Wednesday, September 16, 2009

Prometheus Prevails in a Victory for Biotechnology and Personalized Medicine

In past posts I have discussed Prometheus v. Mayo, which addresses the issue of whether a diagnostic method for providing personalized therapeutic treatment is patent eligible under Bilski (click here for background on the case). In an amicus brief I filed on behalf of myself and several other law professors, we argued that such claims should be patent eligible, and a contrary decision by the court could adversely impact future innovation in diagnostics and personalized medicine. Today a unanimous panel of the Federal Circuit agreed (click here for opinion).

Claim 1 of US Patent Number 6,355,623 is representative of the claims issue:

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

wherein the level of 6-thioguanine less than about 230 pmol per 8.times.10.sup.8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and

wherein the level of 6-thioguanine greater than about 400 pmol per 8.times.10.sup.8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

In its opinion, the Federal Circuit held that the both the step of administering a drug and the step of determining the level of drug metabolite in the patient are sufficiently transformative to satisfy the transformation prong of the Bilski machine-or-transformation test. The court did not address the issue of whether the claims satisfied the machine prong of the test, since satisfaction of the transformation prong was sufficient to find all of the claims at issue patent eligible.

With respect to the administration step, the court held that administration of the drug to a patient results in “various chemical and physical changes of the drug’s metabolites that enable their concentrations to be determined” is clearly transformative. The court found that “the asserted claims are in effect claims to methods of treatment, which are always transformative when a defined group of drugs is administered to the body to ameliorate the effects of an undesired condition,” and that "the human body necessarily undergoes a transformation" upon the administration of the drug. The court rejected Mayo’s argument that metabolism of a man-made drug is a natural phenomenon merely because it involves natural processes, pointing out that all transformations operate by natural principles.

If the Federal Circuit had stopped there, its holding would have left unresolved the question of whether a diagnostic claim that does not recite an administration step would satisfy the Bilski test. For example, many diagnostic claims simply recite a step of determining the presence of some biomarker, such as a genetic mutation or profile, or the level of a metabolite. In some cases, explicit recitation of an administration step would not be practical for the patentee. For example, if the invention is a method of identifying a genetic mutation which results in a predisposition for cancer, it would be difficult to include a step requiring administration of the drug without rendering the patent highly susceptible to circumvention.

Fortunately, the Federal Circuit went on to hold that determining the level of drug metabolites in the patient's body is also transformative, and would have been independently sufficient to render the claim patent eligible, finding that “[d]etermining the levels of [drug metabolites] in a subject necessarily involves a transformation, for those levels cannot be determined by mere inspection.” Examples of transformation include high-pressure liquid chromatography methods, methods of extracting metabolites from the human body, etc. Thus, it appears that any method of diagnosis that would inherently require some physical manipulation or transformation of a sample should satisfy the transformation prong of Bilski. This is good news for genetic diagnostic companies holding method patents that probably claim methods of identifying genetic mutations of medical significance, without being limited to any particular analytic methodologies or patient treatment steps.

Mayo had argued that the transformations involved in sample analysis are mere data gathering steps amounting to nothing more than "insignificant extra-solution activity." But the Federal Circuit rejected this argument, finding that to the contrary, the “transformation is central to the purpose of the claims, since the determining step is, like the administering step, a significant part of the claimed method treatment . . . , central to the claims rather than merely insignificant extra-solution activity.

Mayo had also argued that the “wherein” clauses at the end of the claims were merely unpatentable mental processes, but the Federal Circuit pointed out that in analyzing a claim for patent eligibility one must consider the claim as a whole. The inclusion of mental process steps in an otherwise patent eligible claim is not render the claim patent ineligible.

Amgen v. Hoffman-La Roche: Checking the Wrong Box Could Prove Costly for Amgen

Yesterday the Federal Circuit issued a decision in Amgen v. Hoffman-La Roche, an important case arising out of Amgen’s efforts to block Roche from entering the US market with a competing version of recombinant erythropoietin. Amgen currently sells two recombinant versions of erythropoietin, EPOGEN and ARENESP, and Roche is attempting to enter the market with a PEGylated version of erythropoietin (EPO) under the trade name MIRCERA. The case should be of particular interest to those following the current debate over proposed follow-on biologic legislation, as the MIRCERA product is arguably biosimilar to Amgen's products and would thus qualify as a follow-on biologic. In any event, the case illustrates many of the challenges that biologic innovators will face when attempting to use patents to maintain market exclusivity if follow-on biologic legislation is enacted.

There are many issues at play in the case, but the questions of infringement and obviousness-type double patent are two of the most interesting. Essentially, much of Roche's non-infringement argument is based on its assertion that PEGylation results in substantial structural and functional changes to the protein backbone that render MIRCERA a distinct and non-infringing molecule. Roche has generally lost on this issue. The obviousness-type double patent argument arises out of Roche's contention that Amgen impermissibly obtained multiple patents claiming essentially the same invention, resulting in an undue extension of the effective patent term. Based on a single priority application filed in 1983, Amgen received at least seven patents, one of which has expired (the core erythropoietin gene patent successfully asserted in Amgen v. Chugai (decided by the Federal Circuit in 1991), and five of which were asserted in this action against Roche.

According to my calculations, the last of these patents to expire will be in 2016 (5,955,422), 33 years after the initial filing date and 27 years after EPOGEN was first approved for sale in the US. Note that this sort of de facto patent term extension is not available for patent applications filed after June of 1995, which are limited to a 20 year term after the initial filing date, plus possible extensions due to delays in seeking FDA approval not to exceed 14 years from the date of initial approval of the product.

Here are a few highlights.

Obviousness-Type Double Patenting

35 USC 121 provides a safe harbor that “protects a divisional application, the original application, or any patent issued on either of them from validity challenges based on a patent issuing application subjected to a restriction requirement or on an application filed as a result of a restriction requirement.” The district court found Amgen’s two product patents claiming recombinant erythropoietin therapeutics both arose out of divisional applications, and hence were shielded from invalidation based on obviousness-type double patenting (ODP). The Federal Circuit vacated this judgment, based on its conclusion that the two patents arose out of continuation applications, not divisional applications, and for that reason the Section 121 safe harbor did not apply.

The Federal Circuit seemed to acknowledge that the two product patents arose out of patent applications that satisfied the definition of "divisional application" provided in the Manual of the Patent Examining Procedure (MPEP 201.06):

A later application for an independent or distinct invention, carved out of a pending application and disclosing and claiming only subject matter disclosed in the earlier or parent application, is known as a divisional application or "division."

However, when Amgen filed the applications which led to the product patents, it identified them as continuation applications rather than divisional applications, and checked the continuation application box on the form it submitted to the PTO, and the Federal Circuit held that because Amgen had designated the applications as continuations they would be held to this designation, and thus could not take advantage of a safe harbor available only to divisional applications.

Note that divisional applications are a species of continuation application, so Amgen was correct in identifying the application as a continuation when it was filed. However, it is clear in retrospect that they should have identified it as a divisional application. I think the applications clearly qualified as divisionals under the MPEP definition, a definition which comports with the conventional understanding of the term divisional at that time. More recently, particularly with respect to the proposed continuation rules currently being challenged in Tafas v. Dudas, the PTO has taken to using the term divisional any more narrow sense, limited to applications containing claims that were presented in the initial application but canceled in order to comply with a restriction requirement. In the 1990s when Amgen filed its continuation/divisional applications, I think it could easily have identified the applications as divisionals, and checked the divisional box on the form, and the PTO would not have called them on it. If they had, perhaps the Federal Circuit would have affirmed the district court in its judgment that the patents were shielded from ODP challenge by section 121.

On remand, the district court will have to determine whether the products claimed in the Amgen patents are patently distinct from process claims issued in other related Amgen patents. This will come down to the question of whether at the time the product applications were filed (1993 and 1995) there were alternative processes (not covered by Amgen's process patents) for making the claimed product. In other words, Amgen will likely have to argue for a narrow interpretation of its process patents. This might prove difficult - in the past, Amgen has successfully argued for a broad interpretation of the process patents to encompass, e.g., gene activation technology (Amgen v. Hoechst Marrion Roussel) (as discussed in more detail here). It is unclear whether in 1993 or 1995 alternative processes for producing recombinant erythropoietin were available that would not be encompassed by Amgen's process patents, if those process patents are interpreted as broadly as they have been in litigations.

The issue of ODP could be significant, particular with respect to 5,955,422, the last of the patents in the family to issue. If this patent were to be invalidated on remand, it would effectively reduce Amgen's period of de facto patent exclusivity.

Product-by-process claims

Normally, one of the mantras of patent law is “that which anticipates if earlier will literally infringe if later.” However, the Federal Circuit held that with respect to product-by-process claims:

[T]hat which anticipates if earlier does not necessarily infringe if later. That is because a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim. Similarly, that which infringes if later does not necessarily anticipate if earlier. That is because an accused product may need each limitation in a claim, but not possess features imparted by a process limitation that might distinguish the claimed invention from the prior art.

An interesting asymmetry in the law, which resulted in the following conclusion:

To prove infringement, Amgen had to show that MIRCERA comprises EPO made recombinantly, which the Court concluded it did. Importantly, Amgen was not required to show that MIRCERA was also structurally and functionally different than urinary EPO. In other words, for validity, the court correctly required a source limitations to impart novelty onto EPO but it did not require [prior art EPO purified from urine] to meet the source limitations; for infringement, the court correctly required MIRCERA to satisfy the source limitations, but did not require MIRCERA to differ from urinary EPO.


Roche argued that MIRCERA is not covered by Amgen's product claims because PEGylation (attachment of PEG polymers to the EPO polypeptide backbone) results in substantial structural changes to the molecule that bring it outside the scope of the claim, including loss of a hydrogen atom and a substantial increase in molecular weight. The district court rejected this argument, finding infringement, and the Federal Circuit affirmed, “[b]ecause MIRCERA embodies the human EPO and source limitations of the asserted claims." The court cited nonchemical caselaw for the proposition that “modification by mere addition of elements cannot negate infringement,” and found that this rule applied to PEGylation of EPO. Apparently, so long as the EPO polypeptide backbone is substantially present, any post-translational modification will still be encompassed by the claim. This is consistent with conventional understanding of protein and DNA claims. However, with respect to other chemical compounds (such as small molecule drugs) one is generally not permitted to disclose a molecule backbone and then claim all molecules comprising that backbone, and I wonder if this apparent dichotomy will at some point be addressed. After all, it seems inconsistent with statements and other Federal Circuit decisions to the effect that claims directed to DNA and protein molecules should be treated just like any other chemical compound claim.

Amgen also prevailed on the issue of whether importation of MIRCERA violates 35 USC 271(g). Section 271(g) essentially allows a patent owner to block importation of a product made by a process patented in the US, so long as the product has not been “materially changed by subsequent processes.” Roche argued that PEGylation of EPO results in substantial structural and functional changes relevant to the recombinant EPO produced by the patented processes, thus satisfying the “materially changed” caveat. However, the Federal Circuit held that, “on this record, we think there was sufficient evidence for a jury to conclude that the structural and functional differences between MIRCERA and EPO recited in the process claims were not material.” The Federal Circuit provided little explanation for this conclusion, beyond its finding that "MIRCERA and human EPO stimulate erythropoiesis similarly."