-amylases, used to convert corn into fuel ethanol. According to the order (available here) denying preliminary injunction, Genencor dominated the alpha-amylase market until 1999, when Novozymes entered the market with Liquozyme, a genetically engineered thermostable alpha-amylase. At one point, Liquozyme accounted for more than 80% of the alpha-amylase sold in the fuel ethanol market. In 2008, Genencor responded by introducing its own genetically engineered thermostable alpha-amylases (called GC358). Since then, Novozymes market share has dropped approximately 60%.

The patent being asserted by Novozymes, US patent number 7,713,723 (the ‘723 patent) claims priority to a patent application originally filed in 2000. The original patent application was broadly directed toward alpha-amylase mutants having increased stability at “high temperature and/or low pH conditions, in particular at low calcium concentrations.” However, the claims that ultimately issued in the ‘723 patent, which recite thermostable alpha-amylase variants comprising "a substitution of serine at position 239 relative to the parent alpha-amylase," were not added until 2009, apparently in response to Genencor's marketing of GC358, which presumably includes this mutation. Prior to the introduction of these claims in 2009, the patent application contained no disclosure specifically directed towards substitution of serine at position 239.

Importantly, the '723 patent does not cover Liquozyme, over for that matter any Novozymes product. Liquozyme presumably possesses improved thermostability over the wild type enzyme as a result of a different mutation or set of mutations.

In deciding a motion for preliminary injunction, courts essentially consider four factors: (1) the likelihood the patent owner will ultimately prevail on the merits in the case (i.e., the patent will be found infringed and not invalid); (2) the extent to which the patent owner will experience "irreparable harm" if the infringement is not stopped immediately; (3) the balance of the interests of patent owner an accused infringer; (4) and the public interest. In this case, the district court found that all these factors weighed in favor of Genencor, and denied Novozymes’ motion for preliminary injunction.

Irreparable Harm
The district court decision began by addressing the issue of irreparable harm, the factor which the court found likely to be dispositive by itself. Novozymes argued that it would suffer irreparable harm in the form of diminished reputation, loss of market share and price erosion if Genencor's product were allowed to remain on the market during the course of the litigation. However, the court pointed out that Genencor had entered the market with GC358 in 2008, but that the patent did not issue until May 2010, so that most of Novozymes’ loss in market share occurred when it was perfectly legal for Genencor's product to be on the market. The court surmised that most of the customers who would be inclined to switch from Liquozyme to GC358 had probably already done so, and thus most of the alleged harm identified by Novozymes had already occurred prior to issuance of the patent.

In assessing irreparable harm, the district court found the fact that the patent does not cover any product marketed by Novozymes to be quite significant, pointing out that while Novozymes’ argument that sale of GC358 would harm its reputation "could be persuasive if plaintiffs actually sold a product that practiced the ‘723 patent[,] it is difficult for plaintiffs to argue that their good reputation is contingent on their ability ‘to uniquely make and sell [their] patented alpha-amylase’ when they are not even using the claim technology themselves and identify no plans to do so."

The district court went on to speculate that if "plaintiffs are not trying to protect their own right to provide consumers a product that embodies the patent, then it may be that the patent is nothing more than weapon to prevent defendants from competing with them." In other words, the court seems put off by the fact that Novozymes is not practicing the technology claimed in their patent, treating them as something akin to a non-practicing entity (sometimes referred to as a patent troll).

Likelihood of Success on the Merits
The court also expressed doubt with respect to the likelihood that Novozymes would succeed on the merits of the case, based on the court's determination that there was a substantial likelihood that the asserted patent claims are invalid for lack of enablement and lack of sufficient written description. Both the enablement and written description issues arise out of the failure of the originally filed patent application to sufficiently point out and identify the later claimed substitution of serine at position 239. The patent application identified 33 amino acid positions (including position 239) in alpha-amylase which allegedly can be modified by amino acid substitution, deletion or insertion to result in some increased stability under high temperature and/or low pH conditions. It does not, however, particularly point out position 239, nor does it particularly point out substitution with serine (one of 20 amino acids commonly found in proteins), and it does not correlate the specific mutation particularly with thermostability. Genencor pointed out that the patent specification identified 8.589 x 1042 possible amino acid substitutions, deletions and insertions, and now Novozymes was attempting to claim one of those possibilities that had subsequently been shown by Genencor to provide thermostability.

This case illustrates the difficulty the inventors of genetically engineered proteins face when attempting to obtain adequate patent protection for their inventions. Protein sequence space is vast, and in most cases in which a sequence variant of a protein has been found to have some desirable functional characteristic, there are an astronomical number of alternate sequence modifications that will result in the same functional outcome. I have described this problem in a law review article (available here), and more recently in my amicus brief filed in Ariad v. Lilly (available here). Essentially, the written description and enablement requirements limit the ability of protein engineers to claim protein variants in functional terms, resulting in claims limited to enzyme sharing some degree of structural similarity to variants explicitly disclosed in the patent application. This allows competitors to design around the patent by screening for alternate structural modifications to the amino acid sequence that result in the desired function, as exemplified Genencor’s product that apparently shares the desirable functional characteristics of Novozyme’s product but employs a different structural modification to the amino acid sequence.

Balance of Harms
The court found that the balance of harms in this case favored Genencor, finding that if Genencor were forced off the market the company might "very will be crippled and unable to recover even if the injunction is lifted after the trial." On the other hand, the court found that Novozymes was essentially "asking for assistance in maintaining a monopoly at least until the end of trial."

Public Interest
The fact that Novozymes is not marketing a product covered by the asserted patent also counted against them in the court’s analysis of the effect of an injunction on the public interest. The court found that if Genencor's GC358 were taken off the market customers would be deprived of the patented invention entirely for the course of the litigation proceedings, since Novozymes is not marketing any product covered by the patent. The court found it "somewhat inconsistent for plaintiffs to be arguing on one hand that the ‘723 patent represents an important new invention and then argue on the other hand it should make no difference if no one is allowed to actually use it.”

Thursday, September 9, 2010

BIO Files Amicus Brief Supporting Eli Lilly Petition for En Banc Rehearing of Sun . Lilly

Yesterday the Biotechnology Industry Organization filed an amicus brief supporting Eli Lilly in its petition for en banc rehearing of Sun v. Lilly, a recent Federal Circuit decision pertaining to the doctrine of obviousness-type double patenting, and discussed in a previous post. I participated in the drafting of the BIO amicus brief, a copy of which can be found here.

Thursday, September 2, 2010

Sun Pharmaceuticals v. Eli Lilly: The Creeping Expansion of the Doctrine of Obviousness-Type Double Patenting

In Sun v. Eli Lilly, a panel of the Federal Circuit held a Lilly patent claiming use of the drug gemcitabine (GEMZAR) for the treatment of cancer invalid for obviousness-type double patenting, in view of an earlier Lilly patent claiming the drug per se and its originally discovered use as an antiviral agent. The invalidated patent was set to expire on November 7, 2012, 2.5 years after the expiration of the patent claiming the drug active ingredient (May 15, 2010), so this could result in a substantial reduction in Lilly’s period of marketing exclusivity. Lilly is currently seeking en banc reconsideration by the Federal Circuit.

Sun represents the most recent in a series of Federal Circuit decisions expanding the scope of the judge made doctrine of obviousness type double patenting. In this article, I briefly summarize the history of the expansion, and outline why I think the court should take this opportunity to reconsider the implications of these cases en banc.

Eli Lilly's patent prosecution decisions that resulted in a finding of obviousness type double patenting

It is informative to review the facts of the case. In the early 1980s, a Lilly scientist invented a method for synthesizing a genus of chemical compounds including gemcitabine, something others had previously attempted but failed to accomplish. He also showed that the compound had antiviral activity. Lilly filed a patent application disclosing the genus of chemical compounds and their use as antiviral agents.

The original inventor of the compound, along with a second Lilly inventor, then discovered that gemcitabine has anticancer activities, so these inventors filed a second application claiming methods of using the drug to treat cancer. This application did not claim priority to the first application.

On the same day Lilly filed the second application, it also filed a CIP of the first application. In retrospect, this was a critical mistake. The CIP was apparently filed to expand upon the definition of the disclosed genus of compounds, basically by adding to it species wherein certain R groups could be hydrogens. Significantly, this added disclosure was not necessary in order to patent gemcitabine, since gemcitabine was disclosed in the originally filed patent application.

At that time, there was some uncertainty with respect to the extent to which it was necessary to update the best mode when filing a CIP application (this uncertainty was ultimately addressed in 1994 in Transco). In any event, presumably in an attempt to ensure compliance with the best mode requirement, Lilly also added disclosure of the anticancer properties of the chemical compounds in the CIP.

Ultimately, the CIP application resulted in a patent claiming the drug active ingredient as a composition of matter, and also methods of using it as an antiviral agent. Later, the second patent application issued with claims to methods of using the drug to treat cancer. In Sun v. Lilly, it was the disclosure of anticancer activity added to the first patent by means of the CIP application which was used as the basis for invalidating the second patent claiming that use. In the next section, I explain why this represents a significant expansion of the doctrine of obviousness type double patenting.

The creeping expansion of obviousness type double patenting

The Federal Circuit has established a two-step process for analyzing obviousness type double patenting. First, the court construe the claims in the earlier patent and the claims in the later patent, and determines the differences. Second, it determines whether those differences render the claims patentably distinct.

One fundamental distinction between analysis for obviousness under section 103 and obviousness type double patenting is that when analyzing for double patenting only the claims of the two patents are to be considered. As the Federal Circuit stated in 1992 in General Foods v. Studiengesellschaft Kohle, its "precedent makes clear that the disclosure of a patent cited in support of a double patenting rejection cannot be used as though it were prior art.”

However, in the 2002 decision of Geneva v. GSK, the Federal Circuit began chipping away at this prohibition against using the written description of the earlier patent to invalidate the second patent, and embarked upon what has become a creeping expansion of the doctrine. In that case, the earlier patent claimed a drug active ingredient. The written description portion of the earlier patent also describes a method of using the drug to treat a disease, but significantly, this use of the drug is never mentioned in the patent claims. Nonetheless, the panel used this disclosure in the written description of the first patent to invalidate a second patent claiming that method of use.

This seems to fly in the face of General Foods and the controlling case law. However, the Geneva panel justified its decision to go outside the claims of the first patent in its analysis by reasoning that the claim in the earlier patent "is drawn to a compound having a certain physical property," and thus, "[s[tanding alone, that claim does not adequately disclose the patentable bounds of the invention. Therefore, this court examines the specifications of those patents to ascertain any overlap in the claim scope for the double patenting comparison."

Although the Geneva panel states that it needed to refer to the written description of the first patent to determine the extent of overlap between the claims in the two patents, this explanation does not appear to survive close scrutiny. The claims in the first patent broadly recite chemical compound, with absolutely no limitation respecting the use of the compound. It is black letter law that a patent claiming a chemical compound dominates all uses of the compound as defined by the claims, including methods of using the compound that are not disclosed in the patent specification, and methods that were nonobvious and not even contemplated at the time the patent was filed. While it is undoubtedly appropriate to consult the entire specification in construing the scope of a patent claim, it is unnecessary to consult the specification for methods of using a compound when ascertaining the scope of a patent claim directed to the compound as a composition of matter.

Although the Geneva panel’s use of disclosure in the written description as a basis for invalidating the second patent is questionable, at least the panel provided a policy justification for his decision. The panel correctly noted that in order for chemical compound to be patentable, the patent applicant must disclose a utility for the compound. Since the earlier patent only identified a single utility for the claimed drug, the disclosure of that use was necessary for the patentability of the chemical compound. Thus, while it was incorrect for the panel to suggest that the disclosure of the method of use in the written description was relevant to the question of claim scope, it was clearly relevant to the question of patentability.

The Geneva panel stressed that since the earlier patent disclosed only a single utility of the compound, the claims of the second patent reciting nothing more than that disclosed utility as a method was not patentably distinct. In essence, the panel's decision can be rationalized as a policy of not allowing a second patent on a method of use if that method of use was critical to the patentability of the first patent claiming the molecule per se.

Five years later, the Federal Circuit again was faced with an allegation of double patenting involving a first patent claiming a drug active ingredient and a second patent claiming methods of using the drug active ingredient. In Pfizer v. Teva, the panel once again went beyond the language of the patent claims, and invalidated the second patent because the method of use claimed was disclosed in the written description section of the earlier patent.

Significantly, in Pfizer the first patent disclosed multiple uses of the composition, and the invalidated claims encompassed only some subset of those uses. Thus, the facts of Pfizer are distinguishable from those in Geneva, where the method of use claim was directed to the sole utility disclosed in the earlier patent, and thus presumably necessary takedown to the validity of the first patent. Thus the rationale to justify the Geneva decision, i.e., that the claimed method of use was critical to the patentability of the first patent, does not appear to exist in Pfizer. In effect, Pfizer expanded the rule set forth in Geneva, by holding that the disclosure of multiple uses of a molecule in the first patent renders unpatentable later claims directed towards any of those methods.
The Pfizer decision provides no policy justification for this expansion of the Geneva doctrine, and fails to even acknowledge the expansion. Nonetheless, one might justify it on policy grounds by pointing out that by disclosing multiple methods of use in the original patent application, the inventor was able to stake a claim of priority to these multiple uses by securing an early effective filing date. By choosing to avail itself to this earlier effective filing date, the patent applicant (arguably) should be limited to a single term for all of the patents issuing out of this single priority document.

We then come to the Sun v. Lilly decision, in which the panel further expands the holdings in Geneva and Pfizer by interpreting those decisions as creating a bright line rule that any use disclosed in a patent claiming a drug active ingredient precludes the owner of the patent from obtaining any second patent on one of the disclosed method of use, regardless of whether the claimed method of use was disclosed in the original patent application which provides the effective filing date for the first patent. Unlike the earlier cases, the method of use claimed in the second patent was not disclosed in the originally filed application to which the first patent claims priority.

Note that putative policy justifications for the Geneva and Pfizer decisions do not appear to be present in Sun. Unlike Geneva, the second patent does not claim a method of use that was critical to the patentability of the first patent. The first patent disclosed use of the compound as an antiviral agent, and the patent office issued patent claims directed towards use of the compound as an antiviral, raising a presumption that this is a valid practical utility which would confer patentability on the compound, regardless of the later disclosure of the anticancer activity. Furthermore, unlike the case in Pfizer, the later claimed method of use (anticancer) was not disclosed in the originally filed patent application that led to the first patent, so this first patent application was not available to Lilly to provide an effective priority date for the method of treating anticancer.

In fact, Lilly only ran afoul of obviousness type double patenting because it voluntarily chose to update and supplement the disclosure of the first filed patent application with the disclosure of anticancer activity. They could have avoided the problem by simply prosecuting the originally filed patent application to obtain patent claims covering the drug active ingredient, which it seems clear did not require disclosure of the additional material added by amendment to the CIP. If they wanted to expand the genus of chemical compounds, they could have filed the CIP as a divisional, thereby avoiding the need to add disclosure of the anticancer activity to the gemcitabine composition of matter patent.

In short, if Lilly had a crystal ball and could have foreseen the recent expansion of obviousness type patenting, it could have easily avoided obviousness type double patenting by simply altering its patent filing procedure. But this illustrates how the holding in Sun elevates form over substance.

The decision seems to conflict with 35 USC 103(c)

Congress amended the patent statute by introducing 35 USC 103(c), which basically shields companies from having the inventions of a company’s inventors rendered obvious by prior art created by other inventors at the same company. Congress’s intent was to encourage follow-on innovation and intra-company collaboration.

Originally, 103(c) only included 102(f) and 102(g) prior art, but it was subsequently amended to also include 102(e). In effect, Congress explicitly decided that commonly owned inventions should not be subject to invalidation for obviousness based on subject matter disclosed in a commonly assigned earlier filed patent application. Sun stands congressional intent on its head. By ignoring General Foods, it effectively allows the court to invalidate a patent based on a finding that it claims subject matter that is obvious in view of subject matter disclosed in the specification of an earlier filed commonly assigned patent application. But it goes even farther than that, for in Sun invalidity was based on subject matter added after the effective filing date, and thus not available as 102(e) prior art.

The biotech industry would benefit from en banc review of this issue

A number of issues raised by this and decision that would seem to warrant en banc review. There is clearly a tension between General Foods and Sun and its predecessors. While General Foods states that only the patent claims are to be compared, Geneva opened up the door to using the written description of the earlier patent to invalidate a later patent. In Pfizer and Sun, the door has opened wider and wider. The Federal Circuit should acknowledge this expansion of judge made law and consider whether it is justified by public policy considerations. If the court chooses to go down this route, it should delineate the boundaries of the expanded doctrine.

For one thing, it is unfair to patent owners to change the laws of patentability in a manner that invalidates a valuable patent for patent prosecution decisions made based on the case law at the time. In Festo, the Supreme Court stressed the importance of not altering the law in a way that undercuts the investment backed expectations of the inventive community.

Moving forward, some clarity on the issue would be very helpful. Today's inventors should understand the consequences of adding disclosure to a patent application, in order to rationally decide when to file a patent application, what to include in the disclosure, and when to invest in follow-on research.

For example, based on the Sun decision the wisest course for drug companies would be to file their original composition of matter patent application with a minimal disclosure of methods of using the compound sufficient to satisfy the utility requirement. There is an incentive to prioritize follow-on research on uses not disclosed in the original application, because presumably those uses will not be precluded from being patented separately. Companies might be less inclined to pursue research and development of methods of use disclosed in the earlier patent application, but perhaps that is a reason for the court to rethink the course it has embarked upon.

But who is to say for sure that the doctrine will not be expanded in subsequent decisions to cover methods of use that are not even disclosed in the earlier specification? It would certainly be consistent with the progressive expansion we have seen in going from Geneva to Pfizer to Sun. Uncertainty with respect to the availability of patent protection is a disincentive to future investment in innovation, and it would be nice if the en banc Federal Circuit would clarify the boundaries of the obviousness type double patenting doctrine sooner rather than later.