Genzyme Therapeutic Prods. Ltd. P'ship v. Biomarin Pharm. Inc.

• Decision Date: 14 June 2016
• Citation: 825 F.3d 1360,119 U.S.P.Q.2d 1022
• Parties: Genzyme Therapeutic Products Limited Partnership, Appellant v. Biomarin Pharmaceutical Inc., Appellee
• Court: U.S. Court of Appeals — Federal Circuit

825 F.3d 1360

119 U.S.P.Q.2d 1022

Genzyme Therapeutic Products Limited Partnership, Appellant

v.Biomarin Pharmaceutical Inc., Appellee

United States Court of Appeals, Federal Circuit.

Decided: June 14, 2016

Filko Prugo, O'Melveny & Myers LLP, New York, NY, argued for appellant. Also represented by Anton Metlitsky, Margaret O'Boyle, Eberle Schultz; Deanna Marie Rice, Washington, DC; Christina A. L. Schwarz, Fitzpatrick, Cella, Harper & Scinto, New York, NY.

Gerald Myers Murphy, Jr., Birch Stewart Kolasch & Birch, LLP, Falls Church, VA, argued for appellee. Also represented by MaryAnne Armstrong, Lynde Faun Herzbach, Eugene Perez.

Benjamin T. Hickman, Office of the Solicitor, United States Patent and Trademark Office, Alexandria, VA, argued for intervenor Michelle K. Lee. Also represented by Thomas W. Krause, Scott Weidenfeller, Farheena Yasmeen Rasheed.

Before Moore, Bryso n, and Rey na, Circuit Judges.

Bryson

, Circuit Judge.

This is an appeal from decisions of the Patent Trial and Appeal Board in two inter partes review proceedings. At the behest of petitioner Biomarin Pharmaceutical Inc. (“Biomarin”), the Board held various claims of two patents owned by Genzyme Therapeutics Products Limited Partnership (“Genzyme”) to be unpatentable as obvious. We affirm.

I

A

The patents at issue in this case, U.S. Patent Nos. 7,351,410 (“the '410 patent”)

and 7,655,226 (“the '226 patent”), are both entitled “Treatment of Pompe's Disease” and are directed to treating Pompe's disease with injections of human acid a-glucosidase.

Pompe's disease (also known as “Pompe disease

”) is a genetic condition associated with a deficiency or absence of the lysosomal enzyme acid a-glucosidase (“GAA”). In a healthy individual, GAA breaks down glycogen, a larger molecule, into glucose. A person with Pompe's disease has significantly reduced levels of GAA, or no GAA at all, and so is unable to break down glycogen into glucose. That inability results in glycogen accumulating in the muscles of affected patients in excessive amounts.

Pompe's disease is found in two forms—early-onset and late-onset. Early-onset or infantile Pompe's disease presents shortly after birth and is associated with the patient having no measurable GAA activity. Glycogen accumulates in the patient's heart and skeletal muscles, causing a progressive deterioration of the heart muscles. Without treatment, a patient with early-onset Pompe's disease will die from cardiac or respiratory failure before reaching one year of age.

Patients who have some degree of GAA activity, but less than normal, first develop symptoms after infancy. That condition is referred to as late-onset or juvenile Pompe's disease. Those patients develop progressive muscle weakness and respiratory symptoms due to glycogen buildup in the skeletal muscles, but only rarely do they develop the cardiac symptoms associated with early-onset Pompe's disease.

Following the discovery that Pompe's disease is associated with GAA deficiency, research efforts were focused on treating the disease through enzyme replacement therapy

. Experts hoped that by injecting patients with GAA from other sources they could counteract the effects of harmful glycogen buildup. Early efforts failed, however, because the injected enzyme was predominantly taken up by the patient's liver, reducing glycogen levels there but not in the skeletal or heart muscles where the excess glycogen does the most harm.

Later researchers theorized that the failure of early experiments could be overcome by modifying the injected GAA to include mannose–6–phosphate

(“M–6–P”), which promotes GAA uptake in heart and skeletal muscle cells containing M–6–P receptors, including the cells that failed to take up GAA in prior treatment attempts.

Research along that pathway led to in vitro studies on extracted cells. Those studies were very promising and showed that GAA modified with M–6–P would be taken up by skeletal and heart muscle cells much more efficiently than in the case of prior enzyme replacement therapies

.

Another problem that needed to be solved was how to manufacture human GAA for injection into patients with Pompe's disease. Work on that problem led to the development of a means to manufacture human GAA modified to include M–6–P. Animals such as mice and other mammals could have their genomes altered so that they would produce human GAA that could be extracted by researchers.

Finally, researchers faced the challenge of developing a dosing schedule for the enzyme replacement therapy

. Gaucher disease, a lysosomal protein deficiency condition like Pompe's disease, had been successfully treated with enzyme replacement therapy. Typical dosing schedules for Gaucher disease enzyme treatments were once every two weeks, or once a week if needed. Another known factor bearing on the dosing schedule was the half-life for GAA, which was known to be 6-9 days, suggesting a relatively long dosage interval for recombinant GAA of once per week or once every other week.

By 1997, research had progressed far enough that the Food and Drug Administration approved Duke University's application for Orphan Drug Designation for a new therapy for Pompe's disease based on the injection of a recombinant form of GAA. The University announced in a press release that it would begin testing that treatment on human patients suffering with Pompe's disease.

B

In 2013, Biomarin filed petitions requesting inter partes review of the '410

and '226 patents. For the single claim of the '410 patent, Biomarin sought review on four grounds. The Board instituted review on two of those grounds: the combination of the Duke press release and two references known as Barton and van der Ploeg '88; and the combination of a reference known as Reuser with Barton and van der Ploeg '88. The Board declined to institute review on two other grounds as redundant. For the '226 patent, the Board instituted review of claims 1 and 3 for obviousness based on the Duke press release, Reuser, and a reference known as van Hove. It declined to institute review for anticipation on the basis of the Duke press release alone and for obviousness based on the Duke press release and Reuser. The Board instituted review on claims 4–6 of the '226 patent for obviousness based on the Duke press release, Reuser, Barton, and van der Ploeg '88.

In patent owner responses filed in both inter partes reviews, Genzyme argued that because all of the combinations of references described in vitro experiments, a person of ordinary skill would not find those experiments predictive of results in a human patient. Because the Board did not institute review based on any references that included in vivo data from studies on live animals, Genzyme argued that Biomarin should not be permitted to use any of the prior art showing successful in vivo tests to demonstrate obviousness.

In its reply, Biomarin responded to Genzyme's arguments by citing two in vivo studies, referred to as van der Ploeg '91 and Kikuchi. Van der Ploeg '91 found that the addition of M–6–P to GAA led to significantly increased uptake of GAA in mouse heart and skeletal muscle tissue. A. T. van der Ploeg et al., Intravenous Administration of Phosphorylated Acid a-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice , 87 J. Clinical Investigation 513 (1991). Kikuchi found that GAA deficiencies in Japanese quail suffering from symptoms similar to the symptoms of Pompe's disease could be successfully treated with intravenous injections

of GAA modified with M–6–P. Kikuchi et al., Clinical and Metabolic Correction of Pompe Disease by Enzyme Therapy in Acid Maltase–Deficient Quail , 101 J. Clinical Investigation 827 (1998).

In its final written decisions, the Board found by a preponderance of the evidence that the challenged claims of the '410

and '226 patents would have been obvious. In its analysis of the two patents, the Board noted that Reuser disclosed every claim limitation other than a biweekly dosing schedule, and that the claimed dosing schedule would have been arrived at by routine optimization. For claim 6 of the '226 patent, which is directed to reducing heart muscle symptoms, the Board found that a person of ordinary skill would have understood that an effective treatment for Pompe's disease would treat that condition as well.

Although clinical trials had not been conducted as of December 7, 1998, the priority date of the patents, the Board found that a person of ordinary skill would have been motivated to pursue the clinical development of the therapy disclosed in Reuser. In response to Genzyme's arguments that there would have been no reasonable expectation that the treatment would succeed, the Board said that by December 7, 1998, “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.”

By the 1998 priority date, the Board found, the field related to the development of an enzyme replacement therapy

for Pompe's disease had matured to the point that it was recognized that GAA had to be translationally modified with M–6–P; in vivo studies had been performed in which GAA containing M–6–P had been intravenously administered to mice and Japanese Quail; it was known that human GAA containing M–6–P could be produced in the milk of transgenic animals; and the FDA was granting applications for orphan drug designation for enzyme replacement therapy for Pompe's disease. The Board referred to the Kikuchi and van der Ploeg '91 references as support for its findings as to the state of the art regarding the in vivo studies. Based on the evidence before it, the Board concluded that “a person of ordinary skill in the art would have had a reasonable expectation of success at the time the invention was made,” and “no more than routine processes were needed” to achieve the results recited in the disputed...