United States District Court, E.D. Virginia, Alexandria Division
M. HILTON UNITED STATES DISTRICT JUDGE.
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
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.
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.
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.
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.
Findings of Fact
on the evidence adduced at trial, the Court makes the
following findings of fact.
The Relevant Technology
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.
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
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;
Person of Ordinary Skill in the Art
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.
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.
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.
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.
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.
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.
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."
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.
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.
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.
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.
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.
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
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
The '171 Application
'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.
'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.
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