United States District Court, D. New Jersey
CLAIRE C. CECCHI UNITED STATES DISTRICT JUDGE
patent case was brought by Plaintiffs Immunex Corporation
("Immunex"), Amgen Manufacturing, Limited
("Amgen"), and Hoffman-La Roche, Inc.
("Roche") (collectively, "Plaintiffs")
against Defendants Sandoz Inc., Sandoz International GmbH and
Sandoz GmbH (collectively, "Defendants").
Specifically, this action relates to the validity of claims
11-12 and 35-36 of U.S. Patent No. 8, 063, 182, which covers
the fusion protein etanercept, the active ingredient in
Immunex's product Enbrel® (Joint Trial Exhibit
("JTX")-1("the '182 Patent")), and
claims 3, 8, and 10 of U.S. Patent No. 8, 163, 522, which
covers Enbrel®'s method of manufacture (JTX-2
("the '522 Patent")) (collectively, the
asserted claims of the "Patents-in-Suit").
See ECF No. 18 ¶ 9. Enbrel® is a brand name
biologic drug primarily used to treat rheumatoid arthritis.
Id. ¶¶ 43, 45; ECF No. 688 at 11 ¶
Court held a two-week bench trial in this matter that began
on September 11, 2018 and concluded on September 25, 2018.
ECF Nos. 621-622, 627, 629-635. The parties submitted
post-trial briefing and proposed findings of fact and
conclusions of law through early November 2018. ECF Nos. 648
(corrected at 651 -2 ("PFOF")), 647
(corrected at 649-2 and subsequently corrected
at 650-1 ("DFOF")), 645 (corrected at
651-1 ("Pls. Br.")), 646 (corrected at
649-1 and subsequently corrected at 650-2
("Defs. Br.")). On November 6, 2018, the parties
submitted response briefs. ECF Nos. 653 ("Pls. Reply
Br."), 652 ("Defs. Reply Br."). Closing
arguments were held on November 19, 2018. ECF No. 656.
is the first U.S. Food and Drug Administration
("FDA") approved fusion protein, approved in
November 1998. PFOF ¶¶ 8, 10; DFOF ¶ 12. In
August 2016, the FDA approved Defendants' biosimilar
version of Enbrel®, called Erelzi™. PFOF ¶ 11;
ECF No. 688 at 11 ¶¶ 41-43. Defendants do not
contest infringement of the '182 Patent or the '522
Patent. ECF No. 619; PFOF ¶ 16. Therefore, the issue
left for this Court to decide is whether the Patents-in-Suit
are invalid based on the following legal principles: (1) lack
of written description and enablement; (2) obviousness; and
(3) obviousness-type double patenting.
Opinion constitutes the Court's findings of fact and
conclusions of law pursuant to Federal Rule of Civil
Procedure 52(a). The findings of fact are based on the
Court's observations and credibility determinations of
the witnesses who testified, and a thorough review of all the
evidence admitted at trial. While the Court has reviewed all
of the evidence presented, given the length of the trial
record, the Court includes references only to the evidence
most pertinent to its analysis. For the reasons set forth
below, the Court finds that the Patents-in-Suit are not
Roche was the first to file the patent applications that
eventually issued as the Patents-in-Suit. PFOF ¶ 51.
Thereafter, Plaintiffs Amgen and Immunex obtained certain
rights from Roche pertaining to the Patents-in-Suit, pursuant
to an agreement called the Accord and Satisfaction, which
included the right to take over the prosecution of the
relevant patent applications and the right to commence an
infringement action. JTX-12. Plaintiff Roche is a New Jersey
corporation with its principal place of business in New
Jersey. ECF No. 18 ¶ 3. Plaintiff Immunex is a
Washington corporation with its principal place of business
in California and is a wholly owned subsidiary of non-party
Amgen Inc. Id. ¶ 1. Plaintiff Amgen is a
corporation of the Territory of Bermuda with its principal
place of business in Puerto Rico and is also a wholly owned
subsidiary of non-party Amgen Inc. Id. ¶ 2.
Sandoz Inc. is a Colorado corporation with its principal
place of business in New Jersey. Id. ¶ 4.
Defendant Sandoz International GmbH is a German corporation
with its principal place of business in Germany. Defendant
Sandoz GmbH is an Austrian corporation with its principal
place of business in Austria and is a subsidiary of Sandoz
International GmbH. Id. ¶¶ 6-7. Sandoz
Inc. is the United States agent for Defendants Sandoz
International GmbH and Sandoz GmbH. Id. ¶ 4.
All parties are in the business of developing, manufacturing,
marketing, and selling biopharmaceutical products.
Background of the Invention
active ingredient in the biopharmaceutical drug at issue in
this case is a fusion protein known as etanercept that is
made by combining the extracellular region of a 75 kilodalton
Human Tumor Necrosis Factor Receptor with a portion of an
IgG1 immunoglobulin. This section will first provide the
scientific background of the claimed invention, by explaining
each component and its purpose. Next, the Court will provide
the relevant research and patent history for the
arthritis is an inflammatory auto-immune disease, i.e. a
disease which occurs when "an overactive immune system
attacks an individual's own body," and causes bone
erosion, narrowing of joint space, and irreversible joint
damage. PFOF ¶¶ 32-33. One way to treat rheumatoid
arthritis is to "dampen the immune system" and to
"inhibit inflammatory reactions." Id.
¶¶ 47-48. The immune system is made up of various
cells and antibodies that protect the body from foreign
invaders. Id. ¶ 23. Antibodies have two primary
functions: to bind foreign substances known as antigens, and
to recruit other immune system components to attack antigens.
Id. There are many classes and subclasses of the
antibody immunoglobulin or "Ig", of which IgG is
one such class. Id. ¶¶ 99, 158. There are
four subclasses of human IgG: IgG1, IgG2, IgG3, and IgG4.
a protein, and proteins are made up of "amino acid
residues connected in a strand called a
'polypeptide,' which folds into a three-dimensional
shape that imparts certain structural and functional
characteristics." Id. ¶ 20. Scientists can
identify protein sequences based on the order of amino acids
in the protein, with the beginning portion of the sequence
referred to as the "N-terminus" and the end portion
referred to as the "C-terminus." Id.
an IgG protein, pictured below, consists of two heavy chains
and two light chains, and each chain contains variable and
constant regions. Id. ¶ 24. The constant region
is the portion that interacts with other components of the
immune system to elicit a response. Id. The heavy
chain constant region includes the CHI, the hinge, CH2, and
CH3 domains while the light chain constant region consists of
the CL domain. Id. The variable region of each
chain, labeled here as VH and VL, is what binds to the
component of the immune system, called a cytokine, is a
messenger protein that has a wide variety of functions,
including to initiate an immune response. PFOF ¶ 27. The
body makes dozens of distinct cytokines, one of which is the
Human Tumor Necrosis Factor ("TNF"). Id.
¶¶ 27-29. TNF can be found in an insoluble
(membrane-bound) or soluble (free-flowing) form. Id.
¶ 28. Originally discovered to kill tumor cells, TNF has
many functions and by August 1990, scientists associated it
with inflammatory diseases, such as rheumatoid arthritis.
Id. ¶¶ 28-33.
plays a significant role in auto-immune disorders.
Id. TNF binds to certain proteins called TNF
receptors ("TNFRs") that extend beyond the outer
membrane of a cell. Id. ¶ 30. TNFRs have three
regions: intracellular, transmembrane, and extracellular.
Id. The extracellular portion of the TNFR, which is
the portion that "protrudes outside the cell," can
be split off to produce a "soluble" fragment of the
TNFR that can bind to TNF. Id. ¶¶ 30, 76.
Two types of TNFRs have been identified, one that has a
molecular weight of approximately 55 kilodaltons ("p55
TNFR" or "p55") and one with a molecular
weight of approximately 75 kilodaltons ("p75 TNFR"
or "p75"). Id. ¶¶ 36-38.
the active ingredient in the biopharmaceutical drug
Enbrel® at issue here, is a fusion protein that combines
the extracellular region of a p75 TNFR with an IgG1.
Id. ¶ 9. "A fusion protein is made by
combining DNA sequences encoding parts of different proteins
into one sequence, introducing that sequence into host cells,
and using their natural internal machinery to produce the
desired fusion protein." Id. ¶ 19.
Specifically, etanercept is a "dimeric fusion protein
consisting of the extracellular region of the p75 TNF
receptor" which, as the parties have stipulated, is
"fused to the exon-encoded 'hinge-CH2-CH3' of
the constant region of a human IgG1 antibody heavy
chain." Id. ¶ 9; DFOF ¶ 93; ECF No.
688 at 20 ¶ 68. Etanercept works by binding to and
neutralizing excess TNF in patients with rheumatoid
arthritis, thereby reducing the auto-immune inflammatory
response. PFOF ¶ 244. The graphic below depicts images
of a p75 TNFR and an IgG1 on the left-hand side and
etanercept on the right-hand side. The Patents-in-Suit cover
etanercept and the method of making etanercept. Id.
DFOF ¶¶ 208, 214.
Research and Patent History
1990, "there was a high level of interest in studying
TNF and investigating whether targeting TNF with a
TNF-binding protein would provide a therapeutic benefit by
inhibiting the binding of TNF to its cell-bound
receptors." DFOF ¶¶ 1, 14. At that time,
scientific evidence pointed to at least two TNFRs expressed
by the human body: p55 and p75 TNFR. PFOF ¶¶ 37-38;
DFOF ¶ 2. In April 1990, researchers at Roche (the
"Roche Inventors") published the complete amino
acid sequences for the p55 TNFR and the cDNAs encoding it. PFOF
¶ 39; DFOF ¶¶ 15, 16; JTX-21 at 1. In May
1990, Immunex published an article containing the complete
amino acid sequence for p75 and therein stated that the
researchers isolated a cDNA clone of the receptor. PFOF
¶ 40; Smith, C.A., et. al., A Receptor for Tumor
Necrosis Factor Defines an Unusual Family of Cellular and
Viral Proteins, Science 248: 1019-23 (1990) (JTX-24)
("Smith 1990"); DFOF ¶ 4. Several months later
in July 1990, the Roche Inventors published the complete
amino acid sequence for the p75 TNFR and part of its encoding
cDNA. PFOF ¶ 39; Dembic, Z. et al., Two Human TNF
Receptors Have Similar Extracellular, But Distinct
Intracellular, Domain Sequences, Cytokine 2(4): 231-37
(1990) (JTX-23) ("Dembic 1990"); DFOF ¶ 30.
the same time that the Roche Inventors were publishing
studies on the amino acid sequences in p55 and p75 TNFR, they
were also exploring the possibility of TNFR-Ig fusion
proteins. PFOF ¶ 46. The Roche Inventors were ultimately
successful in creating fusion proteins using both p55 and p75
TNFRs. Id. ¶ 49. The initial fusion protein
used an IgG3 immunoglobulin, however the Roche Inventors'
"pathway of experimental work leading to a TNFR fusion
protein" also contemplated fusion proteins with IgG1 and
IgG2 immunoglobulins. Id. ¶¶ 50, 58-68.
August 31, 1990, the Roche Inventors filed a patent
application in Europe bearing Application No. 90116707
("EP '707 Application") and on September 13,
1990, they filed a U.S. Patent with Application No. 07/580,
013 ('"013 Application"). Id. ¶
51. The Patents-in-Suit claim the benefit of the '013
Application and priority to the European '707
Application. Id. The Patents-in-Suit, as well as the
EP '707 Application and the '013 Application,
encompass a p75 TNFR-IgG1 fusion protein, but because the
parties differ in their assessments of the patent
specifications and validity of the claimed invention, further
details on the Patents-in-Suit will be discussed below.
Id. ¶¶ 50-53; DFOF¶¶ 36-37.
Patents-in-Suit and Relevant Prosecution History
182 Patent, entitled "Human TNF Receptor Fusion
Protein," issued on November 22, 2011 and expires on
November 22, 2028. PFOF ¶ 74; DFOF ¶ 83. The
asserted claims "define a fusion protein consisting of
parts of two different proteins: the extracellular region of
p75 fused to all of the domains of the human IgG1 constant
region other than the first domain." PFOF ¶¶
74-76; see also '182 Patent (JTX-1) col.
initial '013 Application was abandoned, and U.S.
Application No. 08/965, 640 ('"640
Application") was filed on July 21, 1993 as a
continuation. PFOF ¶ 57; DFOF ¶¶ 38-39. The
'640 Application was subject to a restriction requirement
by the United States Patent and Trademark Office
("USPTO") and in response Roche elected to pursue
claims related to the p55 fusion protein, which issued as
U.S. Patent No. 5, 610, 279 ('"279 Patent") on
March 11, 1997. PFOF ¶ 57; DFOF ¶¶ 39-40; ECF
No. 688 at 6 ¶ 9. As a result of the restriction, Roche
then filed two divisional applications on May 19, 1995: U.S.
Application No. 08/444, 790 ('"790
Application"), which issued as the '182 Patent, and
U.S. Application No. 08/444, 791 (the '791
Application"), which issued as the '522 Patent.
See PFOF ¶ 57; DFOF ¶ 41.
2004, prior to issuance of the '182 Patent, Amgen and
Immunex acquired the exclusive right to prosecute the
Patents-in-Suit, among other rights, from Roche pursuant to
an Accord and Satisfaction between non-party Amgen Inc.,
Immunex, and Roche. JTX-12 at 4-6, Article 3, ¶¶
3.1-3.6; see also PFOF ¶ 34; DFOF ¶¶
54, 58, 62. Those rights were later consolidated in Immunex
by a separate agreement. JTX-14. In 2005, Immunex amended the
'790 Application in response to a USPTO office action
requiring the '790 Application to come into consonance
with the restriction requirement. PFOF ¶ 285; DFOF
¶ 73. The '790 Application was again amended in
2006. PFOF ¶ 144; DFOF ¶ 74. Despite the
amendments, the '790 Application was rejected "for
failing to comply with the written description requirement
and as obvious over the applied prior art," and the
rejection was appealed to the Board of Patent Appeals and
Interferences ("BPAI"). Plaintiffs' Trial
Exhibit ("PTX")-6.456 ("BPAI Opinion").
The BPAI reversed the examiner's rejection. PTX-6.456 at
9 (BPAI Opinion reversing rejection by examiner). The
'182 Patent then issued on November 22, 2011. See
generally ' 182 Patent (JTX-1).
The '522 Patent
'522 Patent, entitled "Human TNF Receptor,"
issued on April 24, 2012 and expires on April 24, 2029. PFOF
¶ 74; DFOF ¶ 83. The asserted claims "define a
method of producing [the] fusion protein" defined in the
'182 Patent. '522 Patent (JTX-2) at 47-48 (claims 3,
8, 10); PFOF ¶ 75. The '522 Patent issued from the
'791 Application, which was filed on May 19, 1995 as a
divisional of the '640 Application, along with the
'790 Application which issued as the' 182 Patent.
PFOF ¶ 57; DFOF ¶ 48.
to the '522 Patent's issuance, Amgen and Immunex
amended the '791 Application in 2004, 2007, and 2010 to
include several references related to the full amino acid
sequence for p75. See, e.g., '522 Patent (JTX-2)
col. 3:1-3, Fig. 5; DFOF¶¶ 78-80. Like the
amendments to the '182 Patent, these amendments were
triggered by two USPTO actions, which rejected the '791
application for obviousness and insufficient written
description. PTX-7.351. Despite the amendments, the '791
Application was still rejected, and that rejection was
eventually overcome by citing the '790 Application BPAI
Opinion which dealt with similar issues. PFOF ¶ 323;
JTX-4 at 4952-53. The '522 Patent then issued on April
24, 2012. See generally '522 Patent (JTX-2).
ISSUES TO BE DECIDED
to the commencement of trial, Defendants advised that they
did not contest infringement of the Patents-in-Suit. ECF No.
619. As discussed above, the parties also stipulated that the
term "all of the domains of the constant region of a
human immunoglobulin IgG heavy chain other than the first
domain of said constant region" is construed as meaning
"the exon-encoded 'hinge-CH2-CH3' region of
human [IgG/IgG1]." ECF No. 688 at 20 ¶ 68.
Accordingly, the question before this Court is whether
the' 182 and '522 Patents are invalid due to lack of
written description and enablement, obviousness, and
obviousness-type double patenting.
patents are presumed valid. See 35 U.S.C. §
282(a). To rebut this presumption, Defendants bear the burden
of proving invalidity by clear and convincing evidence.
Titan Tire Corp. v. Case New Holland, Inc.,
566 F.3d 1372, 1376 (Fed. Cir. 2009) ("Because of this
presumption, an alleged infringer who raises invalidity as an
affirmative defense has the ultimate burden of persuasion to
prove invalidity by clear and convincing evidence, as well as
the initial burden of going forward with evidence to support
its invalidity allegation.").
Written Description and Enablement (35 U.S.C. §
patent specification "shall contain a written
description of the invention." 35 U.S.C. § 112. The
specification must "reasonably convey to those skilled
in the art that the inventor had possession of the claimed
subject matter as of the filing date." Ariad Pharm.
Inc. v. Eli Lilly & Co., 598 F.3d 1336,
1351 (Fed. Cir. 2010). The test for written description
"requires an objective inquiry into the four corners of
the specification from the perspective of a person of
ordinary skill in the art." Id. "[W]hether
a patent complies with the written description requirement
will necessarily vary depending on the context. Specifically,
the level of detail required . . . varies depending on the
nature and scope of the claims and on the complexity and
predictability of the relevant technology." Id.
(citation omitted). When reviewing the patent according to
these principles, "[w]ritten description is a question
of fact, judged from the perspective of [a POSA] as of the
relevant filing date." Falko-Gunter Falkner v.
Inglis, 448 F.3d 1357, 1363 (Fed. Cir. 2006) (citing
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64
(Fed. Cir. 1991)).
as to enablement, a patent specification must describe
"the manner and process of making and using [the
invention], in such full, clear, concise, and exact terms as
to enable any person skilled in the art to which it pertains
... to make and use the same ...." 35 U.S.C. § 112.
Moreover, enablement requires that the specification teach a
POSA "how to make and use the full scope of the claimed
invention without undue experimentation." Martek
Bioscis. Corp. v. Nutrinova, Inc., 579 F.3d 1363, 1378
(Fed. Cir. 2009) (citation omitted). A patentee need not
"include in the specification that which is already
known and available to [a POSA]" and "not every
last detail is to be described, else patent specifications
would turn into production specifications, which they were
never intended to be." Koito Mfg. Co. v.
Turn-Key-Tech, LLC, 381 F.3d 1142, 1156 (Fed. Cir. 2004)
(citation omitted). "Enablement is a question of law
involving underlying factual inquiries."
Falkner, 448 F.3d at 1363 (citing Genentech,
Inc. v. NovoNordiskA/S, 108 F.3d 1361, 1365 (Fed. Cir.
1997), In re Wands, 858 F.2d 731, 737 (Fed. Cir.
argue that the Patents-in-Suit are invalid because their
specifications (1) lack a sufficient written description of
the invention and (2) do not enable a POSA to make or use the
invention. Defs. Br. at 20-35. By contrast, Plaintiffs
contend that the specifications are adequate, and that
Defendants failed to prove their written description or
enablement claims by clear and convincing evidence. Pls. Br.
support of their arguments, the parties relied heavily on the
testimony of the following four witnesses: (1)
Defendants' expert Daniel Capon, Ph.D., (2)
Defendants' expert Carl P. Blobel, M.D., Ph.D., (3)
Plaintiffs' expert James Naismith, Ph.D, and (4)
Plaintiffs' expert Hansruedi Loetscher,
Ph.D. For the reasons set forth below, the Court
finds that Defendants failed to prove invalidity based on the
written description and enablement requirements by clear and
convincing evidence, and therefore the Patents-in-Suit are
not invalid under 35 U.S.C. § 112.
The Specifications Meet the Written Description
argue that the specifications are deficient because they
neither sufficiently describe etanercept nor convey that the
Roche Inventors had possession of etanercept, and that
further, the specifications in conjunction with the claims do
not direct a POSA to the specific embodiment of etanercept.
Defs. Br. at 20-32. Plaintiffs counter that the necessary
elements of the claimed invention are adequately described
throughout the specifications, were known and available prior
to August of 1990, and that the specifications adequately
describe the novel combination of those elements to create
etanercept. Pls. Br. at 13-21. Therefore, Plaintiffs contend
that the specifications demonstrate possession and the
patents properly direct a POSA to etanercept. Id.
'182 Patent claims a fusion protein consisting of the
extracellular portion of the p75, as well as the exon-encoded
hinge, CH2 and CH3 domains of human IgG1, while the '522
Patent claims the method of making the fusion protein.'
182 Patent (JTX-1) col. 39:14- 42:34; 9/18 AM (Naismith) Tr.
at 89:2-12, 91:8-14; '522 Patent (JTX-2) col. 45:44-48:4.
The patent specifications of the '182 and '522
Patents identify soluble fragments of p75 TNFR as one of two
TNF binding proteins, i.e. p55 and p75, used in TNFR-IgG
fusion proteins and include both figures and examples that
are referenced in the parties' arguments. There are
multiple figures in the Patents-in-Suit that provide
nucleotide sequences for the TNF binding protein. See
generally ' 182 Patent (JTX-1); '522 Patent
(JTX-2). In analyzing the specifications, it appears mat
Figure 1 of the specifications relates to a p55 TNFR and
Figure 4 relates to a p75 TNFR. Figure 4 is a "[n]ucleotide
sequence... and deduced amino acid sequence... for cDNA
clones derived from" a p75 TNFR, which consists of a
long combination of letters representing those amino acids
and related cDNA combinations. '182 Patent (JTX-1) col.
2:60-62, Fig. 4. The specifications additionally include
multiple examples pertaining to a TNFR-IgG fusion protein. In
the examples, both the '182 and '522 Patents notably
discuss and disclose two nucleotide sequences for portions of
p75-SEQ ID NO: 10 (N-terminus) and SEQ ID NO: 7 (C-terminus).
Patents-in-Suit disclose using "especially preferred
vectors" pCD4-Hγl (DSM 5314, deposited on Apr. 21,
1989) and pCD4-Hγ3 (DSM 5523, deposited on Sept. 14,
1989) "[f]or the expression of proteins which consist of
a soluble fragment of non-soluble TNF-BP [binding protein]
and an immunoglobulin fragment, i.e. all domains except the
first of the constant region of the heavy chain."
'182 Patent (JTX-1) col. 8:56-9:8. The specifications
further state that "the present invention embraces not
only allelic variants, but also those DNA sequences which
result from deletions, substitutions and additions from one
or more nucleotides of the sequences given in FIG. 1 or FIG.
4" and yield TNF-binding proteins. '182 Patent
(JTX-1) col. 5:17-22; '522 Patent (JTX-2) col. 5:29-34.
The Patents-in-Suit also reference the Smith 1990 article-the
Immunex publication that includes the complete amino acid
sequence for p75.' 182 Patent (JTX- 1) col. 5:22-24;
'522 Patent (JTX-2) col. 5:34-37.
The Requisite Components of the Fusion Protein Were Disclosed
in the Specifications and Known Prior to Aueust 1990
Court finds that the specifications of the Patents-in-Suit
sufficiently describe the components of etanercept. A patent
must include sufficient details such that a POSA could
understand the subject invention and recognize that the
inventor possessed it. Ariad, 598 F.3d at 1351.
However, this requirement does not necessarily mean that the
specification of the patent must include every nuanced
detail. Indeed, "[a] patent need not teach,
and preferably omits, what is well known in the art."
Falkner, 448 F.3d at 1365 (quoting
Spectra-Physics, Inc. v. Coherent, Inc.,
827 F.2d 1524, 1534 (Fed. Cir. 1987)); see also Capon v.
Eshhar, 418 F.3d 1349, 1357-58 (Fed. Cir. 2005) (holding
that a patent's specifications do not need to reiterate
the structure, formula, or chemical name of a claimed
invention to satisfy the written description requirement when
that information is already known in the field). The Court
will first analyze the sufficiency of the description of p75,
followed by the sufficiency of the description of the IgG1
portion of the fusion protein.
p75 Is Adequately Described
the Patents-in-Suit, the Court finds that p75 is sufficiently
described. The specifications of the Patents-in-Suit identify
two TNF receptors, p55 and p75, and further note that the
invention embraces allelic variants and DNA sequences
resulting from deletions, substitutions, and additions of one
or more nucleotides of the sequences provided in Figure 1
and/or Figure 4. '182 Patent (JTX-1) col. 4:1-5:24.
Sequence identification numbers, which correspond to p75, are
mentioned throughout the specification (including the
examples therein) and in the claims, and Example 6 explains
that the inventors isolated the p75 TNFR. Id. col.
the prior art demonstrates that the p75 amino acid sequence
was well known to a POSA at the time of the invention. The
Court may look to prior art and trial testimony when
determining what a POSA would have known at the time of the
invention. See, e.g., Ariad, 598 F.3d at 1351
(relying on expert testimony and examples of prior art to
make written description determination); Falkner,
448 F.3d at 1365-66. The parties agreed that by August 1990,
the p75 TNFR was well known to a POSA. PFOF ¶¶
86-87; DFOF ¶ 2. Both the Immunex Smith article and the
Roche Dembic article, which were published in May 1990 and
July 1990 respectively, contain a full recitation of the p75
amino acid sequence. PFOF ¶¶ 89-91; Smith 1990
(JTX-24) at 3-4, Fig. 3B; Dembic 1990 (JTX-23) at 1-2. The
Smith 1990 article, expressly referenced in the
Patents-in-Suit, also notes that "[t]he entire
nucleotide sequence is available upon request and has been
deposited with GenBank, accession number M32315." Smith
1990 (JTX-24) at 3-4, Fig. 3B. GenBank is an amino acid
repository which can match partial amino acid sequences with
full corresponding sequences that have been deposited with
GenBank. See 9/18 AM (Naismith) Tr. at 62:7-16.
Sequences are provided to GenBank as "an information
deposit" in which the DNA sequence letters are submitted
and an "accession number" is the particular
identification number assigned to each submitted sequence.
Id. at 73:17-74:1. Similarly, the Dembic 1990
article contains the entire p75 amino acid
sequence. See Dembic 1990 (JTX-23) at Fig.
1. Ultimately, neither party contests that the prior art
"definitively identified two TNF receptors: the p55 and
the p75" by August 1990. Defs. Br. at 21;
PFOF¶¶ 36-38. The parties further agree that
Immunex scientists in May 1990 and later the Roche Inventors
in July 1990 published the full-length p75 TNFR before the
related European priority patent application was filed in
August 1990. DFOF ¶ 2; PFOF ¶¶ 39-41.
however, argue that because the specifications refer to Smith
1990 as an example of a "deletion" when compared to
Figure 4 (when it was instead the complete sequence of Figure
4), a POSA would not have considered using the Smith 1990
sequence. Defs. Br. at 25. Upon review of the disclosure, the
Court does not believe a POSA would have been deterred from
looking to Smith 1990 for use in the fusion protein due to
the term "deletion." Just prior to that language in
the specification, the invention embraces not only deletions
but also all allelic variants including "substitutions
and additions." '182 Patent (JTX-1) col. 5:17-24. In
fact, a POSA may have been encouraged to look to an outside
reference, such as the Smith 1990 article, that was expressly
called out by name in the specification. 9/18 PM (Naismith)
Tr. at 52:23-53:8. At trial, Plaintiffs' expert Dr.
Naismith credibly testified that the Smith 1990 reference
would have communicated to the ordinary artisan that
"[i]f you hadn't read the paper, go and read it.
They'd think it was a landmark paper." Id.
Thus, the Court agrees with Plaintiffs that despite the word
"deletion," a POSA would have been directed to
Smith 1990 and therefore the full p75 protein.
further support of Plaintiffs' arguments, Example 7
contains the N-terminus sequence designated SEQ ID NO: 10.
'182 Patent (JTX-1) col. 16:22-30. SEQ ID NO: 10 matches
the first 18 amino acids at the N-terminus of the known p75
as published in Smith 1990. Id.; Smith 1990 (JTX-24)
at 3, Fig. 3B. The Patents-in-Suit also include the 18 amino
acid sequences close to the C-terminus of the known p75
protein designated SEQ ID NO: 7. These two disclosed
nucleotide sequences for p75 would have, in addition to
Figure 4 and the Smith 1990 reference, directed a POSA to the
full p75 sequence at the time of the invention. See
'182 Patent (JTX-1) col. 39:13-42:34 (claims of the
'182 Patent specifically requiring the use of the protein
that "comprises the amino acid sequence ... (SEQ ID NO:
10)"), col. 4:18-20, 16:36-38 (identifying SEQ ID NO:7
as a partial amino acid sequence that makes up a preferred
protein); '522 Patent (JTX-2) col. 45:44-48:4 (claims of
the '522 Patent specifying the amino acid described in
SEQ ED NO: 10), col. 4:31-32, 16:57-58 (listing SEQ ID NO:7
as an example of a partial amino acid sequence to be used in
a preferred protein); see also '182 Patent
(JTX-1) col. 5:17-22. With respect to the sequence
identification numbers for SEQ ID NO: 10 and SEQ ID NO: 7,
Plaintiffs' expert Dr. Naismith credibly testified that
there was less than a one-in-a-million chance that the wrong
protein would be produced by GenBank if an inquiry was made
to retrieve the complete p75 sequence corresponding to one of
the sequence identification numbers. See 9/18 AM
(Naismith) Tr. at 68:13-16. Moreover, Dr. Naismith testified
that there was "zero chance" that any other protein
would be returned by GenBank if the request included both SEQ
ID NO: 10 and SEQ ID NO: 7 at that time. Id. at
68:17-25; see also 9/12 PM (Blobel) Tr. at 14:6-12
(Defendants' expert Dr. Blobel also testifying "if
you took a sequence of this receptor, you would presumably
get this receptor back. That's how it
works."). Accordingly, the Patents-in-Suit
sufficiently describe the subject fusion protein using the
known full p75 sequence.
IgG1 and the Fusion Protein are Adequately Described
disclosure of the second necessary part of etanercept was
also adequate because the specification clearly refers to use
of deposited vectors (including "pCD4-Hγ1")
that contain DNA sequences encoding the exon-defined
hinge-CH2-CH3 region of a human IgG1 heavy chain as confirmed
by the declaration of Defendants' expert, Jeffery
Kittendorf, Ph.D., an expert in biochemistry and a Research
Assistant Scientist at the University of Michigan Life
Sciences Institute. ECF No. 688 at 132 ¶ 47; JTX-16 at
32-34; see also 9/17 (Loetscher) Tr. at 57:4-58:25.
11 then provides a recipe to fuse a soluble TNF-binding
fragment directly to that exon-encoded hinge-CH2-CH3 region
of an IgG heavy chain, thereby providing a POSA with the full
fusion protein. '182 Patent (JTX-1) col. 9:3-8; 9/17
(Loetscher) Tr. at 56:10-57:13, 58:18-59:5; 9/18 AM
(Naismith) Tr. at 54:16-21, 90:10-91:7, 92:21-93:8. This
example illustrates utilizing a cDNA fragment that encodes
the extracellular region of a TNF-binding protein, and
describes the process generally using a p55 TNFR as an
illustration. 9/17 (Loetscher) Tr. at 56:5-58:24. A POSA
would have followed that example and used p75 to create
etanercept based on the claims in the Patents-in-Suit and the
specification. See 9/12 PM (Blobel) Tr. at
8:5-10:2, 14:6-12; 9/17 (Loetscher) Tr. at 56:5-58:24; 9/18
AM (Naismith) Tr. at 67:14-68:25, 72:15-73:1, 73:17-74:8,
the parties agree that the IgG1 hinge-CH2-CH3 was also known
in the prior art as of August 1990. DFOF ¶ 167; PFOF
¶¶ 99-100. Thus, because the p75 TNFR sequence and
the IgG1 sequence were well known and accessible to a POSA, a
reproduction of the known sequences was not required to be
explicitly included in the Patents-in-Suit in order to claim
a novel combination of those sequences. See Falkner,
448 F.3d at 1368 (holding that genes and their nucleotide
sequences must not be recited or incorporated by reference
where "accessible literature sources ... as of the
relevant date" contain such information, because
"forced recitation of known sequences in patent
disclosures would only add unnecessary bulk to the
The Patents-in-Suit Demonstrate Possession
extent Defendants assert that Roche never made the claimed
p75-IgG1 fusion protein, such contention is legally
insignificant. Ariad holds that "the written
description requirement does not demand either examples or an
actual reduction to practice; a constructive reduction to
practice that in a definite way identifies the claimed
invention can satisfy the written description
requirement." 598 F.3d at 1352 (citing Falkner,
448 F.3d at 1366-67). Here, as discussed, the claim language
identifies the requisite elements of the subject
invention-the p75 fusion protein combined with the
hinge-CH2-CH3 domains of IgG1-and, in conjunction with the
specification, provides support of possession. Many of the
examples in the Patents-in-Suit further demonstrate that the
Roche Inventors had possession. Accordingly, the Court is
persuaded that the Roche Inventors had possession of the
invention based on the specifications of the Patents-in-
Suit, including the examples within the specifications, and
Amendments to the Prosecution File History Did Not Add New
Court will now consider two amendments to the
Patents-in-Suit, both of which were approved by the USPTO.
First, in 2006, Amgen and Immunex, with assistance from
Roche, deposited a plasmid containing a p75 cDNA with
American Tissue Culture Collection
("ATCC"), and gave it a designation of PTA 7942.
PFOF ¶¶ 93-94; DFOF ¶ 75; see also
JTX- 81 at 19-20 (Plaintiffs' witness Dr. Werner
Lesslauer, one of the Roche Inventors involved in this
project, testifying that Amgen deposited the p75 plasmid,
Roche assisted in the deposit, and it was designated PTA
7942). That same year, Immunex amended the specification of
the '790 application (which resulted in the '182
Patent) to include a reference to Immunex's PTA 7942
plasmid deposit. 9/13 AM (Capon) Tr. at 50:9-51:1; JTX-16 at
29-31. The cDNA for the PTA 7942 plasmid encodes the
full-length p75 TNFR, which is identical to the sequence
reported in Smith 1990. JTX-16 at 29-31. Second, in 2007,
Immunex amended the specification of the '791 application
(which resulted in the '522 Patent) to expressly
incorporate the Smith 1990 protein by reference. Defs. Br. at
33. Immunex also inserted a new figure, Figure 5, that
included the Smith 1990 sequence (in addition to the
reference previously included). Id.
assert that Immunex's decision to take over the
prosecution and amend the specifications of the
Patents-in-Suit is a clear indication that the original
specifications as filed by Roche were deficient. Id.
at 32-33. In addition, Defendants assert that the USPTO did
not have complete information when it approved the amendments
because the Plaintiffs informed the USPTO that the Smith 1990
protein was "99% identical" to Figure 4, when in
fact Defendants contend the two proteins are meaningfully
different. Id. at 33-34. Defendants argue that
Plaintiffs' amendments added what amounts to "new
matter" not previously included in the application,
which is a ground for a patent rejection. See
35 U.S.C. § 132 ("No amendment shall introduce new
matter into the disclosure of the invention."); see
also Defs. Reply Br. at 16 n.13.
contrast, Plaintiffs contend that each amendment did not
contain new matter and that the USPTO properly approved the
valid amendments. Pls. Br. at 16 n.2, 18 n.3; PFOF
¶¶ 11-14. Plaintiffs maintain that the amendment to
include the PTA 7942 plasmid, which encodes the sequence
reported in Smith 1990, complies with USPTO rules because the
plasmid (1) contains p75 cDNA that was identified in the
original specification as variants of a "DNA sequence
encoding the 75/65 kD," (2) was made prior to August
1990, and (3) was properly deposited with the ATCC in 2006.
Pls. Br. at 16 n.2; PFOF ¶¶ 11-14.
Court concludes that the deposited PTA 7942 plasmid was
properly made part of the Patents-in-Suit and did not add new
matter. The Federal Circuit has held that where information
is properly deposited with an independent source, "[a]n
accession number and deposit date add nothing to the written
description of the invention" and are therefore, not
considered new matter. In re Lundak, 773 F.2d 1216,
1223 (Fed. Cir. 1985). Further, the deposited plasmid was
appropriately made part of the Patents-in-Suit as of their
1990 priority dates because as long as the plasmid was
described in the application as-filed, it is not considered
new and may be deposited at any time before issuance. See
In re Lundak, 773 F.2d at 1222-23 ("Lundak's
deposit with the ATCC, which was made after filing but prior
to issuance of his patent, and which is referred to in his
specification, meets the statutory requirements.");
see also 37 C.F.R. § 1.804(a) (" . . . an
original deposit . . . may be made . . . subject to §
1.809, during pendency of the application for
patent."). The Court agrees with the USPTO and
finds that the properly deposited plasmid reflected one of
these variants and did not add new matter. Accordingly, the
Court finds that Plaintiffs' amendments adequately
described the inventive concept at the time of the invention.
the Smith 1990 incorporation, the Court does not find that
Immunex's decision to amend is proof that me original
specifications were deficient. As discussed above, the Court
finds that the Smith 1990 protein was sufficiently described
when it was originally referred to and did not need to be
amended to expressly incorporate it by reference. See,
e.g., Falkner, 448 F.3d at 1365 (finding that "the
absence of incorporation by reference is not
problematic"). The Court therefore finds that the
amendments to the Patents-in-Suit were proper and do not
alter the written description analysis.
The Specification Enables Etanercept
Defendants argue that the claims of the Patents-in-Suit are
not enabled. DFOF ¶ 180; Defs. Br. at 35. Plaintiffs
assert that Defendants' enablement challenge fails
because the Patents-in-Suit identify both p75 TNFR and IgG1
(which were well-known), sufficiently describe how to combine
them to enable a POSA to produce etanercept, and
Defendants' own experts concede that a POSA could have
produced the claimed fusion protein without undue
experimentation by using known methods as of August 1990.
See Pls. Br. at 2, 21-22; see also 9/12 PM
(Blobel) Tr. at 53:19-56:13; 9/13 PM (Capon) Tr. at
enabling, "[t]he specification must 'enable one of
ordinary skill in the art to practice the claimed invention
without undue experimentation.'" Transocean
Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA,
Inc., 617 F.3d 1296, 1305 (Fed. Cir. 2010) (quoting
Nat'l Recovery Techs., Inc. v. Magnetic Separation
Sys., Inc., 166 F.3d 1190, 1196 (Fed. Cir. 1999)).
"Enablement is not precluded by the necessity for some
experimentation such as routine screening." In re
Wands, 858 F.2d at 736-37. However, the experimentation
needed to practice the art must not be undue. Id. at
737. The test for undue experimentation "is not merely
quantitative, since a considerable amount of experimentation
is permissible, if it is merely routine, or if the
specification in question provides a reasonable amount of
guidance with respect to the direction in which the
experimentation should proceed." Id. To
determine whether a disclosure would require undue
experimentation, courts should consider the Wands
factors, which include: (1) the quantity of experimentation
necessary; (2) the amount of direction or guidance presented;
(3) the presence or absence of working examples; (4) the
nature of the invention; (5) the state of the prior art; (6)
the relative skill of those in the art; (7) the
predictability or unpredictability of the art; and (8) the
breadth of the claims. Id.
Court finds that Defendants have failed to show by clear and
convincing evidence that the Patents-in-Suit do not meet the
enablement standard. Preliminarily, both parties agree to a
POSA's relative skill in the art, and each party used
nearly identical definitions and qualifications for their
respective hypothetical POSA. Compare 9/11 PM
(Blobel) Tr. at 30:24-32:5 with 9/20 AM (Wall) Tr.
at 18:6-25. Specifically, the parties' experts
agreed that the p75 protein and the exon-encoded
hinge-CH2-CH3 portion of the IgG1 immunoglobulin sequences
were known before August of 1990, which is the initial date
of the applications. 9/11 PM (Blobel) Tr. at 14:19-15:5 (Dr.
Blobel noting that the claims in the '182 Patent were
directed at "essentially etanercept"); 9/20 AM
(Wall) Tr. at 19:2-12, 92:16-93:2 (Dr. Wall explaining that
the components of etanercept were known by August 1990). Both
of Defendants' experts, namely Dr. Blobel and Dr. Capon,
agreed that a POSA in 1990 would have been able to produce a
fusion protein that is similar to etanercept. 9/12 PM
(Blobel) Tr. at 55:20-56:5 (Dr. Blobel testifying that a POSA
would have been able to produce a fusion protein similar to
etanercept using "ordinary and routine methods utilized
in the art"); 9/13 PM (Capon) Tr. at 73:5-14 (Dr. Capon
testifying to the same). These experts also testified that
the claim scope is both limited to and covers etanercept.
9/11 PM (Blobel) Tr. at 14:19-15:5; 9/13 PM (Capon) Tr. at
82:22-83:3. Regarding the state of the art at the time of the
invention, the parties explicitly agreed that technology
relating to recombinant DNA was developed by 1990 and allowed
for the creation of fusion proteins like etanercept. 9/12 PM
(Blobel) Tr. at 54:13-56:13 (Dr. Blobel testifying regarding
the state of the art in August 1990); see also ECF
No. 688 at 65 ¶ 247.
the Patents-in-Suit, and in particular the '522 Patent,
provide a POSA with sufficient guidance on how to make
etanercept. Specifically, both Patents-in-Suit explain to a
POSA how to prepare a cDNA encoding the extracellular region
of the known p75 protein.' 182 Patent (JTX-1) col.
16:22-48, 5:22-24, 7:24-46; 9/18 AM (Naismith) Tr. at
60:13-62:6; 9/18 PM (Naismith) Tr. at 53:12-54:6; 9/20 AM
(Wall) Tr. at 93:14-94:16. The specifications also provide a
POSA with information regarding how to prepare a cDNA
encoding all of the domains of a human IgG1 constant region,
except the first, including identifying a publicly accessible
exemplary vector pCD4-Hγl. '182 Patent (JTX-1) col.
8:56-9:3; 9/20 AM (Wall) Tr. at 94:17-95:19.
Plaintiffs' witnesses Dr. Naismith and Dr. Loetscher
credibly testified that the' 182 Patent directs a POSA to
follow the recipe set forth in Example 11 contained in the
specification. 9/17 (Loetscher) Tr. at 56:5-9 (Dr. Loetscher
noting that the example "describe[s] the process [of]
how to make TNF receptor fusion proteins"); 9/18 AM
(Naismith) Tr. at 53:22-54:2. Defendants' expert Dr.
Capon even appeared to acknowledge that Example 11 in
conjunction with the prior art would have enabled a POSA to
construct etanercept. See 9/13 PM (Capon) Tr. at
72:3-73:14. Hence, as Plaintiffs submit, a POSA could have
easily made the claimed fusion protein (i.e., a fusion
protein that had the extracellular region of the p75 receptor
with an exon-encoded hinge and the CH2-CH3 region of the IgG1
immunoglobulin) of the '182 Patent in or before August
1990 with only routine experimentation by adapting Example 11
to make the claimed fusion protein. 9/17 (Loetscher) Tr. at
58:18-59:5; 9/18 AM (Naismith) Tr. at 93:12-22 (Dr. Naismith
explaining that a POSA would have been able to make Example
11 in August of 1990); 9/20 AM (Wall) Tr. at 95:17-19 (Dr.
Wall testifying that a POSA would have "been able to
adapt Example 11 to make the claimed fusion protein.");
JTX-82 (Lesslauer Deposition) at 298:11-14, 17. The Court
finds that based on this evidence, Defendants have not met
their burden of proving by clear and convincing evidence that
the Patents-in-Suit fail to meet the enablement standard.
Obviousness (35 U.S.C. § 103)
prove mat an asserted claim of a patent is invalid as obvious
under 35 U.S.C. § 103, a patent challenger bears the
burden of establishing by clear and convincing evidence that
the "differences between the subject matter sought to be
patented and the prior art are such that the subject matter
as a whole would have been obvious at the time the invention
was made to a [POSA]." 35 U.S.C. § 103(a);
see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1360-61 (Fed. Cir. 2007). Obviousness is a question of
law that is predicated on several factual inquiries.
See Graham v. John Deere Co. of Kansas
City, 383 U.S. 1, 17 (1966). Specifically, there are
four basic factual inquiries which concern: (1) the scope and
content of the prior art; (2) the level of ordinary skill in
the art; (3) the differences between the claimed
subject matter and the prior art; and (4) objective indicia
(secondary considerations) of non-obviousness, including
unexpected results, success and praise in the industry,
long-felt but unsolved need, failure of others, and other
indicia. See id.
assert that the Patents-in-Suit are invalid because they are
obvious in view of prior art that would have motivated a POSA
to create etanercept prior to the relevant patent
applications. Defs. Br. at 35-43; see also
Defs. Reply Br. at 19-22. At trial, Defendants asserted six
obviousness combinations of prior art references, two of
which disclose the protein sequence of, and the DNA sequence
that encodes, the p75 extracellular region (Smith 1990 and
Immunex's U.S. Patent No. 5, 395, 760 (JTX-65) (the
"Smith '760 Patent")). PFOF ¶ 147. The
other asserted prior art references disclose Ig fusion
proteins, which combine a receptor protein with various
portions of an Ig heavy chain. Id. Specifically, the
first five (5) combinations are the Smith '760 in view
of: (1) the Seed European Patent Application No. 0325262
("Seed '262"); (2) Byrn, R. et al.,
Biological Properties of a CD4 Immunoadhesin, Nature
344: 667-70 (1990) ("Bryn 1990"); (3) Watson, S. et
al., A Homing Receptor-IgG Chimera as a Probe for
Adhesive Ligands of Lymph Node High Endothelial Venules,
J. Cell. Bio. 110: 2221-2229 (1990) ("Watson
1990"); (4) the Karjalainen European Patent Application
No. 0394827 ("Karjalainen '827"); and (5) the
Capon U.S. Patent No. 5, 116, 964 ("Capon
'964") in further view of Traunecker, A. et al,
Highly Efficient Neutralization of HIV with Recombinant
CD4-immunogloblin Molecules, Nature 339: 68-70 (1989)
("Traunecker 1989"). The sixth combination was
Smith 1990 in view of Watson. Id. ¶ 147 n.3.
Defendants' post-trial arguments regarding these prior
art references focus on motivation. Defs. Br. at 35
("[T]he only real dispute as to obviousness of the
asserted claims concerned motivation."). The Court has
examined the asserted prior art references both alone and in
combination, as discussed below, to determine motivation and
whether it would have been obvious to a POSA to create
addition, Defendants argue that certain secondary
considerations prove, rather than refute, that the
Patents-in-Suit are invalid for obviousness. Id. at
44-50. In support of their obviousness arguments, Defendants
primarily rely on (1) Dr. Blobel, introduced above; and (2)
Arne Skerra, Ph.D, Chair of Biological Chemistry at the
Technical University of Munich, Center of Life Sciences at
Weihenstephan, Freising, Germany. ECF No. 688 at 131-32
¶¶ 43, 49.
contend that Defendants' obviousness arguments fail
because a POSA would not have been motivated to create
etanercept based on the prior art and, in fact, would have
actually been dissuaded by the prior art to create a TNFR-Ig
fusion protein to treat inflammation. Pls. Br. at 22-23.
Further, Plaintiffs counter each of Defendants' secondary
consideration arguments as set forth below and contend that
the secondary considerations support nonobviousness.
Id. at 33-39. Plaintiffs rely on (1) Randolph Wall,
Ph.D., a Distinguished Professor in the Department of
Microbiology, Immunology, and Molecular Genetics at the
Molecular Institute, University of California at Los Angeles
(UCLA) and the David Geffen School of Medicine at UCLA, as an
expert on obviousness (ECF No. 688 at 122 ¶ 22); and (2)
Warner C. Greene, M.D., Ph.D., the Founder and Director of
the Gladstone Institute of ...