By Kevin E. Noonan —

The Federal Circuit affirmed a judgment of invalidity based on obviousness in a decision rendered in Prometheus v Roxane.  In doing so, the Court might also have given an indication of the types of claims for "personalized medicine" (in the form of methods for determining treatment of subsets of individuals suffering from a particular disease)  that it would consider patentable (from one of the least patent friendly judges on the Court).

The case involved ANDA litigation over alosetron, marketed by Prometheus as Lotronex®; this drug is used for treating irritable bowel syndrome (IBS).  The patent-in-suit was U.S. Patent No. 6,284,770 for treating a particular form of IBS (the diarrheal form, or IBS-D) with alosetron.  This patent was found obvious by the District Court over expired U.S. Patent No. 5,360,800, also owned by Prometheus; this patent claimed methods for treating IBS generically with IBS, i.e., treating both IBS-D and its alternative forms, IBS-C (for constipation) and rarer forms (IBS-M and IBS-A).  The drug is believed to work by antagonizing 5-HT₃ receptors in the colon.

The '770 patent had been the subject of reexamination, and Prometheus asserted reexamined claims 5, 10, and 13 (and dependent claims) against Roxane:

5. A method for treating a diarrhea-predominant female IBS patient, while excluding those with predominant constipation, said method comprising:
       assessing whether said diarrhea-predominant female IBS patient has experienced symptoms for at least six months; and
       administering an effective amount of alosetron or a pharmaceutically acceptable derivative thereof to said patient who has experienced symptoms for at least six months, wherein said effective amount is dependent on the condition of the patient and is at the discretion of the attendant physician.
6. The method for treating according to claim 5, further comprising assessing whether said female IBS patient has experienced at least moderate pain prior to administration of alosetron.
7. A method for treating a diarrhea-predominant female IBS patient, while excluding those with predominant constipation, said method comprising:
       assessing whether said diarrhea-predominant female IBS patient has experienced symptoms for at least six months;
       assessing whether said nonconstipated female IBS patient experiences at least moderate base- line pain from IBS; and
       administering an effective amount of alosetron or a pharmaceutically acceptable derivative thereof to said patient who has experienced symptoms for at least six months and who experiences at least moderate baseline pain from IBS, wherein said effective amount is dependent on the condition of the patient and is at the discretion of the attendant physician.

(where underlined portions of the claims indicate amendments made during ex parte reexamination, and italicized portions indicate claim terms at issue before the Court.)

The opinion notes as relevant background that administering alosetron carries sufficient risk that the FDA has placed a "black box" warning on the drug, and that patients having the IBS-C form of the disease should not take it.  These population limitations are in the claims, specifically that the drug should be administered to patient with the IBS-D form of the disease, who have had chronic symptoms for at least six months.  Importantly for both the District Court and the Federal Circuit, limiting the patient population did not reduce the rate at which adverse effects occurred (but did reduce the number of adverse events, since fewer patients were taking the drug).  Even then the District Court found that this reduction in adverse event rate was due to other changes in how the drug was prescribed and not due to any limitations recited in the claims.

The District Court in the ANDA litigation below found that the asserted claims of the '770 patent were obvious even when considered in light of the secondary considerations (long-felt need, expected results, commercial success) raised by Prometheus.  Instead, the District Court found that the claims merely recited elements present in the prior art for which the skilled worker would have had a reasonable expectation of success.  The District Court based its conclusion on the near identity of the prior art to the claimed invention, and also because what difference there was between the art and the claims was "insubstantial."  (In the alternative, the Court found that the claims were also invalid over the '800 patent under the judicially created obviousness-type double patenting (OTDP) doctrine, but the Federal Circuit did not reach the correctness of this determination.)

The Federal Circuit affirmed, in an opinion by Judge Dyk joined by Judges Taranto and Hughes.  The panel appreciated that the '800 patent was the principle prior art reference applied by the District Court against the '770 patent claims in deciding the obviousness question, but that the Court also relied upon scientific references related to IBS and methods for treating the disease.  Like the parties and the District Court, the Federal Circuit considered the relationship between the '800 patent claims and the asserted claims of the patent-in-suit to be between an earlier disclosed genus and a later claimed species, wherein the '800 patent claimed treating IBS sufferers with alosetron and the '770 patent claimed treating only a subset of these patients.  Specifically, the opinion defines this subset as being "(1) [] women (2) with IBS-D (3) who have experienced symptoms for at least six months and (4) who have had moderate pain."  The opinion recognizes that in some cases a species can be patentable over a prior art genus, citing  AbbVie Inc. v. Mathilda & Terence Kennedy Inst. of Rheumatology Tr., 764 F.3d 1366, 1372 (Fed. Cir. 2014) (in the context of OTDP), and Eli Lilly & Co. v. Bd. of Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir. 2003) (with regard to statutory obviousness).

The opinion then addressed and rebuts the distinctions raised by Prometheus for the '770 patent claims and the prior art.  The first is that the claims asserted here are limited to women with IBS-D, but the Court cites prior art research papers that disclosed that 75-80% of IBS-D sufferers are women, and in particular that there was evidence in the art that female IBS-D sufferers treated with alosetron had higher concentrations in their blood than men, suggesting that the drug would be more effective ("[t]his could reasonably suggest that women would have a greater response to the drug than men," citing a study by Hysu from 1995, two years prior to the earliest priority date to which the '770 patent was entitled).  Next was the limitation that alosetron only be administered to women with IBS-D.  The Federal Circuit noted that the District Court had based its rejection of this limitation as distinguishing over the '800 patent on prior art scientific articles teaching that the 5-HT₃ inhibitors (like alosetron) "slowed colonic transit" (although alosetron itself was not tested) and that the skilled worker (a gastroenterologist with three years of experience) would have recognized that this action would benefit IBS-D sufferers and potentially harm patient with IBS-C.  Extrapolating results obtained using healthy volunteers rather than IBS-D sufferers made no difference to the panel because it was supported by expert testimony that the District Court was entitled to rely upon.

With regard to the limitation concerning duration of IBS-D symptoms ("at least six months), the Federal Circuit held that this was common practice, noting that there was ample support in the prior art for this practice and that even Prometheus' own expert had conceded as much.  Similarly the District Court found and the Federal Circuit agreed that assessing pain was one of the criteria for diagnosing IBS.  In addition, the opinion states that conservative medical treatment was consistent with limiting the patient population administered alosetron to those patients in at least moderate pain in view of the known risks associated with this treatment.

[The opinion also cites the decision in the AbbVie case, another case where Judge Dyk wrote the opinion, as being analogous to the situation here.]

Turning to the secondary considerations (or objective indicia of non-obviousness), the opinion one again illustrates the importance of establishing a nexus between the asserted secondary consideration and the non-obviousness of the claimed invention.  For commercial success, the panel opines that the evidence supported the District Court's conclusion that Prometheus had not rebutted Roxane's prima facie case of obviousness based on commercial success because it had not shown sufficient nexus between that success and the limitations in the claims.  Indeed it was worse than this, because the panel believed that there was only weak evidence of increased commercial sales of alosetron after the '770 came out from reexamination.  The District Court concluded that it was marketing, not patenting, that was responsible for whatever success Prometheus could assert and the panel found no reason to second guess that decision.

[In this regard the opinion takes the opportunity to consider the differences between the burden of proof, which never shifts from the accused infringer to the patentee, and the burden of production:  ""once a challenger has presented a prima facie case of invalidity, the patentee has the burden of going forward with rebuttal evidence.  But, all that means is that even though a patentee never must submit evidence to support a conclusion by a judge or jury that a patent remains valid, once a challenger introduces evidence that might lead to a conclusion of invalidity — what we call a prima facie case — the patentee would be well advised to introduce evidence sufficient to rebut that of the challenger," citing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1360 (Fed. Cir. 2007).]

Finally, the opinion rejects Prometheus' challenge to the District Court's decision with regard to unexpected results and long-felt but unmet need, saying that the need was met by "the drug itself, which is covered by the '800 patent" and that the supposed unexpected results were caused by "the new safety precautions, heightened awareness, and warnings issued after Lotronex's reintroduction."

One interesting portion of the opinion is this:

The genus-species distinction may have particular relevance in the field of personalized medicine, where, for example, a particular treatment may be effective with respect to one subset of patients and ineffective (and even harmful) to another subset of patients.  See, e.g., Margaret A. Hamburg & Francis S. Collins, The Path to Personalized Medicine, 363 New Eng. J. Med. 301, 301 (2010).  Singling out a particular subset of patients for treatment (for example, patients with a particular gene) may reflect a new and useful invention that is patent eligible despite the existence of prior art or a prior art patent disclosing the treatment method to patients generally.  An obviousness rejection likely would not be appropriate where the new patient subset displayed unexpected results.  But that is not the situation here.

While admittedly dicta, this passage suggests a willingness by this panel to consider the appreciation of specific patient populations for whom it is desirable (or not) to be administered a particular treatment for a particular disease.  Much of the current discussion on this topic has focused on patent eligibility and rightfully so in view of the recent spate of Supreme Court decisions.  But insofar as those decisions blend concepts of patent eligibility with traditional (Supreme Court) ideas regarding "inventiveness" and "invention," it is certainly noteworthy that this panel seems to indicate that these types of claims, in this context, may recite the ineluctable "something more" that has so far eluded courts and patentees from defining or deciding whether such claims can be obtained or enforced.  It is only a glimmer but perhaps it is a start.

Prometheus Labs., Inc. v. Roxane  Labs., Inc. (Fed. Cir. 2015)
Panel: Circuit Judges Dyk, Taranto, and Hughes
Opinion by Circuit Judge Dyk