By Kevin E. Noonan —

The Federal Circuit affirmed the decision by the Patent Trial and Appeals Board (PTAB) in an inter partes review (IPR) that the claims of Genzyme's U.S Patent Nos. 7,351,410 and 7,655,226 were obvious, in Genzyme Therapeutic Products, Inc. v. Biomarin Pharmaceutical, Inc.

The claims at issue are directed to methods for treating Pompe's disease, a deficiency in the lysosomal enzyme acid α-glucosidase (GAA), which is expressed as an inability to break down glycogen, particularly in muscle, causing glycogen buildup in muscle tissue.  There are two forms of the disease, early onset and late onset, with sufferers of the early onset form having no GAA activity; these infants do not live for more than a year without treatment due to weakening of the heart and muscles involved in respiration.  Late onset patients present (generally) during childhood and rarely develop cardiac symptoms.  According to the opinion, early efforts at enzyme replacement therapy failed because GAA injected into the bloodstream was cleared by the liver before the enzyme could be delivered to skeletal and cardiac muscles.  Later, more successful efforts used GAA modified to include mannose-6-phosphate, which promoted skeletal and cardiac muscles uptake.  In 1997, Duke University applied for Orphan Drug Application for treatment using recombinant GAA modified with M6P, which application was associated with a press release asserted as prior art in the IPR reviewed by the Federal Circuit.

Claim 1 of the '410 patent is representative of the claims involved in the IPR:

A method of treating a human patient with Pompe's disease, comprising intravenously administering biweekly to the patient a therapeutically effective amount of human acid alpha glucosidase, whereby the concentration of accumulated glycogen in the patient is reduced and/or further accumulation of glycogen is arrested.

Biomarin requested an IPR in 2013 based on four grounds for the '410 patent, with the PTAB instituting on two of them:  under § 103 based on the combination of the Duke press release and two prior art references (the Barton reference and van der Ploeg '88 references); and also under § 103 for the combination of the another reference, the Reuser reference, with the Barton and van der Ploeg '88 references.  For the '266 patent, the PTAB instituted under § 103 for claims 1 and 3 based on the combination of the Duke press release, the van der Ploeg '88 reference, and the van Hove reference, and for claims 4-6 based on the combination of the Duke press release, the van der Ploeg '88 reference, the Barton reference, and the Reuser reference.

Genzyme responded to Biomarin's request by arguing that none of the cited references disclosed the results of in vivo tests in humans or animals.  In response, Biomarin asserted two additional references that disclosed in vivo administration of M6P-modified GAA in mouse (van der Ploeg '91) and Japanese quail (Kikuchi).

The Board found the challenged claims to be obvious, based on disclosure in the Reuser reference of all elements of the claimed invention except the dosing interval which, according to the PTAB, was the result of "routine optimization."  The PTAB discounted the effects of no clinical trials having been performed at the earliest priority date, on the grounds that the skilled worker would have been motivated to pursue clinical trials in view of the teaching of the Reuser reference.  With regard to whether there was a reasonable expectation of success, the Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients."  The PTAB based its determination on the cited art, production of recombinant M6P-modified GAA in transgenic animals (milk) and the FDA's Orphan Drug status for enzyme replacement therapy using M6P-modified GAA for treating Pompe's disease.  All that was needed, according to the Board, was the application of "no[thing] more than routine processes" to develop the claimed methods and thus they were obvious.

The Federal Circuit affirmed, in an opinion by Judge Bryson, joined by Judges Moore and Reyna.  The Court rejected Genzyme's procedural challenge under the Administrative Procedures Act (APA), that the Board had erred in relying on "facts and legal arguments" not asserted in the request, as a violation of the Act's notice and opportunity to respond requirements.  While acknowledging that "formal adjudication" such as an IPR imposes "certain procedural requirements" on the PTO under the APA, including "timely notice" and an opportunity to "submit facts and argument" under 5 U.S.C. §§ 554(b)-(c), 557(c), the Court stated that these provisions were intended to prevent an agency from "chang[ing] theories in midstream" without giving a respondent the opportunity to address the changed theory, citing Belden v. Berk-Tek LLC, 805 F.3d 1064, 1080 (Fed. Cir. 2015) (quoting Rodale Press, Inc. v. FTC, 407 F.2d 1252, 1256-57 (D.C. Cir. 1968).  This was not the case here, according to the opinion, because Genzyme had ample notice and opportunity to rebut Biomarin's obviousness case against its claims.  Support for this conclusion was had by noting that the Board based its final determination of obviousness on the same references it used for deciding to institute the IPR.  The fact that the Board cited references (the in vivo references, van der Ploeg '91, and Kikuchi) in its final determination that were not included in the combination used to institute the IPR was not to the contrary, because "the introduction of new evidence in the course of the trial is to be expected in inter partes review trial proceedings and, as long as the opposing party is given notice of the evidence and an opportunity to respond to it, the introduction of such evidence is perfectly permissible under the APA."

Genzyme's argument to the contrary, according to the Court, was based on "misunderstanding of the role of the institution decision in inter partes review proceedings before the Board":

There is no requirement, either in the Board's regulations, in the APA, or as a matter of due process, for the institution decision to anticipate and set forth every legal or factual issue that might arise in the course of the trial.  See Boston Carrier, Inc. v. ICC, 746 F.2d 1555, 1560 (D.C. Cir. 1984) (even when adjudicating charges of misconduct, an agency "is not burdened with the obligation to give every applicant a complete bill of particulars as to every allegation that carrier will confront").  Because the institution decision comes at the outset of the proceedings and the patentee is not obligated to respond before the Board makes its institution decision, it is hardly surprising that the Board cannot predict all the legal or factual questions that the parties may raise during the litigation.

Indeed, the opinion goes on to say that "development of evidence in the course of the trial is in keeping with the oppositional nature of an inter partes review proceeding," with the requestor asserting its invalidity case to the PTAB and the patent owner presenting amendments (sic), and with the Board then deciding whether the challenger has borne the burden of proving invalidity (citing the Senate legislative history of the IPR provisions, despite the differences in how Congress may have thought it was providing for IPRs and the PTAB's decisions on how to implement the statute).

The "critical question" under the APA is "whether Genzyme received 'adequate notice of the issues that would be considered, and ultimately resolved, at that hearing'" the Court opined, citing Pub. Serv. Comm'n of Ky. v. FERC, 397 F.3d 1004, 1012 (D.C. Cir. 2005).  The panel concluded that Genzyme had not shown that there were any issues of fact or law used by the PTAB as the basis of its obviousness determinations for which Genzyme had not had adequate notice or opportunity to be heard.  Finally, the opinion also noted that PTO procedures provide means for moving to exclude evidence (such as 37 C.F.R. § 42.64(c)) or to file a surreply when Biomarin introduced this evidence during the institution proceedings, neither of which procedural avenues Genzyme used.

In this regard it did not help Genzyme's case that it had itself "raised the issue" of the Kikuchi reference, and "other in vivo studies" with regard to whether they should be available to Biomarin as rebuttal evidence.  And the issue had been thoroughly explored at oral argument before the Board, including concessions by Genzyme that the Board could rely on the prior art "as a whole" in making its obviousness determination.  In addition, the panel cited Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359 (Fed. Cir. 2015), for their earlier precedent that the Board erred in not considering prior art because it had not been introduced at the institution phase, with this panel saying that the type of use sanctioned by the Ariosa court was "exactly" how the Board used the in vivo references in this case, as evidence of the state of the prior art at the earliest priority date.

On the merits, Genzyme argued that the Board erred in its claim construction with regard to the "whereby" clause contained in the claims of both the '410 and '226 patents:

whereby the concentration of accumulated glycogen in the patient is reduced and/or further accumulation of glycogen is arrested.

In both the institution decision and the final written determination the Board construed this clause "as describing the result achieved when a patient is given a therapeutically effective dose of GAA" and not as a separate step of the claimed methods.  Genzyme argued that the Board had changed its interpretation of this clause between institution and final determination, but the Court found "no merit in that argument."  Genzyme also argued that the clause should be construed to require reduction in glycogen accumulation to occur in skeletal muscle and not elsewhere in the body (including heart or liver).  The panel rejected this argument based on the Federal Circuit's validation of the Board's use of the "broadest reasonable interpretation" standard for claim construction in In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278 (Fed. Cir. 2015), cert. granted, 136 S. Ct. 890 (2016).  The Board found no claim language that "expressly or impliedly" limited reduction in glycogen accumulation to skeletal muscle, and also found that the portions of the specification Genzyme cited in support of its interpretation in fact supported the Board's broader construction (as did the prosecution history).

The Court also rejected Genzyme's assertion that the Board had erred by not expressly defining the level of skill possessed by the person of ordinary skill in the art, finding no requirement that the Board do so (citing Okajima v. Bourdeau, 261 F.3d 1350, 1354-55 (Fed. Cir. 2001), quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163-64 (Fed. Cir. 1985)) and noting that both parties' description of this level of skill used "nearly identical language."  Finally, the panel rejected Genzyme's argument that the Board's determination that there was a likelihood of success was not supported by substantial evidence based on its understanding of (and extensive citation to) Biomarin's expert's testimony.

Genzyme Therapeutic Products Ltd. v. Biomarin Pharmaceutical Inc. (Fed. Cir. 2016)
Panel: Circuit Judges Moore, Bryson, and Reyna
Opinion by Circuit Judge Bryson