United States: Federal Circuit Emphasizes Need For Reasonable Expectation Of Success

In Genzyme Corp. v. Dr. Reddy's Labs. Ltd., the Federal Circuit affirmed the district court decision upholding Genzyme's Orange Book listed patent for the cancer drug Mozobil® against an obviousness challenge, because the asserted prior art references failed to provide a reasonable expectation of success. While a non-precedential decision, this case illustrates the important role that unpredictability in the art and a lack of expectation of success can play in biotechnology patents.

The Patent at Issue

The patent at issue was Genzyme's U.S. Patent 7,897,590, directed to methods of promoting the flow of stem cells into blood for transfusion using a specific combination of drugs. The stem cells are used to treat non-Hodgkins lymphoma and other blood cancers. The only claim at issue was claim 19, which recites:

A method to obtain progenitor and/or stem cells from a subject which method comprises:
(1) administering G-CSF to said subject in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood of said subject;
(2) administering to said subject 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11- tetraazacyclotetradecane or a pharmaceutically acceptable salt thereof; and
(3) harvesting said progenitor and/or stem cells.

The compound 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane is commonly known as plerixafor.  Plerixafor is the active chemical ingredient in Genzyme's Mozobil® product.

The Asserted Prior Art References

The case stemmed from Dr. Reddy's Abbreviated New Drug Application (ANDA) seeking approval of a generic version of Mozobil®. Dr. Reddy argued that claim 19 was obvious over the combination of a journal article by Hendrix and U.S. Patent 5,824,304 ("Patent 1"), or alternatively over the combination of WO 00/45814 ("Application 1") and Patent 1.

As summarized in the Federal Circuit decision, Hendrix was focused on evaluating the safety and pharmacology of plerixafor for treating HIV. The article reported that after receiving plerixafor, all subjects had an increase in white blood cells ("WBC") in their peripheral blood. In a single line statement, the article hypothesized "binding of plerixafor to CXCR4 may inhibit the chemotactic effects of stromal cell-derived factor 1 (SDF-1) causing release of WBCs from the endothelium and/or stem cells from bone marrow."

Patent 1 disclosed a method of increasing the number of stem cells in peripheral blood by administering a blocking agent of VLA-4 antigens. VLA-4 antigens release stem cells by inhibiting the VLA-4 receptor on the stem cells causing a disruption of the tether between the receptor and the ligand found in bone marrow. Patent 1 also disclosed administering G-CSF to stimulate production of stem cells in the bone marrow.

Dr. Reddy's argued that it would have been obvious to substitute VLA-4 in Patent 1 with plerixafor as taught by Hendrix, to arrive at the method of claim 19.

The District Court Decision

The district court rejected Dr. Reddy's arguments, finding Hendrix and Patent 1 to be non-analogous art, because Hendrix focused on HIV treatment, not cancer treatment. Additionally, the court concluded that even if the references were analogous art, claim 19 still was not obvious because there was "no reasonable expectation of success" that plerixafor would mobilize stem cells in sufficient numbers for harvesting and transplanting. Adding to its reasoning of "no reasonable expectation of success," the court found evidence of a history of failure in the field.

The Federal Circuit Decision

The non-precedential Federal Circuit decision was authored by Judge Chen and joined by Judge Moore and Judge Plager. As noted in the opinion, "[t]he determination of obviousness is a legal conclusion based on underlying facts." After a bench trial, "the district court's factual findings [are reviewed] for clear error and its conclusions of law de novo." Here, the court focused on the district court's factual determination that the cited prior art references did not provide a reasonable expectation of success.

In it reasoning, the Federal Circuit cited the following:

  • Dr. Reddy's expert had testified that a typical stem cell has around one hundred different types of receptors on its surface
  • Patent 1 is focused on blocking the VLA-4 receptor
  • Plerixafor targets a different receptor (CXCR-4) than the VLA-4 receptor
  • CXCR-4 is in a completely different family of receptors than VLA-4
  • Patent 1 never mentions CXCR-4 receptors, SDF-1, or plerixafor
  • There was no evidence that CXCR-4 and VLA-4 have similar mechanisms of action

The Federal Circuit also noted that although Hendrix hypothesized that plerixafor may cause stem cell mobilization, the article did so in "a single, unexplained sentence," and "the rest of the seven-page document focused on elevation of WBC counts."

The Federal Circuit also explained that "[t]he district court's finding that stem cell mobilization
was highly unpredictable at the time of the invention also runs counter to an expectation of success." On that point, the court noted that "[n]o one had ever mobilized stem cells with any CXCR-4 antagonist, let alone plerixafor."

The Federal Circuit applied similar reasoning to upholding the district court's decision regarding the combination of Application 1 and Patent 1. With regard to Application 1, the Federal Circuit noted that, like Hendrix, Application 1 failed to disclose the use of plerixafor to mobilize stem cells, and instead only disclosed a relationship between plerixafor and WBC elevation. The Federal Circuit agreed with the district court that Dr. Reddy's obviousness argument was grounded on "the assumption that a [person of ordinary skill in the art] would have known that white
blood cells are a proxy for stem cells," but "the record included ample evidence showing that an increased WBC count did not necessarily correlate to stem cell mobilization."

Scrutinizing Prior Art Statements

While this decision as a whole caught our attention because the Federal Circuit does not often address the "reasonable expectation of success" requirement in such detail, we also were interested in its scrutiny of Hendrix. Journal articles often include conclusory statements regarding untested hypotheses or nascent theories that scientists in the field take with a grain of salt as the author's personal views or puffing. Yet, USPTO Examiners and parties challenging patents take such statements at face value. The Federal Circuit's finding that Hendrix's hypothesis did not provide a reasonable expectation of success may be useful in countering similar reliance on speculative statements in the prior art, especially those that are made "in an isolated sentence, without explanation," and without supporting testing.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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