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Halozyme, Inc. v. Iancu

United States District Court, E.D. Virginia, Alexandria Division

July 31, 2018

HALOZYME, INC., Plaintiff,
ANDREI IANCU, Defendant.



         THIS MATTER comes before the Court on Plaintiff Halozyme, Inc.'s ("Halozyme") Complaint pursuant to 35 U.S.C. § 145, seeking reversal of a patent rejection decision issued by the United States Patent and Trademark Office ("USPTO").

         I. Background

         Halozyme brought this action pursuant to 35 U.S.C. § 145, challenging a final decision issued by the USPTO's Patent Trial and Appeal Board (the "Board"} which affirmed the rejections of claims in U.S. Patent Application 11/238, 171 ("the '171 application"). The claims were rejected on four independent grounds:

• unpatentable under obviousness-type double pantenting ("ODP") over claims 9 and 10 of U.S. Patent No. 7, 767, 429 ("the M29 patent") in view of the U.S. Patent No. 5, 766, 897 ("Braxton") and U.S. Parent No. 6, 552, 170 ("Thompson");
• unpatentable under ODP over claims 4 and 5 of U.S. Patent No. 7, 846, 431 ("the M31 patent") in view of Braxton and Thompson;
• unpatentable under ODP over claims 5 and 6 of U.S. Patent No. 7, 829, 081 ("the '081 patent") in view of Braxton and Thompson; and
• obvious under 35 U.S.C. § 103(a) over WO 2004/078140 ("Bookbinder"), Braxton, and Thompson.

         Halozyme was informed by the Patent Examiner during prosecution of the patent that timely-filed terminal disclaimers may be used to overcome obviousness-type double patenting rejections, but Halozyme chose not to file a terminal disclaimer to overcome any of the ODP rejections.

         Halozyme is the assignee of the '171 application. The application was filed in September 2005, and is a continuation-in-part application of U.S. Patent Application No. 11/065, 716 ("theA716 application"), which was filed in February 2005.

         Halozyme filed its complaint in this Court on December 19, 2016, alleging that the Board erred in affirming the four rejections made by the Examiner. Halozyme amended its complaint on July 3, 2017, removing its request for judicial review of some of the claims at issue in the action, and adding an allegation that the USPTO erred by considering Bookbinder to be prior art. On August 17, 2017, Halozyme amended its complaint again, leaving only claims 295-298, 300, and 303 at issue in this action. This Court began a bench trial on November 13, 2017, which continued until November 15, 2017.

         II. Findings of Fact

         Based on the evidence adduced at trial, the Court makes the following findings of fact.

         A. The Relevant Technology

         A protein consists of a sequence of amino acids that fold onto each other to create three-dimensional structures. As a result of the folding, some amino acids are buried and not accessible, while others are positioned along the outside of the folded structure and are accessible to the environment surrounding the protein.

         There are 20 amino acids. Four of these amino acids are lysine, cysteine, arginine, and histidine, which are referenced throughout. The first amino acid of a protein is called the N-terminus.

         The relationship between the various terms used throughout to describe the compounds at issue, from the broadest to narrowest, can be illustrated as follows: Glycosaminoglycanase enzymes (broadest term}; Soluble neutral-active hyaluronidase Glycoprotein = sHASEGPs; Human soluble neutral-active hyaluronidase Glycoproteins = human sHASEGPs; PH-20 Hyaluronidase Glycoproteins = rHuPH20s; PEGylated rHuPH20s; PEGPH20 (Halozyme's product; narrowest term).

         B. Person of Ordinary Skill in the Art

         At the time of the '171 application, protein modification was an interdisciplinary field. The Court finds that a person of ordinary skill in the art would have a Ph.D. in chemistry, biochemistry, biology, or engineering, and have about two years of experience working in the field. The USPTO's experts, Dr. Zhaohui Sunny Zhou and Dr. Laird Forrest, each meet or exceed the definition of a person of ordinary skill in the art. Thus each are in a position to render an opinion as to what a skilled artisan would have thought and understood regarding the issues relevant to this case.

         By 2003, it was recognized that using proteins for therapeutic purposes had several limitations. Specifically, when administered to the human body, they may exhibit a short half-life, a propensity to generate neutralizing antibodies, and proteolysis (cleavage of protein by enzymes) . It was also well known by the early 2000s that attaching polyethylene glycol ("PEG") to a protein was a potential solution to overcome these problems. PEG has very low toxicity, excellent solubility in agueous solutions, and extremely low immunogenicity and antigenicity. PEGylation was known to potentially decrease protein activity, but that decrease was generally offset by an increased half-life.

         It was therefore well known that PEGylation generally extends the half-life and improves the biological activity of a protein. Braxton stated that PEGylation is the "most promising" approach to solve the problems of short half-life and immunogenicity. Thompson explained that PEGylation can "overcome obstacles encountered in the clinical use of biologically active molecules," including their short half-life in the blood stream or solubility and aggregation problems. By 2003, PEGylation was the established method of choice for improving the therapeutic use of proteins for pharmacological purposes.

         PEGylation involves the formation of a covalent bond between PEG molecules and a protein. It was well known how to attach PEGs to proteins by 2003. In fact, there were two "main methods" to do so in the early 2000s. The most popular approach was to randomly attach PEGS to an amine group, which could be found on lysine amino acids and the N-terminus of the protein, among other places on the protein.

         By the early 2000s, there were plenty of examples of attaching PEGs to amine groups, and in fact the majority of PEGylated drugs at that time were PEGylated at an amine group. Dr. Zhou testified that lysine PEGylation was the most common method because lysines are one of the more common amino acids and tend to be found on the protein surface, making them accessible and less likely to disrupt the function or structure of the protein. Dr. Zhou also testified that in 2003 there were high quality commercial reagents available to conjugate PEGs to lysines, and there were methods to optimize conjugation for lysines. By 2003, attaching PEGS to amine groups via a succinimidyl (or "NHS") ester reagent was well known in the art.

         The second possible approach for attaching PEGs to proteins was targeting attachment to cysteine amino acids. If a protein naturally includes a cysteine, it can by PEGylated. If it does not, a person skilled in the art can engineer a cysteine into the polypeptide, and then modify that cysteine with PEG. This approach was generally not feasible, however, if the cysteines were located in regions important to the function of the protein.

         In the early 2000s, the biopharmaceutical company Nektar sold a selection of PEGylation reagents. The most popular PEG reagents Nektar sold for lysine attachment were the NHS active esters. Nektar's catalog also included instructions on how to use those reagents. Nektar teaches that multiple PEGs can be attached to a protein at multiple lysines. For lysine active PEGs, Nektar instructs that "several PEGs can be attached to a protein at ¶ 8-9.5 at room temperature, and within 30 minutes, if equal molar amounts of PEG (MW 5, 000 Da) and protein are mixed." The Nektar catalog also explains how to optimize, stating that "[a]nalysis of several reactions with varying ratios of PEG/protein and with varying pH will quickly provide information sufficient to design optimal conditions for desired degrees of PEGylation."

         Nektar routinely partnered with other companies to develop PEGylated proteins, including identification of an appropriate PEGylation reagent, creation of a scalable process, and analytical characterization of the final modified product. The Nektar catalog reported success in PEGylating proteins, stating that their technology and development expertise have been the "driving" force behind more than five products on the market and ten products in clinical development. The catalog also included a "case study" where Nektar partnered with InterMune, reporting that "Nektar scientists created an optimized PEGylated molecule, produced a scalable process, and provided analytical characterization of the final product within three months." Dr. Zhou testified at trial that "figuring out the degrees of PEGylation" in this case study necessarily took "less than three months to do" because it is only part of the first step (creating an "optimized PEGylated molecule") of the three steps that Nektar performed.

         The fact that PEGylation generally increases half-life but decreases activity would motivate a skilled artisan to figure out the optimal degree of PEGylation. The degree of PEGylation is perhaps the most important parameter, because a change in structure can affect function; therefore, a person of ordinary skill in the art would be motivated to optimize the degree of PEGylation by routine optimization methods.

         By the early 2000s, a skill artisan knew how to attach PEGs to a protein, and a person of ordinary skill in the art would know how to control how many PEGs were attached and how to test to see how many PEGs were attached. A skilled artisan could optimize PEGylation by creating a PEGylated protein and then test it for activity and longevity. The degrees of PEGylation could then be varied until the result met the desired criteria for optimization. It was also generally known how to evaluate the pharmacokinetics of a protein, with multiple examples present in the literature.

         Assays to measure hyaluronidase were also known in the art. Bookbinder and the '716 application describe the same prior art assays dating back to the 1940s. They include assays measuring loss of turbidity, loss of viscosity, and the generation of new reducing N-acetylamino groups, and a substrate gel zymography assay. Other assays were also known.

         Although Dr. Flamion testified that "you probably would need to adjust and improve on the existing assays," Dr. Zhou explained that if any assays needed to be adjusted, a person of ordinary skill in the art would know how to do so. Further, when you have multiple assays available, there is a "very high success rate to adopt a new assay." Thus a person of ordinary skill in the art would be motivated to optimize the degree of PEGylation, would know how to do so, and would expect to be successful in doing so.

         By the early 2000s, a number of PEGylated proteins had been approved by the FDA. The majority of these attached the PEGs at lysines and the N-terminal amino acid of the protein. By 2005, the amino acid sequence of human PH20 was known. At this time a skilled artisan would know that the cysteines in hyaluronidase involve some disulfide bonds, and because of this would not be a good target for PEGylation. This would motivate a skilled artisan to look to lysine PEGylation instead.

         A skilled artisan in the early 2000s would also know how to formulate protein compositions for systemic use, including PEGylated compositions, and was motivated to do so. There was no testimony adduced at trial to suggest that any special ingredients were required to formulate a composition of hyaluronidase for systemic use, or that PEGylated hyaluronidase requires any special formulations for systemic administration.

         C. The '171 Application

         The '171 application lists six people as its inventors: Louis H. Bookbinder, Anirban Kundu, Gregory I. Frost, Michael F. Haller, Gilbert A. Keller, and Tyler M. Dylan. Halozyme filed a petition with the USPTO during the prosecution of the application to remove Haller, Keller, and Dylan as inventors.

         The '171 application is directed to glycosaminoglycanase enzymes; specifically, to "Neutral-Active, Soluble Hyaluronidase Glycoproteins" (or "sHASEGPs") . The application discloses "the human soluble PH-20 Hyaluronidase Glycoproteins (also referred to herein as rHuPH20s)," and discloses that "[c]hemical modifications of a SHASEGP" with "polymers such as polyethylene glycol and dextran" are able to "shield" sHASEGPs from "removal from circulation and the immune system as well as glycosylation receptors for mannose and asialoglycoprotein," and thus, "prolong the [] half-life" of the sHASEGP. The application also discloses modifications using polyethylene glycol to further prolong half-life and specifically discloses a modification accomplished by lysine PEGylation. One example in the '171 application, Example 21-A, discloses using succinimidyl PEGs to form PEGylated PH20 modified with "about three to six" PEG molecules, which were purified to yield compositions having "specific activities of approximately 25, 000 Unit/mg protein hyaluronidase activity." Example 21-A also discloses that a PEGylated PH20 modified with "about three to six" PEG molecules was observed to have a significantly longer serum half-life in comparison to unPEGylated PH20 when tested on mice. PEGylated PH20 modified with "about three to six" PEG molecules also had a significantly greater effectiveness in a rat stroke model.

         The' 171 application discloses and provides examples of sHASEGPs being delivered systemically, and lists examples of pharmaceutically acceptable carriers, vehicles, and agents. The '171 application further discloses a variety of assays for testing hyaluronidase activity. The application discloses SEQ ID NO: 1, which it identifies as the polypeptide sequence of human hyaluronidase, and SEQ ID NO: 4, which corresponds to amino acids 36-483 of SEQ ID NO: 1. The application discloses that insulin can be used as an ...

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