Last week, the Federal Circuit completed its review of a series of patents relating to treating Pompe disease and invalidated by inter partes review before the U.S. Patent and Trademark Office's Patent Trial and Appeal Board (PTAB), in Duke University v. BioMarin Pharmaceutical Inc.
The drug recited in the challenged clams of the patent-at-issue, U.S. Patent 7,056,712, covers (as did two other patents, U.S. Patent Nos. 7,351,410 and 7,655,226, previously invalidated by the PTAB) methods for administering acid α-glucosidase ("GAA") used as an enzyme replacement therapy for treating glycogen storage disease type II (Pompe disease). This disease is caused by GAA deficiency, resulting in an accumulation of glycogen in tissues such as the heart and skeletal muscle. Pompe disease is treated by administering to the patient a therapeutically effective amount of the protein a recombinant human version of this protein (rhGAA), produced in precursor form in Chinese hamster ovary (CHO) cell cultures. The drug is marketed by Genzyme, the patent owner of the two related patents involved in these IPR proceedings.
BioMarin Pharmaceutical Inc. filed IPR petitions against these three patents in 2013. The PTAB determined that the claims of the two Genzyme patents were obvious in view of various combinations of references. The PTAB further determined that the claims of the Duke patent were either anticipated or obvious in view of similar cited art.
The '712 patent claims are supported by a disclosure directed to treating the most serious (infantile) form of the disease. Two independent claims are representative:
1. A method of treating glycogen storage disease type II in a human individual having glycogen storage disease type II, comprising administering to the individual a therapeutically effective amount of human acid α-glucosidase periodically at an administration interval, wherein the human acid α-glucosidase was produced in chinese [sic] hamster ovary cell cultures.
20. A method of treating cardiomyopathy associated with glycogen storage disease type II in an human individual having glycogen storage disease type II, comprising administering to the individual a therapeutically effective amount of human acid α-glucosidase periodically at an administration interval, wherein the human acid α-glucosidase was produced in chinese [sic] hamster ovary cell culture.
In addition, and important for this appeal, two dependent claims were also invalidated:
9. The method of claim 1, wherein the human acid α-glucosidase is a precursor of recombinant human acid α-glucosidase that has been produced in chinese [sic] hamster ovary cell cultures." (emphasis in opinion)
19. The method of claim 1, [wherein the human acid α-glucosidase is administered in conjunction with an immunosuppressant and] "wherein the immunosuppressant is administered prior to any administration of human acid α-glucosidase to the individual." (emphasis in opinion).
Altogether, claims 1-9, 11, 12, 15, and 18-21 of the '712 patent were invalidated by the PTAB. All claims were found invalid for being anticipated by U.S. Patent 7,351,410 and/or obvious over the combination of PCT Publication WO 97/05771 with a scientific journal publication (Van Hove) that disclosed purification of precursor rhGAA, either alone or in combination with other references, including one to Brady et al. that disclosed using neutralizing antibody production in patients given Ceredase to manage Gaucher's disease (another lysosomal storage disorder).
With regard to dependent claims 9 and 19, the Board interpreted the "precursor" limitation in claim 9 to include methods using administration of combinations of precursor and other forms of rhGAA, and that the timing of administration of immunosuppressants recited in claim 19 was prior to the first administration of rhGAA to a patient.
The '410 patent and '771 application both disclosed methods for producing rhGAA in transgenic animals as well as using rhGAA for treating Pompe disease by enzyme replacement therapy. In addition, both references disclosed recombinant production in CHO cells as an alternative source to transgenic animals. Both also disclosed precursor forms of rhGAA as well as smaller intermediate and mature forms, and disclosed that administrating the precursor form is preferred. Specifically with regard to the grounds for finding the '712 claims invalid, the '410 patent teaches that GAA from transgenic animals, human urine, and rhGAA from CHO cells are equivalently efficient for treating Pompe disease. Moreover, the '410 patent teaches a method for purifying "large quantities" of rhGAA from CHO cells.
The PTAB found claims 1-9, 12, 15, 20, and 21 were anticipated by the '410 patent. The Board rejected Duke's arguments regarding differences between transgenic animal-derived human GAA and CHO cell-derived rhGAA based on disclosure in the '410 patent that GAA from these disparate sources were equivalent for treating Pompe disease. With regard to claim 9, the Board found that the '410 patent disclosed treating Pompe disease with mixtures of GAA that were predominantly (>50%) comprised of the precursor form.
Alternatively, the Board found that all challenged claims were obvious over the combination of the '410 patent and the '771 application, with or without further consideration of the Brady reference. The Board's conclusions paralleled the reasoning for anticipation, finding the disclosures in the cited references would have provided the required reasonable expectation of success from the combination. The Board also held that, for claim 19 the Brady reference taught immunosuppression on the first day of GAA administration "in an 'effort to immunosuppress the patient' and reduce neutralizing antibodies in the individual," which was enough to support its obviousness determination.
Finally, the Board was not persuaded by any of the evidence regarding Duke's assertion of the objective indicia of non-obviousness (long-felt need, failure of others, unexpected results, licensing, commercial success, praise, and industry acceptance), due to a perceived failure to establish a nexus between the claims and any of the indicia.
The Board granted rehearing to reconsider the obviousness determination of claim 19 over the Brady reference, and held that "Brady does not disclose administering immunosuppressant prior to any and all administration of hGAA, as required by claim 19." Nevertheless, two of the Administrative Patent Judges still found the claim obvious, based on expert testimony of BioMarin's expert and their own determination that "[t]he choice of administering immunosuppressant before an adverse immune response develops in a patient, or after a patient has experienced an adverse immune response, are predictable variations producing the same result—prevention of an adverse immune response to foreign protein." The remaining APJ was unconvinced, saying that "[w]hile Dr. Pastores' conclusory statements may indicate what 'could be' done if 'there is a high incidence' of antibody response, he does not explain, nor provide evidence showing, what an ordinary artisan would have done in this regard prior to the filing date of the '712 patent, or what one would have understood in relation to incidents of 'high antibody titers' in response to exogenous enzyme therapy" (emphasis in opinion).
The Federal Circuit affirmed the Board with regard to all claims except claims 9 and 19, in an opinion by Judge Lourie joined by Judges O'Malley and Taranto. The Court's analysis focused on independent claims 1 and 20 (because Duke had not argued that dependent claims 2-8, 12, 15, and 21 were independently patentable) with regard to anticipation, and found that there was substantial evidence supporting the Board's conclusion that these claims were anticipated by the '410 patent. The panel was not convinced of the distinction Duke attempted to draw between the hGAA produced in the milk of transgenic animals and the rhGAA produced in CHO cells. This result was based on the disclosure in the '410 patent specification, which was so "sufficiently clear and on point to constitute substantial evidence to support the Board's anticipation findings," so much so that expert testimony was not required, according to the opinion.
(In passing, the Court also rejected Duke's argument regarding the Board's assertion of invalidity based on "theories [] BioMarin never raised" in support of IPR initiation, saying that Duke had been given an opportunity to respond and illustrating once again the Court's reluctance to review IPR initiation questions raised by the parties to an IPR.)
Turning to dependent claim 9, the Court addressed Duke's challenge to the Board's construction of the claim term "precursor" regarding the species of rhGAA recited in the '712 patent claims. This question was decided de novo by the Federal Circuit, because only intrinsic evidence was considered by the Board. The Court disagreed with the Board's construction, that the claim encompassed administration of GAA formulations comprising hGAA species in addition to the precursor form of the molecule. Rather, the panel agreed with Duke that the term should be construed to mean "exclusively a precursor of recombinant hGAA that has been produced in CHO cell cultures," based on the structure of the language of the claim and the written description of the '712 specification. This the cited art did not teach, according to the Court, and reversed the Board's finding that claim 9 was anticipated.
With regard to obviousness, the issue as to claims 1-8, 12, 15, 20, and 21 was mooted by the Court's affirmance that these claims were anticipated as the Board held, and thus they were no longer discussed with regard to the panel's review of the PTAB's decision. As to claim 9, the Court vacated the Board's decision because they did "not have the benefit of the Board's considered analysis whether claim 9 would have been obvious under the correct construction"; specifically, "the Board did not determine whether [the cited references] teach or suggest administering exclusively a precursor of rhGAA produced in CHO cell cultures." The panel remanded the obviousness question to the Board for reconsideration based on the Court's construction of the term "precursor." Further with regard to the claim 9 rejection, the Court also stated that:
Duke also argues that there was no motivation to combine Reuser and Van Hove, there was no reasonable expectation of success from that combination, and its proffered objective indicia support a conclusion of nonobviousness. On remand, the Board is to consider these arguments and provide a meaningful discussion of its analysis of them.
And in a footnote, the Court said that "[n]otably, Duke's objections to the Board's treatment of its evidence of objective indicia of non-obviousness—including its failure to apply a presumption of nexus—appear well taken."
For claim 19, the opinion states that the Court agreed with Duke that the PTAB had erred in finding that BioMarin had borne its burden of establishing obviousness. The Court did not find substantial evidence that "the prophylactic administration of an immunosuppressant would have been a predictable variation of the use of immunosuppressant disclosed in Brady." The panel said neither party disputed that the Board properly found that Brady reference not to disclose administering immunosuppressant prior to "any and all" occurrences of GAA administration, and that the Board had used expert testimony to "bridge the gap" in arriving at its obviousness determination. However, the Federal Circuit found that testimony "falls short" of what was required "because it does not address what an ordinary artisan would have done or understood regarding prophylactic administration of immunosuppressants in the context of GAA enzyme replacement therapy prior to the priority date of the '712 patent. It merely suggests what 'could be' done 'if there is a high incidence' of antibody response," citing specific portions of that testimony to support its conclusion. In addition, the opinion states that there was no evidence adduced by BioMarin to support the predicate that a "high incidence of patients" would develop high antibody titres as a result of rhGAA therapy. Indeed, Brady affirmatively teaches that "[v]ery few patients with Gaucher disease who are treated with [enzyme replacement therapy] develop a neutralizing antibody to the exogenous enzyme" and refers to this phenomenon as "rare" according to the opinion. The panel concludes that:
[T]he evidence of record does not establish the conditions precedent (a high incidence of patients with high antibody titers to the enzyme) to the prophylactic administration of immunosuppressants according to the expert's testimony. Such conclusory expert testimony cannot support an obviousness conclusion.
In view of the Court's final decision regarding nonobviousness of Claim 19, it seems that Duke has a claim that would prevent BioMarin or other competitors from inducing infringement of rhGAA administration in the presence of an immunosuppressant administered prior to rhGAA administration (absent assertion of additional prior art). And it is possible that the Board will not invalidate claim 9 on remand, thus permitting Duke (and its licensees) to have an exclusive position on rhGAA produced from CHO cells for treating Pompe disease.
Duke University v. Biomarin Pharmaceutical Inc. (Fed. Cir. 2017)
Nonprecedential disposition
Panel: Circuit Judges Lourie, O'Malley, and Taranto
Opinion by Circuit Judge Lourie
