Friday, March 16, 2012

District Court Decision in Case Involving Centocor's IL-12 Antibody Stelara

In the 1990s Centocor and Abbott both developed human antibodies specific for interleukin 12 ("IL-12", a cytokine), and filed patent applications broadly claiming isolated antibodies that bind IL-12. Abbott's work has resulted in a pharmaceutical composition (briakinumab )that is currently in late stage clinical trials, and two US patents, (6,914,128 and 7,504,485). Centocor's has resulted in the FDA approved drug Stelara. In 2007 an interference was declared between Abbott's ‘128 patent and a pending Centocor patent application, and in 2009 the BPAI decided the interference in favor of Abbott.

Both companies’ antibody products bind to the P40 subunit of IL-12 (it was not clear to me from reading the decision whether the products bind to the same epitope, although I suspect they do not). The antibodies have substantially different amino acid sequences, and were developed independently using different methodologies.

Abbott has sued Centocor, seeking a declaration that Stelara infringes its ‘128 and ‘485 patents. Centocor has sued Abbott seeking a declaration that its product does not infringe the patents, and that the patents are invalid. Centocor has also petitioned the district court for judicial review of the interference decision pursuant to 35 USC 146. All three actions are currently pending before the District Court of Massachusetts.

On March 9, the District Court issued an order deciding multiple motions of summary judgment filed by both parties. Here is a quick summary of some of those decisions.

Issue Preclusion
Abbott filed a motion arguing that Centocor is precluded from raising invalidity of the ‘128 patent as a defense because it raised the issue during the interference and lost. The District Court denied this motion, based on its determination that the BPAI’s decision in the interference was not a "binding final judgment." The court found that under 35 USC 146 a party that loses the interference before the BPAI can seek a de novo trial in Federal District Court on validity issues previously decided by the BPAI, and thus the decision of the board cannot be a "binding final judgment" with preclusive effect in a subsequent infringement action.

A number of Abbott's claims define the claimed antibody in terms of the dissociation constant, or "Kd” value, for the interaction between the antibody and its target IL-12. Kd is a measure of the affinity of the antibody-antigen interaction, i.e., the strength with which the antibody binds, or attaches to, the antigen. Kd can be determined by measuring the rate constants at which the antibody attaches to and detaches from the antigen. One way of measuring these on and off rates is by use of a technique called surface plasmon resonance ("SPR"), using for example a BIAcore instrument. Abbott's patent specifications disclose that Kd can be determined by SPR using the BIACore System, and identify four scientific articles describing the process.

Centocor argued that the specification did not provide specific instructions that would permit a person reasonably skilled in the art to unambiguously determine the KD value of an antibody using SPR, and asked the court to rule the claims invalid for indefiniteness. Specifically, Centocor argued that SPR could yield different Kd values for the same antibody when tested using different experimental parameters. In particular, Centocor pointed out that the claims do not specify surface density or flow rate parameters.

The district court rejected this argument however. The court read Federal Circuit precedent as establishing that when multiple acceptable standards or methods exist for testing whether a product meets a claim limitation, the patent is indefinite if it does not specify the appropriate standard or method to be used. However, a claim is not indefinite when it does specify the method of measurement, even if it omits details about how to implement the method, so long as a person of ordinary skill could infer those details using industry standards or professional judgment. In this case, the court held that a person skilled in conducting SPR assays could determine the appropriate parameters and adequately discern the bounds of the Kd limitations.

The court found that Centocor had provided no expert testimony refuting Abbott's expert’s testimony that best practices take these parameters into account, and can provide reliable Kd data. The lack of rebuttal testimony probably was a factor in the District Court deciding the issue of definiteness in favor of Abbott on a motion for summary judgment.

The court also found it significant that many issued US patents claim include claims encompassing antibodies defined in terms of particular binding characteristics as measured by SPR, and none of these patents recite the specific experimental parameters for the SPR assays. Centocor itself is the named assignee on three such patents.

Written Description
The court denied Centocor's motion seeking summary judgment that certain claims in the patent are invalid for lack of adequate written description. All of the challenged claims are directed to genuses of functionally defined antibodies. Abbott conceded that its patents do not disclose common structural features for the claimed genuses.

According to the court, the sole issue with respect to adequate written description is whether the patents disclose species that constitute a representative set within each genus claim, reciting the ambiguous standard set forth in UC v. Eli Lilly and its progeny.

Abbott's patent specification discloses multiple antibodies falling within the scope of the claims, but Centocor argued that this disclosure was inadequate because all of the disclosed antibodies share very similar amino acid sequences, while the functionally defined claims would encompass a broad range of amino acid sequences. The high degree of sequence homology of the examples arises from the fact that they are all derived from a single common precursor antibody.

In contrast, Centocor's product Stelara originated from a different antibody, and different methodology, and has amino acid sequence that is substantially different from the set of examples disclosed in Abbott's patents. Centocor makes the not unreasonable argument that if Abbott's claims are broad enough to encompass Stelara, then they are too broad to be adequately represented by the group of highly similar antibodies disclosed in Abbott's patents.

However, the court found that compliance with the written description requirement, a question of fact, could not be decided on summary judgment. Significantly, the parties’ experts disputed the significance of the differences in amino acid sequence between the disclosed antibodies and the range of amino acid sequences encompassed by the claims.

It is interesting to compare the adequacy of written description in this case with the Federal Circuit's decision last year in Centocor v. Abbott, discussed here. Both cases involve the same parties and claims directed towards antibodies, but the earlier decision involved antibodies to human TNF-alpha. In the earlier decision, the Federal Circuit held the antibody claim at issue to be invalid for inadequate written description as a matter of law. The Federal Circuit’s decision seemed to hinge on the facts that the antigen (TNF-alpha) had been previously characterized, and the production of the claimed antibody "comprising a human constant region" was not routine. Both of those criteria seem to be satisfied in the current case involving IL-12 antibody. In distinguishing the Federal Circuit's decision in the earlier Centocor case, the district court pointed out that in the TNF-alpha case the specification did not describe a single antibody falling within the scope of the claim.

Prior Art
Centocor also asked the court to rule that Abbott's earlier work on IL-12 antibodies, and also Centocor's on Stelara, constitute 102(g) prior art with respect to Abbott's claims. The court denied these motions.

I found one aspect of the court's decision particularly interesting. The court assigned Centocor's invention of Stelara a priority date of April 30, 1998. Centocor pointed out that one of the inventors listed on the Abbott patents, Stuart Friedrich, was not employed by Abbott earlier than August 1998, and hence could not have contributed to Abbott's IL-12 research project before then. Centocor argued that the inclusion of Mr. Friedrich as a joint inventor proves the conception was not complete before August 1998.

The district court rejected this argument, however, stating that the proof of priority to a genus claim requires less than what is required to establish adequate written description of that claim. The court went on to conclude that "it is plausible that Abbott invented a species of pharmaceutical composition within the scope of this claims before Centocor's priority date of April 30, 1998, but nevertheless required contributions from Mr. Friedrich after that date in order to establish the patentability of Abbott's genus claims under 35 USC 112.”

In other words, the district court seems to be saying that an individual can be a joint inventor of a chemical genus even if he does not contribute to the conception of the genus, but only contributes to providing adequate disclosure to establish compliance with section 112. I don't know if there is any precedent to support this unconventional definition of joint inventorship - the District Court does not seem to cite to any.

The court held some of Abbott's claims infringed by Stelara.

All of the claims include a limitation to "human antibody," and Centocor unsuccessfully argued that its product is not a human antibody as that term is properly construed in the claims. In particular, the court had construed "human antibody" to mean "an antibody that is derived from human DNA and not from the DNA of any non-human species." Centocor argued that the DNA that encodes its antibody is likely to contain nucleotide sequences that were inserted through N-nucleotide addition inside the cell of a transgenic mouse during production of the antibody. While Abbott conceded that N-nucleotide addition could have occurred, the court concluded that any nucleotide added by this non-template based phenomenon would not be derived from a non-human germline, and thus would not constitute the DNA of a non-human species. It went on to conclude that Stelara satisfies the "human antibody" limitation of the claims.

Based on this interpretation of "human antibody," the court held that Stelara infringes some of the asserted patent claims broadly directed towards pharmaceutical compositions comprising isolated human antibody capable of binding to an epitope on the P40 subunit of IL-12 (see for example claim 1 of US patent 7,504,485).

However, many of the asserted claims also include limitations that can only be ascertained by analytical testing, such as threshold Kd value or IC50. The district court declined to determine the infringement of these claims on summary judgment, given the fact that the experts disputed the results of tests that had been performed, and disagreed as to the methodology to be employed in performing the tests.


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