Tag Archives: Eli Lilly

The Federal Circuit decisions in Cancer Research Technology Ltd. v. Barr Labs., Inc. (Nov. 2010) and In Re ’318 Patent Infringement Litigation ("Janssen") (Sep. 2009) present an interesting contrast in utility issues. In Cancer Research, the USPTO raised utility rejections that the applicant eventually overcame and the patent was found to be enforceable, while in Janssen, the USPTO never raised the issue but both the district court and the Federal Circuit found the patent invalid for lack of utility. The Federal Circuit may address a similar situation again this week, when it hears oral arguments in Eli Lilly & Co. v. Actavis on Thursday.

The Janssen Case

The Janssen Patent & Prosecution History

The patent at issue in Janssen (U.S. 4,663,318) was directed to:

A method of treating Alzheimer’s disease and related dementias which comprises administering to a patient suffering from such a disease a therapeutically effective amount of galanthamine or a pharmaceutically-acceptable acid addition salt thereof.  

As characterized by the Federal Circuit:

The specification of the ’318 patent was just over one page in length, and, according to the courts, provided almost no basis for its stated conclusion that it was possible to administer "an effective Alzheimer’s disease cognitively-enhancing amount of galanthamine."

The specification cited prior art publications reporting the administration of galanthamine to humans or animals for other purposes with other effects, such as increasing plasma cortisol levels in humans, increasing short-term memory in dogs, and antagonizing scopolamine-induced amnesia in rats. But, the specification did not explain how these results supported the use of galanthamine to treat Alzheimer’s disease.

The USPTO rejected the claims for obviousness, but withdrew the rejection when the applicant explained that the subjects in the prior art studies were "normal," and so the "circumstances [of the prior art studies] [had] no relevance to Alzheimer’s disease." The applicant also stated:

[E]xperiments [are] underway using animal models which are expected to show that treatment with galanthamine does result in an improvement in the condition of those suffering from Alzheimer’s disease.

The USPTO granted the ’318 patent without asking for that data and, indeed, before the data were available.

The ’318 Patent Litigation

Janssen’s product received FDA approval in 2001. In 2005, a number of generic drug manufacturers filed Abbreviated New Drug Applications (ANDAs) with "Paragraph IV" certifications alleging that the ’318 patent was invalid.

The district court found that the patent was invalid for lack of enablement under 35 USC § 112 for failing to demonstrate a utility under 35 USC § 101. On appeal, the Federal Circuit summarized several principles of the utility requirement in the context of therapeutic methods:

• patents claiming new methods of treatment typically are supported by test results
• testing need not be conducted by the inventor
• human trials are not required for a therapeutic invention to be patentable
• results from animal tests or in vitro experiments can be sufficient

Because the ’318 patent had no data whatsoever "involving the use of galanthamine to treat Alzheimer’s-like conditions," the Federal Circuit affirmed the finding of invalidity.

The Brana Footnote

In In re Brana (Fed. Cir. 1995), the court held that data submitted during prosecution

can be used to substantiate any doubts as to the asserted utility [in the specification] since this pertains to the accuracy of a statement already in the specification. . . .  It does not render an insufficient disclosure enabling, but instead goes to prove that the disclosure was in fact enabling when filed (i.e., demonstrated utility).

 In a footnote that I find troubling, the Federal Circuit in Janssen distinguished Brana on two grounds:

(1) the finding in Brana did not depend on the post-filing date test results and
(2) in Brana the testing was submitted to the USPTO during prosecution.

But, in Brana the court did say that

Even if one skilled in the art would have reasonably questioned the asserted utility, i.e., even if the PTO met its initial burden thereby shifting the burden to the applicants to offer rebuttal evidence, applicants proffered sufficient evidence to convince one of skill in the art of the asserted utility. . . . Such evidence alone should have been sufficient to satisfy applicants’ burden.

Moreover, the Janssen opinion offers no rationale for drawing a line between data submitted to the USPTO during prosecution and data submitted to a court during litigation.

The Cancer Research Case 

The Cancer Research Patent & Prosecution History

The patent at issue in Cancer Research (U.S. 5,260,291) was directed to a class of tetrazine derivatives and therapeutic methods using them, including methods of treating cancer. The teachings relating to anti-cancer use are found in this paragraph:

The new tetrazine derivatives of general formula I possess valuable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukaemias. They possess useful activity against glioma and mycosis fungoides. They have proved particularly active in mice at daily doses between 0.5 and 16 mg/kg animal body weight, administered intraperitoneally, against TLX5 (S) lymphomas according to the procedure of Gescher et al, Biochem. Pharmacol. (1981), 30, 89, and ADJ/PC6A and M5076 (reticulum cell sarcoma). Against leukaemia L1210, grafted intraperitoneally, intracerebrally and intravenously, and P388, according to the procedure described in "Methods of Development of New Anticancer Drugs" (NCI Monograph 45, March 1977, pages 147-149, National Cancer Institute, Bethesda, United States), the compounds were active both intraperitoneally and orally at doses of between 2.5 and 10 mg/kg animal body weight. Inhibition of both primary tumour and metastasis was obtained against the Lewis lung carcinoma by similar dosage regimes. Against the B16 melanoma and C38 tumour in mice (NCI Monograph 45, op cit.) the compounds were active intraperitoneally at doses of between 6.25 and 25 mg/kg animal body weight.

The examples relate to the synthesis of the compounds and pharmaceutical compositions.

The USPTO rejected the cancer treatment claims for lack of utility. (Indeed, back in those days—1983—the treatment of cancer was viewed as "per se" in-credible by the USPTO—you might as well have been claiming a perpetual motion machine or cold fusion method). The USPTO examiner indicated that the rejection could be overcome with human clinical data.

Instead of responding to the Office Action, the applicant abandoned the application in favor of a continuation application. That application eventually was rejected for lack of utility. Again, the applicant simply abandoned the application in favor of a continuation application. This cycle continued for eight more times (a near impossibility now with the 20-year term), until the final continuation application was filed in 1991.

By 1991, the applicant had obtained some favorable human clinical data (and some less favorable data), but it was never submitted to the USPTO.  Rather, in the 1991 continuation application the applicant challenged the utility rejection, citing the animal data in the specification and favorable case law on point. Eventually, the USPTO was convinced, and the patent was granted in 1993.

The Cancer Research Litigation

The patentee obtained FDA approval for a product within the scope of the patent (Temodar®) in August 1999, and obtained a 1,006 day Patent Term Extension under 35 USC § 156. In 2007, Barr filed an ANDA with a Paragraph IV certification alleging that the patent was unenforceable for prosecution laches and inequitable conduct.

Although the district court agreed with Barr, the Federal Circuit reversed on both counts.

On the laches issue, the Federal Circuit found that Barr could not prevail because it did not allege any prejudice due to the prosecution delays. (The court also noted that the facts here are not likely to be repeated in view of the 20-year term.)

On the inequitable conduct issue, the Federal Circuit found that the district court had erred by relying "solely on its finding of materiality to infer intent." Moreover, the Federal Circuit stated that while the publication of the clinical trial data at issue "does not foreclose a finding of deceptive intent," it "is inconsistent with finding that intent to deceive is the single most reasonable inference to draw from the evidence."

 The Eli Lilly Case

The Eli Lilly case relates to Lilly’s Straterra® product for ADHD. The patent at issue is U.S. 5,658,590 which claims:

A method of treating attention-deficit/hyperactivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine.

In addition to making assertions of usefulness and disclosing appropriate therapeutic doses, the specification states the following regarding tomoxetine’s activity:

Tomoxetine is a well-known drug, the chemical name of which is (R)-(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. It is regularly used as a salt, and salts are included in the term tomoxetine as used here. See, for example, Gehlert, et al., Neuroscience Letters 157, 203-06 (1993), for a discussion of the mechanism of tomoxetine’s activity as a norepinephrine reuptake inhibitor. Tomoxetine is quite active in that function, and moreover is substantially free of other central nervous system activities at the concentrations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.

In the pending ANDA litigation, the claims were challenged for lack of enablement. The district court followed Janssen by finding that Eli Lilly could not rely on post-filing date evidence to support utility because it had not been submitted to the USPTO, but noted that unlike Janssen, Eli Lilly had explained how the prior art discussed in the specification would have been understood to support utility.  Thus, the court denied the motion for summary judgment of invalidity.

As noted above, the Federal Circuit is scheduled to hear oral arguments in this case on Thursday, December 9, 2010.

Solving Utility Problems

I am troubled by the doctrine that seems to be sprouting from these cases:

An applicant can solve a utility problem—overcome a utility/enablement rejection—with post filing-date evidence as long as the problem is raised by the USPTO examiner, but a patentee cannot solve the same problem with the same evidence if its not raised until litigation.

Because this "doctrine" stems from a mere footnote in Janssen that provides no supporting rationale, I am at a loss as to where it comes from and why the court finds the need to draw this line.

Given the ever-evolving nature of patent law—where thresholds, standards and burdens can change with each Federal Circuit or Supreme Court decision—there is always a possibility that a patent that satisfied the law as it was understood, interpreted and applied at the time of prosecution may require additional evidence to establish that it satisfies a higher (or different) threshold, standard, or burden that may apply when it is challenged years later. Why should the patentee be limited to evidence made of record at the USPTO when the USPTO had no reason to require more evidence at the time and the applicant had no reason to believe that more was warranted? 

Maybe the Federal Circuit will take a closer look at this "doctrine" in the Eli Lilly case. If if doesn’t reconsider it or rein it in, I hope it will at least explain it.