By Kevin E. Noonan —

The old proverb "success has many fathers, while failure is an orphan" comes to mind when considering the Federal Circuit's decision in Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc.  In the Court's decision, repeated failures, even by Lilly scientists in developing its osteoporosis drug Evista® (raloxifene hydrochloride), were sufficient to defeat Teva's counterclaim that patent claims related to methods of use were obvious.

The action arose following Teva's ANDA filing containing a Paragraph IV certification that the patents-in-suit were invalid (there was no discussion in the opinion of any inequitable conduct allegations below).  The patents fell within three broad categories, and included the Bone Loss patents (U.S. Patent No. 6,906,086 and Reissue Patents Nos. RE39,049; and RE38,968), the Low Dose patent (Reissue Patent No. RE39,050) and the Particle Size patents (U.S. Patents Nos. 6,458,811 and 6,894,064).  Specific claims representative of the patents-in-suit include the following:

Claim 1 of the '086 patent (Bone Loss patent):

A method of inhibiting post-menopausal bone loss in a post-menopausal woman in need of treatment to prevent or treat post-menopausal osteoporosis comprising administering a single daily oral dose to said woman of an effective amount of [raloxifene] hydrochloride.

Claim 14 of the '050 reissue patent (Low Dose patent):

A method of preventing post-menopausal osteoporosis in a post-menopausal woman in need of treatment to prevent post-menopausal osteoporosis comprising administering to said woman a hydrochloride salt of . . . [raloxifene] in an amount of 60 mg/day.

Claim 1 of the '811 patent (Particle Size patent; emphasis added):

A compound of formula I . . . [raloxifene] and pharmaceutically acceptable salts and solvates thereof, characterized in that the compound is in particulate form, said particles having a mean particle size of less than about 25 microns, at least about 90% of said particles have a size of less than about 50 microns.

The District Court (Judge Sarah Evans Parker) found the Bone Loss and Low Dose patents not invalid under §§ 103 and 112, 1st paragraph (enablement), but that the Particle patents were invalid for failing to satisfy the written description requirement under 112, 1st paragraph, and granted a permanent injunction keeping generic raloxifene hydrochloride off the market until Lilly's patents expire.

Relevant to the Federal Circuit's analysis was the developmental history of raloxifene.  Originally pursued as an "antiestrogen" breast cancer treatment (similar in mode of action to tamoxifen), clinical experience with the drug showed low bioavailability in humans (despite significant bioavailability in experimental animals).  This result appeared to be related to the presence of free hydroxyl groups in raloxifene that were modified by conjugation with glucaronide as part of the detoxification and elimination pathways in humans.  The Court cited several prior art references disclosing low bioavailability and that raloxifene underwent "rapid metabolic conversion."  These included the Buzdar reference (1988) that disclosed results showing that raloxifene elicited no complete or partial responses for breast cancer patients resistant to tamoxifen (although the reference did not directly attribute these results to low bioavailability).  These bioavailability concerns regarding raloxifene were an express ground for the District Court to find that Lilly's claims for its Bone Loss and Low Dose patents were non-obvious, since the known low bioavailability for raloxifene would have precluded the skilled worker from having a reasonable expectation that the drug would be clinically useful for treating osteoporosis.

In its opinion, written by Chief Judge Rader joined by Judge Linn and Judge Prost, the Court affirmed the District Court's determination that Teva had not provided clear and convincing evidence that the claims of the Bone Loss or Low Dose patents were obvious.  On appeal, Teva argued three prior art references in support of its obviousness arguments.  U.S. Patent No. 5,075,321 (Schreiber patent) disclosed the use of raloxifene for treating autoimmune disorders (and according to the opinion was the basis for Lilly reissuing three of the patents-in-suit).  The Court found that this reference did not provide clear and convincing evidence of obviousness, because osteoporosis is not an autoimmune disease, and the evidence suggested different mechanisms of action.  "Without a closer relationship, Teva cannot show that an ordinarily skilled artisan would have expected Dr. Schrieber's article to have relevance for the treatment of postmenopausal osteoporosis," the Court said.  The opinion also rejected Teva's argument that the reference is relevant for showing clinically-significant bioavailability for raloxifene, based on the different uses (osteoporosis versus autoimmune disorders) as well as the fact that what was prior art in the Schrieber reference was based on animal studies that did not address the bioavailability issue in humans.

The second reference, a scientific journal article by Jordan, disclosed rat studies on the effects of tamoxifen and raloxifene on bone density.  According to the Court's opinion, "Dr. Jordan concluded that these results 'may have important implications for the clinical [human] applications of antiestrogens'" and that "'[i]t is possible . . . that in the future, tamoxifen could be considered to be used as a substitute for estrogen [for the prevention of osteoporosis in postmenopausal women]'" (emphasis added).  The reference also contained an assertion calling for clinical investigation of the use of tamoxifen for treating osteoporosis.  Unfortunately for Teva's argument, the Federal Circuit did not consider these teachings relevant for the use of raloxifene, because the reference suggested that tamoxifen, not raloxifene, be explored for use as an osteoporosis treatment.  In addition, not only was the reference silent as to the bioavailability issue, but the opinion cited the District Court's reasoning that the Jordan reference "exemplified" the bioavailability concerns with raloxifene and that the skilled worker "'would not have had a reasonable expectation of success in using raloxifene to treat human postmenopausal osteoporosis.'"  The Federal Circuit particularly faulted the portion of Teva's arguments relying on how Lilly scientists interpreted the Jordan results in support of its case for obviousness, since these inventors have greater than ordinary skill.  In addition, the Lilly scientists possessed internal information relating to the capacity for conjugation of raloxifene to be reversed in vivo (resulting in improved bioavailability), but this knowledge was also unavailing in support of Teva's arguments the court held, relying on KSR Int'l. Co. v. Teleflex Inc. ("The question is not whether the combination was obvious to the patentee but whether the combination was obvious to a person of ordinary skill in the art.")  Not expressly stated in the Court's opinion was the extent to which its determination was affected by Lilly scientists possessing information not within the knowledge of the worker of ordinary skill.

Finally, with regard to the Jones patent (which disclosed raloxifene), the opinion relied on this patent having been filed before any of the bioavailability results were obtained or concerns were raised, and that "[t]he record does not contain any reason that a person of ordinary skill would have ignored those later publications."  The Court also said that further evidence, specifically the results of the "failed" Buzdar study, would have precluded the skilled worker from having a reasonable expectation of success using raloxifene.  The Court rejected Teva's arguments that the Buzdar reference did not attribute its results to bioavailability issues, saying the skilled worker could draw that inference.

The Court came to the same conclusions and affirmed the lower court's non-obviousness determination for the claims of the Low Dose patent.  On appeal, Teva also argued that these claims were invalid under the doctrine of obviousness-type double patenting, based in part on the District Court's finding that the nature of the experiments to determine a clinically-effective low dose were routine (in its analysis addressing Teva's enablement challenge to these claims).  The Federal Circuit noted that this challenge was not raised below, and that the "record is insufficiently clear for it to conclude that the proper resolution is beyond any doubt."  Possibly significant (in view of the several recent instances of claims being invalidated for obviousness-type double patenting), the Court expressly stated that the policy rationales raised by Teva (that these patents extended Lilly's exclusivity term for Evista®) were not great enough to overcome the procedural deficiencies.

Teva also challenged the Bone Loss and Low Dose patents in the District Court on enablement grounds, and the Federal Circuit also affirmed the District Court's determination that the claims of these patents were enabled.  Teva's enablement challenge sounded in operability under 35 U.S.C. § 112, 1st paragraph (which the Court has held has its own utility requirement distinct from the utility requirement under § 101; In re Brana).  Here, the opinion cites the Manual of Patent Examining Procedure for its provisions relating to the effect of human clinical trials on the question of operability raised under 35 U.S.C. § 112, 1st paragraph (i.e., that having an on-going clinical trial is evidence that the invention is sufficiently operable for patenting purposes):

Before a drug can enter human clinical trials, the sponsor, often the applicant, must provide a convincing rationale to those especially skilled in the art (e.g., the Food and Drug Administration) that the investigation may be successful.  Such a rational would provide a basis for the sponsor's expectation that the investigation may be successful.  In order to determine a protocol for phase I testing, the first phase of the clinical investigation, some credible rationale of how the drug might be effective or could be effective would be necessary.  Thus, as a general rule, if an applicant has initiated human clinical trials for a therapeutic product or process, Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility.  MPEP (2008) § 2107.03 at IV (emphasis added).

The Court's opinion recognized that Teva's arguments relate to an inherent "Catch 22" regarding the relationship between the enablement requirement and the lack of a reasonable expectation of success in an obviousness determination:

To the extent that Teva revisits this [obviousness] argument in the enablement context, it appears to contend that Lilly's actions provide circumstantial evidence that an ordinarily skilled artisan would not have found helpful the facts on which the district court relied to hold that the patents are enabled.  This court rejects that argument as well, and for essentially the same reason:  it conflates the expertise of Lilly scientists with the knowledge of one of ordinary skill in the art.  . . .  Indeed, Lilly appears to have had many advantages that a person of ordinary skill would not have had, not the least of which was the FDA's prior approval of Lilly's IND application.  Lilly's reliance on those advantages rather than its knowledge of Black's conjugate studies [relating to greater than expected bioavailability] to proceed with human trials does not create clear and convincing evidence that a person of ordinary skill would fail to find comfort in the latter.

The Federal Circuit also affirmed the District Court's finding that the asserted claims of the Particle Size patents were invalid for failure to satisfy the written description requirement of 35 U.S.C. § 112, 1st paragraph.  These patents disclosed a range of particle sizes that increased bioavailability, wherein "within the claimed particle size range, the raloxifene particles provide 'surprisingly consistent in vivo absorption/bioavailability characteristics.'"  The District Court construed the relevant claim language, "in particulate form," to include the size of the particles either in the pure active pharmaceutical ingredient (API) or in the tablet after formulation (which construction benefited Lilly's contention that the API had been prepared with easily-dissociated particles so that the API, but not the formulated tablet, would fall outside the scope of the Particle Size patent claims).  Unfortunately for Lilly, however, the District Court found that the patent specifications did not disclose or describe determining particle size in the formulated tablet, and the Federal Circuit agreed:

[A]fter reading the patent, a person of ordinary skill in the art would not understand how to extract raloxifene particles from a formulation in order to determine whether they fall within the claimed particle size range and, in fact, would have no indication that size measurements on anything other than unformulated raloxifene would bear any relevance to the invention.

The Court affirmed, because since satisfaction of the written description requirement is a question of fact, it could not find that the District Court's decision was clearly erroneous, in particular due to admissions by Lilly's own expert regarding whether these embodiments were disclosed.

Since the Federal Circuit affirmed the District Court's decision that neither the Bone Loss nor the Low Dose patents are invalid, the injunction preventing Teva from providing generic raloxifene hydrochloride stands until expiration of the last expiring of these patents (March 2, 2014).

Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2010)
Panel:  Chief Judge Rader and Circuit Judges Linn and Prost
Opinion by Chief Judge Rader