Nektar Therapeutics

Patent Trials and Appeals Board

Jul 30, 2021

IPR2019-01394 (P.T.A.B. Jul. 30, 2021)

Trials@uspto.gov Paper 68
571-272-7822 Entered: July 30, 2021

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

NOF CORPORATION,
Petitioner,
v.
NEKTAR THERAPEUTICS,
Patent Owner.

IPR2019-01394
Patent 7,026,440 B2

Before ERICA A. FRANKLIN, ZHENYU YANG, and
JON B. TORNQUIST, Administrative Patent Judges.
TORNQUIST, Administrative Patent Judge.

JUDGMENT
Final Written Decision
Determining All Challenged Claims Unpatentable
35 U.S.C. § 318(a)

IPR2019-01394
Patent 7,026,440 B2
2
I. INTRODUCTION
A. Background
NOF Corporation (“Petitioner”) filed a Petition (Paper 1, “Pet.”)
requesting an inter partes review of claims 1–20 and 29–35 of U.S. Patent
No. 7,026,440 B2 (Ex. 1001, “the ’440 patent”). Nektar Therapeutics
(“Patent Owner”) filed a Preliminary Response to the Petition. Upon review
of the parties’ arguments and supporting evidence, on February 5, 2020, we
instituted an inter partes review of all claims and grounds asserted in the
Petition (Paper 22, “Institution Decision” or “Inst. Dec.”).
Patent Owner subsequently filed a Response (Paper 49, “PO Resp.”),
Petitioner filed a Reply (Paper 53, “Pet. Reply”), and Patent Owner filed a
Sur-Reply (Paper 57, “Sur-Reply”).
In support of its Petition, Petitioner originally relied upon the
declaration testimony of Dr. Yuji Yamamoto. Ex. 1083. In light of
scheduling difficulties caused by COVID-19, however, we authorized
Petitioner to replace Dr. Yamamoto’s declaration with that of Dr. Todd
Emrick (Ex. 10841), who also filed a reply declaration (Ex. 1095).
Patent Owner relies on the declaration testimony of Dr. Steven R.
Little. Ex. 2036.
With authorization, Petitioner filed a motion requesting a good cause
extension of the deadline for issuing a final written decision in this
proceeding. Paper 39. Patent Owner opposed this motion. Paper 41. On
July 31, 2020, a revised Due Date Appendix was issued and on January 29,

1 In view of the replacement of Dr. Yamamoto’s declaration (Ex. 1083) with
an essentially identical declaration from Dr. Emrick (Ex. 1084), we treat all
citations to Exhibit 1083 in the Papers and Exhibits as citations to
Exhibit 1084.
IPR2019-01394
Patent 7,026,440 B2
3
2021, the time to administer the present proceeding was extended by up to
six months, i.e., from February 5, 2021, up to August 5, 2021. Paper 48
(Revised Due Date Appendix); Paper 62, 2–3 (good cause extension granted
by the Chief Administrative Patent Judge); Paper 63, 2–3 (Panel Order
extending the current proceeding by up to six months).
An oral hearing was held on February 8, 2021, and a transcript of the
hearing is included in the record. Paper 67 (“Tr.”).
B. Related Proceedings
Petitioner identifies Nektar Therapeutics et al. v. Bayer Healthcare,
LLC, 1-18-cv-01355 (D. Del. August 31, 2018) as a related matter. Pet. 2.
Patent Owner identifies Baxalta Incorporated v. Bayer Healthcare LLC, No.
17-1316 (D. Del.) (consolidated) as a related matter. Paper 6, 1.
Institution was granted with respect to related patents in IPR2019-
01397 and IPR2019-01398 and denied with respect to related patents in
IPR2019-01392, IPR2019-01395, and IPR2019-01396. Pet. 2; Paper 6, 1–2;
IPR2019-01392, Paper 23; IPR2019-01395, Paper 27; IPR2019-01396,
Paper 19.
C. The ’440 Patent
The ’440 patent discloses “branched, reactive water soluble polymers
useful for conjugating to biologically active molecules” and “methods for
making and utilizing such polymers.” Ex. 1001, 1:15–18. The ’440 patent
explains that it was known in the art that covalent attachment of hydrophilic
polymer poly(ethylene glycol), or PEG, may increase water solubility and
bioavailability of biologically active molecules, particularly hydrophobic
molecules. Id. at 1:22–30 (citing Greenwald, et al., J. Org. Chem., 60:331–
336 (1995)). The total molecular weight of the attached polymers is chosen
to provide the advantageous characteristics typically associated with PEG
IPR2019-01394
Patent 7,026,440 B2
4
polymer attachment, while at the same time avoiding “adversely impacting
the bioactivity of the parent molecule.” Id. at 1:30–35.
The ’440 patent discloses that methods for forming branched
polymers attached to a central core and having a single reactive group for
conjugation to a biologically active molecule were known in the art. Id. at
1:55–1:62. The ’440 patent states, however, that these known methods
required “extensive purification of the PEG polymers prior to attachment to
the core molecule” and removal of “partially pegylated polymer
intermediates.” Id. at 1:62–2:3. Thus, according to the ’440 patent, there
remained a need in the art for branched polymer reagents that “provide the
benefits associated with branched polymers (i.e., high overall molecular
weight in a single non-linear polymer molecule), but are easier to synthesize
or provide more flexibility in their design than prior art reagents.” Id. at
2:4–9.
The ’440 patent instructs that the “branched reactive polymer of the
invention will typically comprise at least two water-soluble and non-peptidic
polymer arms, such as poly(ethylene glycol) arms, covalently attached to an
aliphatic hydrocarbon core structure bearing a single functional group.” Id.
at 7:18–22. “Typically, the total number average molecular weight of the
branched reactive polymers of the invention will be about 500 to about
100,000 daltons (Da), preferably about 5,000 to about 60,000 Da, most
preferably about 8,000 to about 40,000 Da.” Id. at 7:4–8. “Unless otherwise
noted” in the ’440 patent, molecular weight is expressed “as number average
molecular weight (Mn), which is defined
ΣNiMi
ΣNi
, wherein Ni is the number of
polymer molecules (or the number of moles of those molecules) having
molecular weight Mi.” Id. at 4:51–63.
IPR2019-01394
Patent 7,026,440 B2
5
D. Illustrative Claim
Claim 1 is illustrative of the challenged claims and is reproduced below:
1. A branched reactive polymer having the structure:

Y—(X)p-R(—X′-POLY)q

wherein:

R is an aliphatic hydrocarbon having a length of at least three
carbon atoms;

each POLY is a water soluble and non-peptide polymer,
wherein the molecular weight of each POLY is selected such
that the total molecular weight or2 the branched reactive
polymer is independently selected from the group consisting
of poly(alkylene glycol), poly(oxyethylated polyol),
poly(olefinic alcohol), poly(vinylpyrrolidone),
poly(hydroxyalkylmethacrylamide),
poly(hydroxyalkylmethacrylate), polysaccharides, poly(α-
hydroxy acid), poly(vinyl alcohol), plyphosphazene,
polyoxazoline, poly(N-acryloylmorpholine), and copolymers,
terpolymers, and mixtures thereof is at least about 5,000 Da;

X′ is a heteroatom linkage;

X is a linker;

p is 0 or 1; q is 2 to about 10; and

2 Although the claim uses the word “or,” this appears to be a typographical
error and both parties asserts that the relevant claim language requires a
branched reactive polymer with a “a total molecular weight of at least about
5,000 Da.” PO Resp. 3 (“However, Petitioner did not establish that the cited
polymers had a total molecular weight of at least about 5,000 Da”), 47–48;
Pet. 13, 19, 58; Ex. 2036 ¶ 383 (Little Declaration); see Fitbit, Inc. v.
Valencell, Inc., 964 F.3d 1112, 1119–20 (Fed. Cir. 2020) (holding the Board
erred in not correcting a “conspicuous” and undisputed claim error related to
antecedent basis).
IPR2019-01394
Patent 7,026,440 B2
6
Y is a functional group reactive with an electrophilic or
nucleophilic group.
Ex. 1001, 24:7–30.
E. Prior Art and Instituted Grounds of Unpatentabilty
We instituted review of claims 1–20 and 29–35 of the ’440 patent on
the following grounds:
Claims Challenged 35 U.S.C. §3 Reference(s)/Basis
1–16, 19, 20, 29–35 103(a) Bentley4
16–18, 30 103(a) Bentley, Liebigs5
1–3, 5, 7–10, 12–16, 20, 29–35 103(a) Harris6
29, 31 102(b) Harris
1–15, 17, 19, 20, 29, 31–33, 35 102(b) JP-5427
1–15, 17, 19, 20, 29, 31–35 103(a) JP-542, MDD8
16–18, 30 103(a) JP-542, Bentley

II. ANALYSIS
A. Claim Construction
In this proceeding, the claims of the ’440 patent are construed “using
the same claim construction standard that would be used to construe the
claim in a civil action under 35 U.S.C. [§] 282(b).” 37 C.F.R. § 42.100(b)

3 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
Stat. 284, 287–88 (2011), amended 35 U.S.C. §§ 102 and 103, effective
March 16, 2013. Because the effective filing date of the challenged claims
of the ’440 patent is before this date, the pre-AIA version of these statutes
apply. See 35 U.S.C. § 100(i)(2) (2018); Ex. 1001, code (22).
4 US 5,990,237, issued November 23, 1999 (Ex. 1015).
5 Edwin Weber, Neutral ligands with surfactant structure – Synthesis,
Complexation, Ion Transfer, Liebigs Ann. Chem., 770–801, 1983 (Ex. 1019,
English translation; Ex. 1020, original German language publication).
6 US 5,932,462, issued August 3, 1999 (Ex. 1016).
7 Sanchika et al., JP P2000-1542A, published January 7, 2000 (Ex. 1017).
8 Steven A. Charles, et al., Improving Hepatitis C Therapy, Modern Drug
Discovery, September 2000 (Ex. 1029).
IPR2019-01394
Patent 7,026,440 B2
7
(2019). Under that standard, the words of a claim are generally given their
“ordinary and customary meaning,” which is the meaning the term would
have had to a person of ordinary skill at the time of the invention, in the
context of the entire patent including the specification. Phillips v. AWH
Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc). The parties
dispute the meaning of the term “functional group,” whether claim 1
requires a “functional group” that reacts readily with an electrophilic or
nucleophilic group, and the correct method for determining the “total
molecular weight of the branched reactive polymer.” We address these
issues below.
1. “functional group”
Claim 1 requires that “Y is a functional group reactive with an
electrophilic or nucleophilic group.” Ex. 1001, 24:29–30. Petitioner
contends that the term “functional group” in claim 1 means “the portions of
molecules that perform some function or activity and are reactive with other
molecules, including protected functional groups.” Pet. 11. Patent Owner
contends that “functional group” means “a distinct, definable portion or unit
of a molecule that performs a function.” PO Resp. 7.
The written description of the ’440 patent explains that
the terms ‘functional group,’ ‘active moiety,’ ‘reactive site,’
‘chemically reactive group,’ and ‘chemically reactive moiety’
are used in the art and herein to refer to distinct, definable
portions or units of a molecule. The terms are somewhat
synonymous in the chemical arts and are used herein to indicate
the portions of molecules that perform some function or activity
and are reactive with other molecules.
Ex. 1001, 3:35–42.
Given the express definitions provided in the ’440 patent, we agree
with Petitioner that a “functional group” is a portion of a molecule that
IPR2019-01394
Patent 7,026,440 B2
8
performs a function or activity and is reactive with other molecules, and with
Patent Owner that a “functional group” is a “distinct, definable” portion of a
molecule. Id. Accordingly, we construe the term “functional group” to
mean the “distinct, definable portions of molecules that perform some
function or activity and are reactive with other molecules.”9 We also agree
with Petitioner that the term “functional group” includes “protected
functional groups.” See id. at 3:35–42, 3:56–57 (“As used herein, the term
‘functional group’ includes protected functional groups.”); Pet. 11.
2. “reactive . . . functional group”
The preamble of claim 1 recites a “branched reactive polymer” and
the ’440 patent instructs that “[t]he term ‘active,’ when used in conjunction
with a functional group, is intended to include those functional groups that
react readily with electrophilic or nucleophilic groups on other molecules.”
Ex. 1001, 3:42–48, 3:56–57. Patent Owner contends that the term “reactive”
in the preamble of claim 1 serves to describe the “functional group” in the
body of the claim, and because the term “reactive” contains the word
“active” one of ordinary skill in the art would have understood that the
functional group of claim 1 must react readily with other chemical moieties.
PO Resp. 10.
We are not persuaded by this argument because the ’440 patent
expressly defines a “functional group” as being “reactive with other
molecules.” Ex. 1001, 3:35–42 (“The terms are somewhat synonymous in

9 Neither party argues that defining the term “functional group” as “a portion
of a molecule” or as a “distinct, definable” portion of a molecule will affect
the outcome of this proceeding. Pet. 11; PO Resp. 6–11; Pet. Reply 3–4.
We nevertheless provide an express construction to provide context to Patent
Owner’s arguments, discussed below, that claim 1 requires a particular type
of “functional group.”
IPR2019-01394
Patent 7,026,440 B2
9
the chemical arts and are used herein to indicate the portions of molecules
that perform some function or activity and are reactive with other
molecules.”), 10:55–59 (explaining that the Y functional group of the
invention “can be any functional group suitable for reaction with a
functional group on a biologically active molecule or a functional group that
is a precursor thereof”); Pet. Reply 4. It is only when the term “active”—as
opposed to “reactive”—is used to describe the “functional group” that it
must react readily with electrophilic or nucleophilic groups on other
molecules. Ex. 1001, 3:42–45. And because the term “active” is not used in
claim 1 to refer to the recited “functional group,” we do not construe claim 1
to require a “functional group” that will react readily with electrophilic or
nucleophilic groups.
3. “total molecular weight of the branched reactive polymer”
Claim 1 requires that the “total molecular weight o[f] the branched
reactive polymer is . . . at least about 5,000 Da.” Ex. 1001, 24:15–24.
Molecular weight is calculated in the ’440 patent as follows:
Unless otherwise noted, molecular weight is expressed herein as
number average molecular weight (Mn), which is defined “as number
ΣNiMi
ΣNi
,
wherein Ni is the number of polymer molecules (or the number of
moles of those molecules) having molecular weight Mi.

Id. at 4:51–63.
Patent Owner contends that the ’440 patent defines molecular weight
in terms of the polymeric backbone and thereby excludes the capping
groups, aliphatic core, linker, heteroatom, and functional group from the
calculation of molecular weight. PO Resp. 48 (citing Ex. 1001, 4:51–63).
IPR2019-01394
Patent 7,026,440 B2
10
In the Institution Decision, we found Patent Owner’s general
argument persuasive in view of the formula provided in the ’440 patent and
in view of the fact that Petitioner appeared to calculate molecular weight in
the Bentley-based grounds using only the molecular weight of the polymer’s
PEG arms. Inst. Dec. 33.
In its Reply, Petitioner contends that Patent Owner’s method of
calculating total molecular weight is incorrect because all portions of the
“branched reactive polymer” must be included in the calculation.
Pet. Reply 22 (citing Ex. 1095 ¶¶ 229–233, 263–266). In support of
Petitioner’s argument, Dr. Emrick testifies that the ΣNiMi/ΣNi formula set
forth in the ’440 patent requires the inclusion of all molecules of the
branched reactive polymer, which is consistent with the prosecution history
of related U.S. Patent 8,808,45310 (“the ’453 patent”), in which the
applicants included all portions of the branched reactive polymer in their
calculation of molecular weight. Ex. 1095 ¶¶ 229–232.
When considering the meaning of a disputed claim term we look first
to the intrinsic evidence of record, including the claims, written description,
and, if in evidence, the prosecution history. Vitronics Corp. v.
Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996) (“Such intrinsic
evidence is the most significant source of the legally operative meaning of
disputed claim language.”).
a) Claims
Claim 1 recites a “branched reactive polymer having the structure:
Y—(X)p-R(—X′-POLY)q,” and requires that the “total molecular weight

10 The ’453 patent is a continuing application of the ’440 patent. Ex. 1004,
4:53–63, code (60).
IPR2019-01394
Patent 7,026,440 B2
11
o[f] the branched reactive polymer . . . is at least about 5,000 Da.”
Ex. 1001, 24:7–24 (emphasis added). Because all of the constituents of the
formula, including the linkers and the functional group, are part of the
“branched reactive polymer,” claim 1 of the ’440 patent strongly suggest
that all constituent parts of the branched reactive polymer are included in the
calculation of total molecular weight.
b) Written Description
The written description is generally consistent with the conclusion
that all constituent parts of the branched reactive polymer are used in
calculating total molecular weight, explaining that the branched reactive
polymers of the invention will “typically comprise at least two water-soluble
and non-peptidic polymer arms, such as poly(ethylene glycol) arms,
covalently attached to an aliphatic hydrocarbon core structure bearing a
single functional group.” Ex. 1001, 7:18–38; see id. at 2:30–41.
Patent Owner’s conclusion that only the PEG arms are included in the
calculation of total molecular weight is not, however, without some support
in the ’440 patent. For example, the formula of the ’440 patent requires
summing the number of “polymer molecules,” and the ’440 patent explains
that the terms “polymer” and “polymer backbone” are used interchangeably
to represent the repeating portions of, for example, the PEG arms. Id. at
4:40–48. The ’440 patent also discloses that the “number average molecular
weight of the branched reactive polymers of the invention will be about 500
to about 100,000 daltons” and that each polymer arm “will typically have a
molecular weight of about 250 Da to about 50,000 Da.” Id. at 7:4–10. The
close alignment of these values suggests that molecular weight is primarily
imparted by the polymer arms, and not by the linkers, core molecule, etc.
IPR2019-01394
Patent 7,026,440 B2
12
That said, the ’440 patent goes on to instruct that the functional
groups, linkers, and core molecule are part of the branched reactive polymer
and the relevant formula requires summing the molecular weight of all
polymer molecules. Id. at 4:49–63, 7:18–22, 10:30–33, 11:55–58. As such,
the written description of the ’440 patent is consistent with the conclusion
that all portions of the branched reactive polymer are included in the
calculation of molecular weight.
c) Prosecution History
Molecular weight calculations were discussed during prosecution of
the ’440 patent and the related ’453 patent. During prosecution of the ’440
patent, the applicants argued that a Shimomura reference did not anticipate
the pending claims because “the total number of ethylene oxide groups on
the adduct molecules must be between 15 and 90,” which would result in a
“total polymer molecular weight” of less than about 4,000 Da. Ex. 2001,
692. Patent Owner calculates that if the non-PEG portions of Shimomura’s
compounds were included in the calculation, it would result in a total
molecular weight of greater than 4,000 Da. PO Resp. 48 (citing Paper 8,
48–49) (Patent Owner’s Preliminary Response). Upon review of this portion
of the prosecution history, we agree with Patent Owner that the applicants’
arguments during prosecution of the ’440 patent are consistent with Patent
Owner’s argument that molecular weight is calculated based only on the
PEG polymer chains. Id.
In contrast to the calculation method used during prosecution of the
’440 patent, during prosecution of the ’453 patent—which contains the same
formula as the ’440 patent for calculating molecular weight—the applicants
expressly included the non-PEG portions of the compound in their
calculation of molecular weight. Ex. 1011, 65 (noting that the mPEG arms
IPR2019-01394
Patent 7,026,440 B2
13
had a molecular weight of 5,000 Da (with a combined weight of 10,000 Da),
and “[t]he remaining portion of the US-PEG (after coupling to
erythropoietin) only contributes about ~230 Daltons to the molecular
weight”); Ex. 1004, 4:53–63, code (60). This expressly supports Petitioner’s
argument that all constituents of the branched reactive polymer should be
considered in determining molecular weight. See Microsoft Corp. v. Multi-
Tech Sys., Inc., 357 F.3d 1340, 1349–50 (Fed. Cir. 2004) (noting that “the
prosecution history of one patent is relevant to an understanding of the scope
of a common term in a second patent stemming from the same parent
application”).
Considering the relevant prosecution history as a whole, we find that
the applicants’ arguments during prosecution support both Petitioner’s and
Patent Owner’s arguments regarding how molecular weight should be
calculated in the ’440 patent.
d) Conclusion
Upon consideration of the intrinsic record as a whole, we find that
claim 1 of the ’440 patent strongly suggests that all the constituent parts of
the “branched reactive polymer” are included in the calculation of molecular
weight. We further find that this conclusion is consistent with the written
description of the ’440 patent and the relevant prosecution history.
Accordingly, we construe the term “total molecular weight o[f] the branched
reactive polymer” in claim 1 to require inclusion of all components of the
“branched reactive polymer” in the calculation of total molecular weight.
B. Principles of Law
To anticipate a claim under 35 U.S.C. § 102(b), a reference must
disclose, explicitly or inherently, each and every element of the claimed
IPR2019-01394
Patent 7,026,440 B2
14
invention arranged or combined in the same way as in the claim. In re
Gleave, 560 F.3d 1331, 1334 (Fed. Cir. 2009).
A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
differences between the claimed subject matter 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 person having ordinary skill in the art to which said
subject matter pertains. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
(2007). The question of obviousness is resolved on the basis of underlying
factual determinations, including (1) the scope and content of the prior art;
(2) any differences between the claimed subject matter and the prior art;
(3) the level of ordinary skill in the art; and (4) if in the record, objective
evidence of nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18
(1966).
C. Level of Ordinary Skill in the Art
Petitioner contends a person of ordinary skill in the art would have
had a Ph.D. in chemistry, biochemistry, materials science, or a related field
and 3–5 years of experience working in the field of synthesis of active PEG
polymers for PEGylation of biological molecules. Pet. 12 (citing
Ex. 1084 ¶¶ 45–48). Petitioner also contends that a person of ordinary skill
in the art could alternatively have been “a highly skilled scientist having an
advanced degree, but with additional years of experience working with
PEGylation polymer synthesis and chemistries for modification of
biomolecules in lieu of a Ph.D.” Id.
Patent Owner contends a person of ordinary skill in the art would have
had “at least a master’s degree in organic chemistry, biochemistry, or a
compatible discipline with several years of experience with water-soluble
polymers useful for conjugation to biologically active molecules, their
IPR2019-01394
Patent 7,026,440 B2
15
synthesis, characterization, and/or application to biologically active
molecules.” PO Resp. 11.
The parties’ definitions of the ordinarily skilled artisan are similar,
requiring an advanced degree in a relevant field and several years of
experience in synthesizing or applying water-soluble polymers, such as
PEG, to biologic molecules. Compare Pet. 12, with PO Resp. 11. The
parties’ definitions differ in that Petitioner requires experience working
directly with active PEG polymers for conjugation to biological molecules,
whereas Patent Owner’s definition allows for experience with the broader
group of “water-soluble polymers useful for conjugation to biologically
active molecules.” Pet. 12; PO Resp. 11. Upon review of the ’440 patent
and the prior art of record, we adopt Patent Owner’s definition of one of
ordinary skill in the art, as it is consistent with the disclosures of the ’440
patent and the prior art of record, and more inclusively describes the suitable
experience for one of ordinary skill in the art. We note, however, that
neither party asserts that selection between the two definitions of the level of
ordinary skill in the art would impact any issue presented in this case.11
D. Claims 1–15, 17, 19, 20, 29, 31–33, and 35 as Anticipated by JP-542
Petitioner contends that claims 1–15, 17, 19, 20, 29, 31–33, and 35 are
anticipated by JP-542. Pet. 56–75.

11 Petitioner argues in its Reply that Patent Owner fails to account for the
general knowledge of one of ordinary skill in the art, but does not argue that
this general knowledge would differ between the two proffered definitions
of one of ordinary skill in the art. Pet. Reply 12–13 (citing Ex. 1084 ¶¶ 78,
208–210, 242–244).
IPR2019-01394
Patent 7,026,440 B2
16
1. JP-542
JP-542 discloses “a carboxyl-group-containing polyoxyalkylene
compound that is used to modify a compound or a drug” in order to stabilize
the drug, decrease its antigenicity, or prolong its residence time in the body.
Ex. 1017, Abstract.
The polymer of formula (1) of JP-542 is reproduced below:

Formula (1) illustrates the general structure of the inventive polyoxyalkylene
polymers of JP-542. Id. ¶ 6. In formula (1), R1 is a hydrogen atom, a 1- to
24-carbon hydrocarbon group, or a 1- to 24-carbon acyl group; R2 is a 3- or
4-carbon hydrocarbon group; R3 is a 1- to 10-carbon hydrocarbon group; AO
is a 3- or 4-carbon oxyalkylene; Y is either a hydrogen atom or an active
group illustrated by formula (2) or (3); n is 1 to 1000; m is 0 to 250; and
n/(n+m) is no less than 0.8; wherein the oxyethylene and the 3 or 4 carbon
oxyalkylene “may be added in blocks or randomly.” Id. ¶ 8.
IPR2019-01394
Patent 7,026,440 B2
17
Formulas (2) and (3) of JP-542 are reproduced below:

Formulas (2) and (3) represent preferred active groups for use in the
compound of formula (1). Id. ¶ 17.
The polymers of formula (8) and (10) of JP-542 are reproduced
below:

IPR2019-01394
Patent 7,026,440 B2
18
The polymers of formula (8) and (10) are intermediates used to synthesize
various polymers disclosed in JP-542. Id. ¶¶ 33, 41, 44, 47.
JP-542 also discloses example polymer species falling within the
scope of formula (1) that may be conjugated to a compound or drug,
including the polymers of formula (14) and (15), which are reproduced
below:

Formula (14) depicts a branched polyalkylene polymer and formula (15)
depicts a linear polyalkylene polymer, both of which are conjugated to the
active group illustrated in formula (2). Id. ¶¶ 9, 52, 56.
In Test Example 1 and Comparative Test Example 1 of JP-542, the
compounds of formulas (14) and (15), respectively, were reacted with
L-asparaginase. Id. ¶¶ 54–57. The resulting PEGlyated compounds were
then tested for antigenicity and enzyme activity. Id. ¶¶ 57–58, Table 1. The
results from these tests are reproduced below:
IPR2019-01394
Patent 7,026,440 B2
19

Table 1 above provides the test results for Test Example 1 and Comparative
Test Example 1. As shown in Table 1, the compound of Test Example 1 had
zero antigenicity, yet still retained 35 to 40% of its enzyme activity. Id.
¶¶ 54, 58. Conversely, the compound of Comparative Test Example 1 had
an antibody binding capacity of 35% (i.e., some level of antigenicity) and
retained only 15 to 22% of its enzyme activity. Id. ¶¶ 54–58.
2. Analysis: Claim 1
Petitioner contends the polymer of formula (14) of JP-542 anticipates
claim 1 of the ’440 patent. Pet. 56–59. In support of this argument,
Petitioner provides the following annotated version of the polymer of
formula (14):
IPR2019-01394
Patent 7,026,440 B2
20

Pet. 56. In the figure set forth above, Petitioner included annotations and
color coding to show its mapping of the constituents parts of the polymer of
formula (14) to the limitations of claim 1. As shown in its annotated figure,
Petitioner persuasively demonstrates that in the polymer of formula (14):
R (red) is a three-carbon aliphatic hydrocarbon, POLY (green) consists of a
branched poly(alkylene glycol) wherein q=2, X′ (uncolored) constitute –O–
linkages, X (blue) is an –OCH2CH2CH2–S–CH2 linker wherein p=1, and
Y (purple) is an NHS “active ester” functional group. Id. at 56–58. With
respect to molecular weight, Petitioner contends the polymer of formula (14)
has a calculated molecular weight of 5,162 Da. Id. at 58.
Patent Owner does not expressly dispute that the polymer of
formula (14) of JP-542 discloses the R, POLY, X′, X, Y, p, and q limitations
IPR2019-01394
Patent 7,026,440 B2
21
of claim 1, but contends that Petitioner has not demonstrated that the
5,162 Da molecular weight reported in JP-542 was “calculated in the way
required by the ’440 patent.” PO Resp. 47–49. According to Patent Owner,
when only the polymer arms are considered in the calculation of molecular
weight, the total molecular weight of the polymer of formula (14) is actually
4,752 Da, i.e., less than “about 5,000 Da.” Id. at 48–49.
As discussed in Section II.A.3, we construe claim 1 to require that all
constituent parts of the “branched reactive polymer” be included in the
calculation of “total molecular weight.” When this calculation method is
used, Petitioner persuasively demonstrates that the total molecular weight of
the polymer of formula (14) is 5,162 Da. Accordingly, Petitioner
demonstrates by a preponderance of the evidence that the polymer of
formula (14) discloses every limitation of claim 1 of the ’440 patent and
therefore anticipates this claim.
3. Analysis: Claims 2–8, 11–15, 17, 19, 20, 32, 33, and 35
Petitioner persuasively identifies where every limitation of claims 2–
8, 11–15, 17, 19, 20, 32, 33, and 35 is expressly or inherently disclosed by
the polymers of formula (8) and/or formula (14) of JP-542. Pet. 59–70. For
example, Petitioner demonstrates that in the polymer of formula (14) the X′
heteroatom is an ether (–O–) (claim 2), q = 2 (claim 3), each POLY is
symmetrically located on the aliphatic hydrocarbon (claim 4), R comprises
three carbon atoms (claims 5 and 6), each POLY and the Y functional group
are attached to different carbon atoms of R (claim 7), each POLY is
covalently attached to a hydroxyl functional group (claims 8 and 11), the Y
group is an “active ester” (claim 12), and each POLY is a branched
poly(alkylene oxide) in the form of poly(ethylene glycol) (claims 13 and
14). Id. at 59–65. Petitioner further demonstrates that the polymer of
IPR2019-01394
Patent 7,026,440 B2
22
formula (14) was reacted to form a biologically active conjugate with
asparaginase wherein X′ is –O– (claim 20), the molecular weight of each
poly of the polymer of formula (14) is selected to result in a total molecular
weight for the branched reactive polymer (5,162 Da) that falls within the
recited ranges of about 5,000 to about 60,000 Da (claim 33) and about 5,000
to about 100,000 Da (claim 32), and each POLY in the polymer of
formula (14) has a molecular weight of 2,451 Da, which Petitioner contends
is “about 2,500 to about 30,000 Da” (claim 35). Id. at 65–70.
With respect to the polymer of formula (8), Petitioner demonstrates
that the –O– (ether linkage) of the polymer of formula (8)12 is a heteroatom
(claim 15) and that the polymer of formula (8) includes an allyl ether
protecting group (claim 17). Id. at 65–67.
Finally, Petitioner demonstrates that the polymers of formula (8)
and (14) have the structure depicted in claim 19. Id. at 68.
Patent Owner presents no evidence or argument, beyond its arguments
related to claim 1, contesting Petitioner’s evidence and arguments with
respect to dependent claims 2–8, 11–15, 17, 19, 20, 32, 33, and 35. See
generally PO Resp. 47–49; Sur-Reply 23.
Upon review of Petitioner’s and Patent Owner’s arguments and
supporting evidence, we find that Petitioner persuasively demonstrates that
the polymers of formula (8) and/or formula (14) of JP-542 disclose every
limitation of claims 2–8, 11–15, 17, 19, 20, 32, 33, and 35. Therefore, these
claims are anticipated by JP-542.

12 Petitioner persuasively demonstrates, and Patent Owner does not
expressly dispute, that the polymer of formula (8) discloses every limitation
of claim 1. Pet. 57.
IPR2019-01394
Patent 7,026,440 B2
23
4. Analysis: Claims 9 and 10
Claim 9 requires a capping group selected from the group “consisting
of alkoxy, alkyl, benzyl, aryl, and aryloxy” and claim 10 requires a methoxy
capping group. Ex. 1001, 24:47–51. The polymers of formula (8) and (14)
do not have capping groups. Petitioner contends, however, that there is a
general preference for methyl capping groups in the art, and JP-542
discloses that methyl groups are a preferred capping group. Pet. 62–63. In
view of the general prevalence of methyl capped poly(alkylene oxide) chains
in the PEGylation art, as well as the pattern of preference for methyl capped
poly(alkylene oxide) chains in JP-542, Petitioner contends that one of
ordinary skill in the art “would immediately envision and be in possession of
the branched polymers of JP-542 formula (8) and formula (14) with methyl
end-caps.” Id.
The polymers of formula (8) and (14) expressly include hydroxyl
termini, not one of the recited capping groups. Petitioner’s arguments
regarding the general preference for methyl capping groups expressed in the
art and in JP-542 invoke the doctrine of obviousness, not anticipation. Id.
at 62; see NetMoney IN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed.
Cir. 2008) (“But differences between the prior art reference and the claimed
invention, however slight, invoke the question of obviousness, not
anticipation.”). As such, we find claims 9 and 10 are not anticipated by
JP-542.
5. Analysis: Claims 29 and 31
a) Claim 29
Independent claim 29 is similar to independent claim 1, but specifies
that X′ is –NH–, –O–, or –S–, and that Y can be any “functional group.”
Ex. 1001, 26:14–35. Petitioner contends that the polymer of formula (10) of
IPR2019-01394
Patent 7,026,440 B2
24
JP-542 discloses every limitation of claim 29, including an allyl
(CH2CH=CH2) functional group. Pet. 70–73.
Patent Owner contends that claim 29 is not anticipated by JP-542
because “Petitioner has not shown that the allyl group will ‘react readily’
with any other molecule.” PO Resp. 50.
Upon review of the record as a whole, we find that Petitioner explains
sufficiently where the polymer of formula (10) discloses every limitation of
claim 29, including an allyl functional group. Patent Owner’s counter
argument is not persuasive because we do not construe either claim 1 or
claim 29 to require a functional group that “reacts readily” with any other
molecule. See Section II.A.2. Accordingly, claim 29 is anticipated by
JP-542.
b) Claim 31
Claim 31 is similar to claim 29, but requires covalent attachment of a
biologically active molecule to the branched reactive polymer. Ex. 1001,
26:54–27:9. Petitioner contends that one of ordinary skill in the art would
have understood that when the polymer of formula (14) was conjugated to
L-asparaginase (a biologically active molecule) in JP-542 the resulting
polymer had a structure that anticipates claim 31. Pet. 73–75. In particular,
Petitioner contends that one of ordinary skill in the art would immediately
understand and envisage that the resulting polymer had the following
formula:
IPR2019-01394
Patent 7,026,440 B2
25

The above formula depicts Petitioner’s interpretation of the structure of the
polymer of formula (14) when conjugated with L-asparaginase (identified as
W in the above formula). Id. at 75 (citing Ex. 1084 ¶ 473).
Patent Owner contends JP-542 provides no formula for the polymer
resulting from the conjugation of formula (14) with L-asparaginase and
Petitioner’s conclusory statements regarding the polymer of Test Example 1
“do not meet the high bar of inherent anticipation.” PO Resp. 51–52.
JP-542 discloses the formula for the polymer of formula (14),
discloses reacting the polymer of formula (14) with L-asparaginase, and
provides the reaction conditions for this conjugation. Ex. 1017 ¶ 54.
Although JP-542 does not provide a figure, formula, or description of the
resulting branched polymer, Dr. Emrick testifies that one of ordinary skill in
the art would understand that the resulting polymer would be represented by
the formula set forth above. Ex. 1084 ¶ 473. This testimony is credible and
Patent Owner provides no persuasive argument or evidence to call into
question Mr. Emrick’s conclusions. Thus, we credit the testimony of
Dr. Emrick that one of ordinary skill in the art would immediately envisage
the formula for the conjugate of L-asparaginase and the polymer of formula
(14) expressly discussed in JP-542 and his testimony that the resulting
structure anticipates claim 31. See Kennemetal, Inc. v. Ingersoll Cutting
IPR2019-01394
Patent 7,026,440 B2
26
Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015) (noting that a reference may
anticipate a claim “if a person of skill in the art, reading the reference, would
‘at once envisage’ the claimed arrangement or combination” (quoting In re
Petering, 301 F.2d 676, 681 (CCPA 1962)). Accordingly, Petitioner
demonstrates by a preponderance of the evidence that claim 31 is anticipated
by JP-542.
6. Conclusion
For the reasons set forth above, Petitioner demonstrates by a
preponderance of the evidence that JP-542 anticipates claims 1–8, 11–15,
17, 19, 20, 29, 31–33 and 35 of the ’440 patent. Petitioner has not
demonstrated by a preponderance of the evidence, however, that claims 9
and 10 are anticipated by JP-542.
E. Obviousness of Claims 1–16, 19, 20, and 29–35 over Bentley
Petitioner contends the subject matter of claims 1–16, 19, 20, and 29–
35 of the ’440 patent would have been obvious over the disclosures of
Bentley. Pet. 17–31.
1. Bentley
Bentley discloses a method of coupling a poly(ethylene glycol)
polymer (PEG) to a biomaterial. Ex. 1015, 1:8–11. Bentley explains that
both linear and branched PEG molecules had been used in the art to improve
the solubility of “water insoluble compound[s],” without altering the
compound’s biological activity. Id. at 1:60–2:1. Bentley further explains
that conjugation of PEG to a drug molecule may result in enhanced blood
circulation lifetime for the conjugated drug due to reduced kidney clearance
and reduced immunogenicity. Id. at 2:6–11.
Bentley explains that conjugation of PEG to a drug molecule requires
the use of an activated derivative “having a functional group at the terminus
IPR2019-01394
Patent 7,026,440 B2
27
suitable for reaction with a group on the other molecule.” Id. at 2:12–15.
For example, a hydroxyl group on the PEG compound can be converted to
an aldehyde group (forming PEG acetaldehyde) and then this aldehyde
group can be covalently linked to an amine group on a target molecule in a
process called reductive amination. Id. at 2:15–20.
Bentley indicates that one problem reported in the art with respect to
the use of PEG acetaldehyde is its high reactivity, “which leads to
condensation side reactions.” Id. at 2:42–45. Bentley also reports that PEG
acetaldehyde is “difficult to prepare in high purity,” requiring additional
purification steps that result in the “loss of valuable bioactive molecules,
such as proteins.” Id. at 2:46–54. To overcome these difficulties, Bentley
discloses the use of activated PEG molecules having an aldehyde hydrate
moiety. Id. at 3:2–9. According to Bentley, the use of an aldehyde hydrate
moiety to conjugate PEG to a target molecule avoids the condensation and
oxidation reactions that hindered prior art conjugation methods. Id. at 3:9–
15.
The activated PEG polymer of Bentley may be linear or branched and
typically has an average molecular weight of from 200 to 100,000 Da. Id. at
6:35–36. As biological properties may vary based on molecular weight and
the degree of branching, Bentley discloses that “not all” of the disclosed
derivatives “may be useful for biological or biotechnical applications.” Id.
at 6:35–39.
Bentley reports that “[f]or many biological and biotechnical
applications, substantially linear, straight-chain PEG acetaldehyde hydrate is
useful.” Id. at 6:40–42. This linear PEG may be capped on one end with a
relatively nonreactive moiety, such as methyl, benzyl and aryl moieties, and
conjugated to either a “surface” or a “substance” “selected from, e.g.,
IPR2019-01394
Patent 7,026,440 B2
28
proteins, peptides, oligonucleotides, polysaccharides and small drug
molecules.” Id. at 6:12–15, 6:44–52, 7:44–46. According to Bentley,
“[b]roadly speaking, any material having a reactive amine group accessible
to the activated polymer having an aldehyde hydrate group can be used in
the present invention.” Id. at 6:15–18.
“Another form of activated PEG aldehyde is dendritic activated PEG
in which multiple arms of PEG are attached to a central core structure.” Id.
at 6:64–66. These dendritic PEGs are commonly known as “star” molecules
and can be represented by the formula Q[poly]y, wherein Q is a branching
core moiety and y is from 2 to about 100. Id. at 6:66–7:6. Bentley notes
that such “star” molecules are generally described in Merrill (U.S. Patent
No. 5,171,264), which is incorporated by reference in Bentley. Id. at 7:5–8.
Bentley discloses that the aldehyde hydrate moiety on the “star”
molecules can be used to provide an active functional group on the end of
the PEG chain extending from the core, or may act as a linker for joining a
functional group to the star molecule arms. Id. at 7:8–12.
Additionally, the aldehyde hydrate moiety can also be linked
directly to the core molecule having PEG chains extending
from the core. One example of such a dendritic activated PEG
has a formula of
[RO–(CH2CH2O)mCH2CH2–O–CH2]2CH–O–(CH2)nCH(OH)2
wherein R is H, alkyl, benzyl, or aryl; m ranges from about 5 to
about 3000, [and] n ranges from 1 to 6.
Id. at 7:12–20.
IPR2019-01394
Patent 7,026,440 B2
29
2. Analysis: Claim 1
Petitioner contends the dendritic “star” molecule of Bentley identified
above may be drawn as follows:

Pet. 18. The figure above is Petitioner’s depiction of the chemical structure
identified at column 7, lines 16–20 of Bentley.13 Id. (citing Ex. 1015, 7:12–
20). Petitioner maps the limitations of claim 1 to this structure in the
following annotated figure:

The figure reproduced above is an annotated and color-coded depiction of
Bentley’s star molecule. Id. at 17–18. Referring to its annotated figure,
Petitioner persuasively demonstrates that Bentley discloses a branched
reactive poly(alkylene glycol) polymer having the formula Y—(X)p-R(—

13 We refer to the polymer described at column 7, lines 16–20 of Bentley
alternatively as “Bentley’s star molecule” or “Bentley’s genus.”
IPR2019-01394
Patent 7,026,440 B2
30
X′-POLY)q (Pet. 13–14), wherein R is an aliphatic hydrocarbon having three
carbon atoms (red) (id. at 14–15), each POLY chain is composed of
“poly(alkylene glycol),” a water soluble and a non-peptide polymer (green)
(id. at 15), X′ is an ether (–O–) heteroatom linkage (grey) (id. at 16), X is a
linker (–O–(CH2)n–) wherein p is 1 (blue) (id.), q (the number of polymer
arms) is 2 (id.), and Y is an aldehyde hydrate functional group (–CH(OH)2)
(purple) that is reactive with an electrophilic or nucleophilic group (id.
at 17).
With respect to the requirement that the total molecular weight of the
branched reactive polymer is “at least about 5,000 Da,” Petitioner contends
that “m” in Bentley’s star molecule ranges from about 5 to about 3,000,
which describes a molecular weight range of about 220 Da to about 132,000
Da for each PEG chain (POLY), and results in a total polymer molecular
weight range for the branched reactive polymer of at least 440 to about
264,000 Da. Id. at 18–19 (citing Ex. 1015, 7:12–20, 14:59–65; Ex. 1084
¶¶ 305–306). Petitioner further contends that the overlap in the disclosed
range (at least 440 to about 264,000 Da) with the claimed range (at least
about 5,000 Da) renders the claimed range prima facie obvious. Id. at 19
(citing In re Peterson, 315 F.3d 1325, 1329–30 (Fed. Cir. 2003); Ex. 1084
¶¶ 307–309).
Petitioner contends that one of ordinary skill in the art “would have
had a reasonable expectation of success in preparing polymers of different
[molecular weights] above 5,000 Da and within Bentley’s suggested ranges
by increasing the length of the PEG polymer arms through polymerization or
substitution of large PEG chains as known in the art.” Id. (citing Ex. 1015,
1:14–47, 14:59–65 (Claim 21); Ex. 1084 ¶ 308; Exs. 1016–17).
IPR2019-01394
Patent 7,026,440 B2
31
Patent Owner asserts that Petitioner’s arguments with respect to
claim 1 fail because: (1) Petitioner fails to apply a “lead compound”
analysis, (2) Petitioner fails to demonstrate that the reasoning of Peterson
applies to the facts of this case, (3) Petitioner has not shown that one of
ordinary skill in the art would have selected the identified genus of polymers
in Bentley for further development, (4) Petitioner has not shown that one of
ordinary skill in the art would have selected individual species of polymers
from Bentley’s genus having the claimed molecular weight ranges,
(5) Petitioner has not demonstrated a reasonable expectation of success in
achieving the claimed invention, and (6) indicia of non-obviousness rebut
any prima facie case of obviousness. PO Resp. 14–29, 57–60. We address
these arguments below.
a) Law of Obviousness
One overarching dispute between the parties is how the law of
obviousness applies in this case. Petitioner argues that we should apply
standard principles of obviousness. Pet. 18–19; Pet. Reply 1–2. Patent
Owner argues that we must (or at least should) apply a “lead compound”
analysis when assessing whether the claimed genus of chemical compounds
would have been obvious over the prior art of record. PO Resp. 1–2, 14;
Sur-Reply 9.
The case law regarding “when a species is patentable over a genus
claimed in the prior art is less than clear.” Takeda Chem. Indus. v.
Alphapharm Pty., Ltd., 492 F.3d 1350, 1364 (Fed. Cir. 2007) (Dyk, J.,
concurring). We look, therefore, to the general law of obviousness for
guidance. In KSR, the Supreme Court instructed that we must take “an
expansive and flexible approach to the obviousness question,” focusing on
“whether there was an apparent reason to combine the known elements in
IPR2019-01394
Patent 7,026,440 B2
32
the fashion claimed by the patent at issue.” KSR, 550 U.S. at 415, 419. In
conducting this analysis, we must “consider all disclosures of the prior art”
(In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991)), and we do not require that
a petitioner “prove that a person of ordinary skill would have been motivated
to select one prior art disclosure over another.” Infineum USA L.P. v.
Chevron Oronite Co., 2021 WL 210722, at *6 (Fed. Cir. Jan. 21, 2021)(non-
precedential). Nor must a petitioner demonstrate that the “prior art suggests
that the combination claimed” in the patent “is the preferred, or most
desirable, combination.” In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir.
2004); Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed.
Cir. 1989) (noting that in an obviousness inquiry “all disclosures of the prior
art, including unpreferred embodiments, must be considered”).
Applying these general principles, a party may take many different
paths in establishing that a patent claim would have been obvious over the
prior art. One of these paths is based on structural similarity between a
claimed chemical compound and a prior art compound. See Otsuka Pharm.
Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012); Eisai Co. Ltd. v.
Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed. Cir. 2008). When a
party chooses to argue that a patent claim would have been obvious based on
structural similarity to a known compound, this can be proven “by
identification of some motivation that would have led one of ordinary skill
in the art to select and then modify a known compound (i.e., a lead
compound) in a particular way to achieve the claimed compound.” Eisai,
533 F.3d at 1357.
A lead compound analysis is not the only way to demonstrate
obviousness of a claimed compound or genus of compounds, however, and
any rigid application of the lead compound doctrine risks running afoul of
IPR2019-01394
Patent 7,026,440 B2
33
the broad, flexible obviousness test set forth by the Supreme Court in KSR.
See Otsuka, 678 F.3d at 1291 (noting that new compounds may be made out
of theoretical concerns “rather than from attempts to improve on prior art
compounds”); Altana Pharm. AG v. Teva Pharms. USA, Inc., 566 F.3d 999,
1008 (Fed. Cir. 2009) (noting that a “restrictive view of the lead compound
test would present a rigid test similar to the teaching-suggestion-motivation
test that the Supreme Court explicitly rejected in KSR”). Here, Petitioner
argues that the genus of Bentley, in view of its disclosure of molecular
weight ranges that overlap the claimed range, renders claim 1 obvious. This
analysis relies upon established case law regarding obviousness based on
overlapping ranges. See Peterson, 315 F.3d 1329–30. Thus, we find that a
“lead compound” analysis is not the most appropriate analytical framework
in this case.
b) Overlapping Ranges
(1) The Parties’ Arguments
As noted above, relying on the reasoning set forth in Peterson,
Petitioner contends that the 440 to about 264,000 Da molecular weight range
taught or suggested in Bentley renders the claimed molecular weight range
of “at least about 5,000 Da” prima facie obvious. Pet. 19.
Patent Owner argues that, unlike the ranges of a single composition at
issue in Peterson, claim 1 “does not recite a single composition but rather a
set of chemical compounds,” i.e., “the group of branched reactive polymers
having the structure Y—(X)p-R(—X′-POLY)q.” PO Resp. 14–15. And
because Bentley discloses “a genus covering a different set of polymers,
which includes between about 5 and 3,000 ethylene glycol subunits,” Patent
Owner contends that Peterson is inapposite. Id. at 15.
IPR2019-01394
Patent 7,026,440 B2
34
Patent Owner further argues that even if Peterson applied to the facts
of this case, Peterson is limited to selecting a narrow range from within a
somewhat broader range, and Dr. Little determined that the cited genus of
Bentley is not narrow, covering at least 300,000 distinct species. Id. at 16–
17. Patent Owner contends that the facts of this case are therefore more
similar to those addressed in In re Baird, 16 F.3d 380 (Fed. Cir. 1994) and
In re Jones, 958 F.2d 347 (Fed. Cir. 1992), where it was found that a prior
art genus does not, by itself, render obvious specific compounds that fall
within that prior art genus. PO Resp. 15–16.
In response, Petitioner argues that Bentley’s genus, in the context of
the claimed chemical formula, “is tantamount to a species” because Y, X, R,
X′, POLY, and q are fixed, and the only claim limitation not expressly
disclosed in Bentley is the overlapping molecular weight ranges. Pet. Reply
6. Petitioner further argues that molecular weight is known to be a result-
effective variable for PEG polymers and, when “the general conditions of a
claim are disclosed in the prior art, it is not inventive to discover the
optimum or workable ranges by routine experimentation.” Id. at 6–7
(quoting In re Aller, 220 F.2d 454, 456 (CCPA 1955)).
Patent Owner contends Petitioner’s assertion that Bentley’s genus is
tantamount to a species is an improper new argument that “is designed to
excuse Petitioner’s failure to account for the complexity of the chemical
arts.” Sur-Reply 15. Patent Owner further contends that Petitioner’s
“attempts to minimize the tremendous structural variety associated with the
different molecular weights” ultimately fail because Petitioner does not rebut
Dr. Little’s calculation that the genus of Bentley encompasses more than
300,000 distinct species. Id.
IPR2019-01394
Patent 7,026,440 B2
35
(2) Analysis
In the context of the formula of claim 1, Petitioner persuasively
demonstrates—in both the Petition and the Reply—that the variables Y,
(X)p, R, X′, POLY, p, and q are fixed and result in a polymer that falls
within the structural formula of claim 1 of the ’440 patent. Pet. 13–18;
Pet. Reply 6. In particular, R is a three carbon aliphatic hydrocarbon (Pet.
14–15), POLY is poly(alkylene glycol) (id. at 15), X′ is –O– (id. at 16), X is
–O–(CH2)n– (wherein n is 1–6) (id.), p=1 (id.), q is 2 (id.), and Y is an
aldehyde hydrate functional group (id. at 17).
The only variable set forth in Bentley that could potentially result in a
species outside the scope of claim 1 is molecular weight. The claimed
molecular weight range (“at least about 5,000 Da”) is, however, obvious
over the range disclosed in Bentley (between about 440 and 264,000 Da) for
at least two interrelated reasons. First, when a variable is “result-effective”
and “the general conditions of a claim are disclosed in the prior art, it is not
inventive to discover the optimum or workable ranges by routine
experimentation.” In re Applied Materials, 692 F.3d 1289, 1295 (Fed. Cir.
2012) (quoting Aller, 220 F.2d at 456). It is undisputed that the molecular
weight range recited for Bentley’s polymers overlaps the claimed range of
“about 5,000 Da,” thereby disclosing the “general conditions of the claim.”
Id. (noting that any overlap between the claimed and disclosed ranges serves
to disclose the “general conditions” of the claim).
The evidence of record also persuasively demonstrates that molecular
weight is a result-effective variable for PEG polymers, whether they are
attached to a biologically active molecule or to surfaces, such as in a
IPR2019-01394
Patent 7,026,440 B2
36
hydrogel.14 Ex. 1015, 6:35–37; Ex. 1016, 32:52–33:7, 35:54–57; Ex. 2020,
Table 1 (Merrill polyethylene oxide star molecule patent); Ex. 1029, 4;
Ex. 1095 ¶ 227; see E.I. DuPont de Nemours & Co. v. Synvina CV, 904 F.3d
996, 1006 (Fed. Cir. 2018) (noting that a variable is “result-effective” if it
was recognized in the prior art that a “property is affected by the variable”).
For example, Bentley discloses that the biological properties of a PEG
conjugated compound “can vary with molecular weight” (Ex. 1015, 6:35–
37), MDD found that the size and branching of PEG polymers “directly
influenced the pharmacokinetic properties and biological activity” of a
protein drug (Ex. 1029, 4), and Merrill discloses that the properties of a
hydrogel depend on the molecular weight of each individual polymer arm
and the total molecular weight of the PEG molecule (Ex. 2020, Table 1;
PO Resp. 25–26 (Patent Owner asserting that optimal properties were
achieved with lower molecular weights for each polymer arm)).
Given that molecular weight is a result-effective variable and the
general conditions of the claim are disclosed in Bentley, Petitioner has
satisfied its burden to show that it would not have been inventive to optimize
molecular weight within the range recited in claim 1.
Second, “even a slight overlap in range establishes a prima facie case
of obviousness.” Peterson, 315 F.3d at 1329. The burden of production
then shifts to Patent Owner to demonstrate that the invention would not in
fact have been obvious, “generally by showing that the claimed range
achieves unexpected results relative to the prior art.” Id. at 1330 (quoting In

14 The parties vigorously dispute whether Bentley’s genus of polymers is
intended for attachment to biologically active molecules or to surfaces, such
as the hydrogels of Merrill. Pet. 19; PO Resp. 22–26; Pet. Reply 8–15. In
either case, though, molecular weight is a result-effective variable.
IPR2019-01394
Patent 7,026,440 B2
37
re Geisler, 116 F.3d 1465, 1469–70 (Fed. Cir. 1997)). Patent Owner does
not attempt to demonstrate that the claimed molecular weight range achieves
unexpected results relative to Bentley, or any other piece of prior art.
Accordingly, we find that claim 1 would have been prima facie obvious over
Bentley.15
We disagree with Patent Owner that the reasoning of Peterson is
inapplicable in this case. PO Resp. 14–15. Peterson applies the decades-old
legal principle that in cases involving overlapping ranges “even a slight
overlap in range establishes a prima facie case of obviousness.” Peterson,
315 F.3d at 1329. This legal principle is not restricted to certain types of
technologies or claims, e.g., claims reciting a single composition versus a set
of chemical compounds. See E.I. DuPont, 904 F.3d at 1006.
Patent Owner further asserts that even if the reasoning of Peterson is
applicable, it is limited to situations where a narrow range is selected from
within a somewhat broader range, and Dr. Little determined that the cited
genus of Bentley is not narrow, covering at least 300,000 distinct species.
PO Resp. 16–17. Patent Owner contends the facts of this case are similar to
those in Genetics Institute v. Novartis Vaccines and Diagnostics, 655 F.3d
1291, 1306 (Fed. Cir. 2011), where the prior art disclosed “a large breadth of
possible protein variants” and provided “no motivation to optimize for some
value within” the disclosed range. Id. at 17; Genetics Institute, 655 F.3d at
1306.
Patent Owner’s argument is unavailing because Peterson focuses on
whether the disclosed range is “somewhat broader” than the claimed range,

15 Patent Owner asserts that the prior art would have discouraged selection of
molecular weights within the claimed range. PO Resp. 25. We address and
reject this argument in Section II.E.2.(c).(2) below.
IPR2019-01394
Patent 7,026,440 B2
38
and Dr. Little does not assert that the molecular weight range of Bentley is
broader than the molecular weight range recited in claim 1 of the ’440
patent. See Peterson, 315 F.3d at 1329–30. Indeed, the unbounded range of
“at least about 5,000 Da” recited in claim 1 appears to be much broader than
the bounded range of Bentley.16 Moreover, Dr. Little’s calculation of over
300,000 potential species within Bentley’s formula takes into account the
possibility of varying R, m, and n in Bentley’s formula. Ex. 2036 ¶¶ 235–
239. Petitioner persuasively demonstrates, however, that the calculations
based on varying R and n utilize a false reference point, as all of these
polymers fall within the scope of the genus of claim 1.
Genetics Institute does not suggest a different conclusion because the
disclosed polymers of Bentley differ (in relevant part) only in the molecular
weight of the polymer arms, and the evidence of record demonstrates that
there was ample reason to optimize within the molecular weight range set

16 As generally alluded to by Patent Owner, a prior art range may be so large
that it effectively does “not teach any specific amounts or combinations.”
See Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305 (Fed. Cir. 2015). In
that case, the burden of producing evidence of teaching away, unexpected
results, and other pertinent secondary considerations does not shift to Patent
Owner. Id. The evidence of record, however, demonstrates that the 5 to
3,000 range of ethylene glycol subunits in Bentley, resulting in a total
molecular weight for the polymer of between 440 and 264,000 Da, is not so
large as to effectively not teach any specific amounts. For example, Merrill
discloses molecular weight ranges of 100,000 to 300,000 Da for star
molecules, as well as specific examples having molecular weights from
79,000 to 229,000 Da for Type I stars and 190,000 to 371,000 Da for Type II
stars. Ex. 2020, 3:61–64, Table I. Likewise, Harris discloses multi-armed
PEG polymers with molecular weights from about 100 to 100,000 Da, and
specifically claims two-armed PEG polymers having a molecular weight
from about 40,000 to 100,000 Da. Ex. 1016, Abstract, 37:18–38, 37:62–65,
40:27–36 (Claims 1, 8, 19).

IPR2019-01394
Patent 7,026,440 B2
39
forth in Bentley. See Genetics Institute, 655 F.3d at 1306 (noting that the
prior art reference provided a motivation to make smaller, truncated
proteins, not the larger truncated proteins recited in the claim at issue);
Ex. 1015, 6:35–36 (“PEG typically has average molecular weights of from
200 to 100,000.”); Pet. Reply 8.
In view of the foregoing, we find that the case law regarding
overlapping ranges, as set forth in Peterson and Applied Materials, applies
in this case and that the molecular weight range of claim 1 is prima facie
obvious over the overlapping molecular weight range disclosed in Bentley.
c) Selecting the Genus and Sub-Genus of Bentley
Applying a lead compound analysis, Patent Owner contends that
Petitioner fails to adequately demonstrate that one of ordinary skill in the art
would have (1) selected Bentley’s genus from the within the other classes of
molecules disclosed in Bentley, and (2) selected polymer species from
within Bentley’s genus that have a molecular weight that is within the
claimed range. PO Resp. 1–2, 18–26 (citing Otsuka, 678 F.3d at 1291).
(1) Selection of Bentley’s Genus
Patent Owner argues that Petitioner fails to identify any reason that
one of ordinary skill in the art would have selected the specific genus of
Bentley relied upon by Petitioner as a lead compound from among the
numerous disclosures of Bentley. PO Resp. 19–20. According to Patent
Owner, “[b]y focusing on the cited dendritic genus versus the other
embodiments [disclosed in Bentley], it is apparent that Petitioner’s reliance
on the asserted Bentley polymers is the product of hindsight.” Id. at 20.
For the reasons discussed above, we do not apply a “lead compound”
analysis in this case. Accordingly, Petitioner need not show that one of
ordinary skill in the art would have selected Bentley’s genus over all other
IPR2019-01394
Patent 7,026,440 B2
40
disclosures in the reference, or all other disclosures in the prior art. See
Infineum USA, 2021 WL 210722, at *6. In any event, Merrill provides a
utility for star molecules in general and Dr. Emrick persuasively explains
why one of ordinary skill in the art would have understood that Bentley’s
star molecules are in fact useful for conjugation to biologically active
molecules. Ex. 1015, 6:64–7:20; Ex. 1084 ¶ 308; Ex. 1095 ¶¶ 156–162
(Dr. Emrick testifying that the use of inert end-capping indicates that
Bentley’s genus of polymers is not limited to use in hydrogels); see also PO
Resp. 30–31 (Patent Owner asserting that use of inert end-capping would
render the star molecules of Bentley “ineffective for their intended
purpose”). Thus, the evidence of record provides sufficient reason to select
the particular genus of Bentley for further development and optimization.
(2) Selection of a Sub-Genus with Molecular Weights of “at least about
5,000 Da”
Patent Owner asserts that even if one of ordinary skill in the art would
have selected the particular genus of Bentely relied upon by Petitioner,
Petitioner has not demonstrated that one of ordinary skill in the art would
have selected from within this disclosure the sub-genus of compounds
having molecular weights of “at least about 5,000 Da.” PO Resp. 25–26.
Patent Owner reasons that “Merrill contains experimental data that would
have discouraged” a person of ordinary skill in the art from selecting
“polymers corresponding to the claimed molecular weight.” Id. at 25. In
particular, Patent Owner contends Merrill teaches that it “is desirable to have
a high value of [OH] and a low swelling ratio q in order that the biomaterial
remain approximately in the shape in which it was cast” Id. at 25–26
(quoting Ex. 2020, 7:37–40). And, according to Patent Owner, Merrill’s
experimental data indicates that the greatest value of [OH] was exhibited by
IPR2019-01394
Patent 7,026,440 B2
41
star molecules with individual arms having a molecular weight (MPEO) of
3,460 Da. Id. at 26 (citing Ex. 2020, Table 1).
Patent Owner’s arguments are based on a lead compound analysis,
which for the reasons discussed above, we do not apply in this case. That
said, the prior art must be considered for all that it teaches, including
teachings that may lead towards or away from the claimed invention. See
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). On
this point, we are not persuaded that Merrill teaches away from total
molecular weights above “about 5,000 Da.”
Similar to the genus disclosed in Bentley, each of the star molecules
tested in Merrill had at least two arms. Ex. 2020, Table 1; Ex. 1015, 7:17–
18. Applying Patent Owner’s argument that 3,460 Da polymer arms are
preferred in Merrill, this results in minimum total molecular weight of at
least 6,920 Da (3,460 x 2) for the star molecules of Bentley, which falls
squarely within the claimed range of “at least about 5,000 Da.” Moreover,
Patent Owner does not assert that Merrill teaches away from using two-
armed star molecules for conjugation to biologically active molecules, or
using total molecular weights above “at least about 5,000 Da” for such
conjugates. Thus, regardless of whether the genus of Bentley is used as a
star molecule for a hydrogel or for conjugation to a biologically active
material, we find that Merrill does not teach away from total molecular
weights above “about 5,000 Da.”
Patent Owner also argues that the genus of polymers disclosed in
Bentley are merely intermediates that would have to be coupled to the core
of an undisclosed star molecule. PO Resp. 20–21. Absent some motivation
for doing so, Patent Owner contends “it cannot be said that it would have
been obvious to stop the process for synthesizing the disclosed end product
IPR2019-01394
Patent 7,026,440 B2
42
and isolate the claimed intermediate.” Id. at 21 (quoting In re Gyurik, 596
F.2d 1012, 1018 (CCPA 1979)).
Petitioner argues in response that Bentley’s molecules are not
intermediates, but instead fully-activated derivatives in which the aldehyde
hydrate moiety is “linked directly to the core molecule having PEG chains
extending from the core.” Pet. Reply 11–12.
As noted by Petitioner, Bentley describes the claimed genus as having
PEG chains extending from the core, which requires that the core be part of
the recited, activated compounds. Ex. 1015, 7:12–14; Pet. Reply 11–12.
Thus, we agree with Petitioner that Bentley’s polymers are fully-activated
derivatives ready for use. Pet. Reply 11. We note, however, that even if the
recited genus was an intermediate or precursor for formation of a completed
star molecule, this is reason enough for one of ordinary skill in the art to
form such compounds, i.e., for their subsequent attachment to a core
molecule. See Gyurik, 596 F.2d at 1019 (Baldwin, J., concurring) (noting
that it is irrelevant that a chemical compound is an intermediate or precursor
if “some practical reason were provided for recovering the claimed
precursor”).
(3) Conclusion with Respect to Reason to Select the Genus and Sub-
Genus of Bentley
For the reasons set forth above, we find that Petitioner demonstrates
by a preponderance of the evidence that one of ordinary skill in the art using
routine optimization would have selected a subgenus of polymers from
within Bentley’s genus that reads on every limitation of claim 1 of the ’440
patent.
IPR2019-01394
Patent 7,026,440 B2
43
d) Reasonable Expectation of Success
To demonstrate obviousness, Petitioner has the burden to demonstrate
both that a skilled artisan would have been motivated to combine the
teachings of the prior art and that the skilled artisan would have had a
reasonable expectation of success in so doing. Intelligent Bio-Systems, Inc.
v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir. 2016) (“The
reasonable expectation of success requirement refers to the likelihood of
success in combining references to meet the limitations of the claimed
invention.”).
Petitioner contends that one of ordinary skill in the art “would have
had a reasonable expectation of success in preparing polymers of different
[molecular weights] above 5,000 Da and within Bentley’s suggested ranges
by increasing the length of the PEG polymer arms through polymerization or
substitution of larger PEG chains as known in the art.” Pet. 19 (citing
Ex. 1084 ¶¶ 308; Ex. 1015, 1:14–47, 14:59–65 (Claim 21); Ex. 1016; Ex.
1017).
Patent Owner contends Petitioner “must do more than generally assert
that a [person of ordinary skill in the art] knew how to lengthen PEG arms.”
PO Resp. 27. Rather, according to Patent Owner, “Petitioner must explain
with specificity how such teachings would have been applied to the polymer
genus that Petitioner relies upon.” Id. On this point, Patent Owner contends
that Dr. Emrick admitted that “issues arise” as you get to high molecular
weights, including “unwanted termination reactions that will interrupt
molecular weight growth for some chains but not for others.” Id. at 28
(citing Ex. 2040, 43:8–23 (Emrick deposition)). Patent Owner contends
these effects may “lead to increases in polydispersity” and “may well”
constitute a negative effect. Id.
IPR2019-01394
Patent 7,026,440 B2
44
Petitioner argues in its Reply that the expectation of success need only
be reasonable, not absolute, and this “claim element is directed to a well-
known, result-effective variable (MW) in overlapping ranges.”
Pet. Reply 16. Petitioner also contends that Bentley is presumed enabled
and Patent Owner’s polydispersity arguments “are misplaced because there
are no polydispersity limitations in the claims.” Id. (citing Ex. 1095 ¶¶ 51,
141, 219).
As noted above, molecular weight is a result-effective variable for
PEG polymers and it was well known in the art that the length of PEG arms
of a branched polymer could be successfully extended over a broad range of
molecular weights. For example, Harris discloses two-armed PEG polymers
with molecular weights as low as 100 and as high as 100,000 Da that “can
be prepared in a simple, one-step reaction.” Ex. 1016, 7:33–40 (“Relatively
pure polymer molecules of high molecular weight can be created.”), 18:31–
45, 37:58–65 (Claims 7, 8). Consistent with these disclosures, the ’440
patent acknowledges that Harris’s methods are “useful for attaching a high
molecular weight polymer to a molecule at a single attachment site.”
Ex. 1001, 1:55–2:3. Although the methods of Harris may be more difficult
than those disclosed in the ’440 patent, we credit the testimony of
Dr. Emrick that one of ordinary skill would have reasonably expected
success in using such methods to achieve molecular weights within the range
recited in claim 1 of the ’440 patent. Ex. 1084 ¶ 308; Ex. 1095 ¶ 220.
This conclusion is further supported by the fact that Bentley is
presumptively enabled, is Patent Owner’s own patent (see Exs. 1096–1101),
and claim 21 of Bentley provides for the same number of extensions of the
PEG polymer as are recited in claim 1 of the ’440 patent and Bentley
discloses no concerns with being able to successfully extend the PEG arms
IPR2019-01394
Patent 7,026,440 B2
45
without undue experimentation. See Abbott Labs. v. Andrx Pharms., Inc.,
452 F.3d 1331, 1341–42 (Fed. Cir. 2006) (presuming that a party that filed
and prosecuted a prior art reference represented to the Patent and Trademark
Office that its claims satisfy “the written description and enablement
requirements of 35 U.S.C. § 112”).
In view of the foregoing, we find that Petitioner sufficiently
demonstrates that one of ordinary skill in the art would have had a
reasonable expectation of success in producing the polymers of Bentley’s
genus.
e) Secondary Indicia of Non-Obviousness
Objective indicia of non-obviousness, or “secondary considerations,”
guard against hindsight reasoning in an obviousness analysis, and are often
“the most probative and cogent evidence in the record.” WBIP, LLC v.
Kohler Co., 829 F.3d 1317, 1328 (Fed. Cir. 2016) (citations omitted). As
such, objective indicia of non-obviousness must be considered in every case
in which they are presented. Id. (citing Transocean Offshore Deepwater
Drilling Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir.
2012)).
Objective indicia of non-obviousness include: (1) commercial
success; (2) long-felt but unsolved needs; (3) failure of others; (4) copying;
(5) praise in the art; (6) unexpected results; and (7) industry acceptance.
Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120,
1129 (Fed. Cir. 2000) (citing Graham, 383 U.S. at 17 and Allen Archery,
Inc. v. Browning Mfg. Co., 819 F.2d 1087, 1092 (Fed. Cir. 1987)).
Patent Owner contends that there was a “long-felt but unmet need for
the claimed branched reactive polymer and biologically active conjugates
IPR2019-01394
Patent 7,026,440 B2
46
thereof in the ’440 patent.” PO Resp. 58. According to Patent Owner, the
’440 patent expressly sets out this need as follows:
There remains a need in the art for new branched polymer
reagents that provide the benefits associated with branched
polymers (i.e., high overall molecular weight in a single non-
linear polymer molecule), but are easier to synthesize or
provide more flexibility in their design than prior art reagents.
Id. (quoting Ex. 1001, 2:4–9). Pointing to several other portions of the
’440 patent, Patent Owner argues that the ’440 patent satisfied this long-felt
need by providing “a branched reactive polymer and biologically active
conjugates thereof that are more easily synthesized and purified.” Id. at 58–
60.
In its Sur-Reply, Patent Owner notes that Dr. Emrick testified that
difficulties associated with high molecular weight polymers have been
known for 80 years and that examples “where very high molecular weights
are made with a low polydispersity are impressive.” Sur-Reply 24–25.
Patent Owner further notes that Dr. Little testified that overcoming
polydispersity issues with high molecular weight polymers is precisely what
the inventor’s claimed structure is designed to do. Id. (citing Ex. 1093,
120:5–13, 118:18–123:7 (Little deposition); Ex. 2040, 41:23–42:2 (Emrick
deposition)).
Patent Owner’s evidence of long-felt need is not persuasive for at
least two reasons. First, Patent Owner’s evidence of long-felt need stems
primarily from self-serving statements in the ’440 patent, and not from
independent sources. PO Resp. 58–60. Second, as Petitioner notes, to be
relevant, the evidence of secondary considerations must result from
something that is “both claimed and novel.” Pet. Reply 24 (citing In re Kao,
639 F.3d 1057, 1058 (Fed. Cir. 2011)). Polydispersity levels (as well as
IPR2019-01394
Patent 7,026,440 B2
47
methods of producing the polymers) are not recited in the challenged claims,
and Patent Owner presents no evidence that generally producing high
molecular weight polymers was novel. Indeed, Bentley discloses every
limitation of claim 1, either expressly or via overlapping ranges, and claims
polymers with a molecular weight of over 200,000 Da. Id. at 24–25.
Likewise, Harris specifically claims high molecular weight PEG polymers
(100,000 Da) and indicates that these compounds can be formed using a
“simple” method. Ex. 1016, 7:33–40 (“Relatively pure polymer molecules
of high molecular weight can be created.”), 18:31–45, 37:58–65 (Claims 7,
8).
In view of the foregoing, we find that Patent Owner’s evidence of
secondary considerations is entitled to little, if any, weight. Each of our
obviousness analyses below are made in view of this conclusion.
f) Conclusion with Respect to Claim 1
Upon consideration of Petitioner’s and Patent Owner’s arguments and
supporting evidence, including Patent Owner’s evidence of secondary
considerations, we determine that Petitioner demonstrates by a
preponderance of the evidence that claim 1 would have been obvious over
Bentley.
3. Analysis: Claims 2–15 and 32–35
With respect to dependent claims 2–15, 19, and 32–35, Petitioner
identifies where Bentley teaches or suggests every limitation of these claims.
Pet. 20–30. Patent Owner does not expressly contest Petitioner’s arguments,
apart from its arguments with respect to claim 1. Upon review of
Petitioner’s arguments and supporting evidence, we find that Petitioner
demonstrates by a preponderance of the evidence that claims 2–15, 19, and
32–35 would have been obvious over Bentley.
IPR2019-01394
Patent 7,026,440 B2
48
4. Analysis: Claims 16, 20, and 29–31
Patent Owner contests whether Petitioner sufficiently demonstrates
that the subject matter of dependent claims 16, 20, and 29–31 is taught or
suggested in Bentley. PO Resp. 29–30. In view of our determinations
(discussed above and below) that claims 16–18 and 30 would have been
obvious over Bentley and Liebigs, that claims 16, 20, and 29–31 would have
been obvious over Harris, and claims 20, 29, and 31 are anticipated by
JP-542, we decline to address the parties’ dispute here as to whether claims
16, 20, and 29–31 would also have been obvious over Bentley alone. See
SAS Inst. Inc. v. Iancu, 138 S. Ct. 1348, 1359 (2018) (holding a petitioner “is
entitled to a final written decision addressing all of the claims it has
challenged”); Boston Sci. Scimed, Inc. v. Cook Grp. Inc., Nos. 2019-1594, -
1604, -1605, 2020 WL 2071962, at *4 (Fed. Cir. Apr. 30, 2020) (non-
precedential) (recognizing that the “Board need not address issues that are
not necessary to the resolution of the proceeding” and, thus, agreeing that
the Board has “discretion to decline to decide additional
instituted grounds once the petitioner has prevailed on all its challenged
claims”).
F. Obviousness of Claims 16–18 and 30 over Bentley and Liebigs
Claim 16 depends from claim 1 and further requires that “p is 0 and Y
is a hydroxyl,” claim 17 depends from claim 1 and further requires that
“Y has the structure –O-Gp, wherein Gp is a protective group,” and claim 18
depends from claim 17 and further requires that “Gp is selected from the
group consisting of benzyl, acetal and dihydropyranyl.” Ex. 1001, 25:10–
16. Independent claim 30 is similar to claim 1, but requires a polymer that
has a terminal hydroxyl moiety. Id. at 26:36–38.
IPR2019-01394
Patent 7,026,440 B2
49
Petitioner contends the subject matter of claims 16–18 and 30 would
have been obvious over the combined disclosures of Bentley and Liebigs.
Pet. 31–35.
1. Liebigs
Liebigs is an article titled “Neutral ligands with surfactant structure –
Synthesis, Complexation, Ion Transfer.” Ex. 1019, 770.17 Liebigs discloses
several starting materials and associated ligands for forming the disclosed
compounds, including “biologically interesting” polymers based on glycerol.
Id. at 770–774. The following table shows various glycerol ether
compounds and synthesis pathways set forth in Liebigs.

17 Our citations are to the original page numbers of Liebigs.
IPR2019-01394
Patent 7,026,440 B2
50
The table above shows the possible combinations of R1, R2, and R3 for
attachment to the compound of formula 10. In the pathway depicted in 10l,
10m, and 10n, the hydroxyl groups of 10l (2-benzyl-1,3-glycerol) are used to
couple mPEG arms at positions R1 and R2 (as depicted in 10m). Id. at 775.
The –O–benzyl group at R2 (10m) is then deprotected to provide a hydroxyl
at R2 (10n). Ex. 1084 ¶ 366.
2. Analysis
Bentley does not describe a specific synthesis pathway for forming its
star molecules, but does provide general guidance on forming its disclosed
polymers. In particular, Bentley explains that PEG polymers are formed
from a central core molecule, such as glycerol, and that the disclosed
polymer relied upon by Petitioner has a three-carbon core molecule.
Ex. 1015, 1:38–54, 7:1–20; Pet. 31. Bentley further explains that the starting
molecule should have at least one hydroxyl moiety (–OH) available to
participate in chemical reactions and that a –O–benzyl group may be used to
protect a PEG hydroxyl. Ex. 1015, 4:25–32, 10:55–11:32; Pet. 31–32.
Given these disclosures, Petitioner contends one of ordinary skill in
the art seeking to prepare the branched PEG of Bentley would have searched
for a suitable glycerol core upon which to link two PEG chains at the 1 and 3
positions, “while preserving a hydroxyl at the central carbon atom (2-
position) for the subsequent reaction with the halide-substituted compound.”
Pet. 32. Dr. Emrick testifies that Liebigs expressly discloses an appropriate
glycerol core (2-benzyloxy-1,3-propanediol), as well as a synthesis pathway
(10l, 10m, and 10n) that one of ordinary skill in the art would have
understood could be used to create the activated PEG of Bentley. Id. at 32–
33 (Ex. 1084 ¶¶ 366–367). Dr. Emrick further testifies that the intermediary
form having mPEG arms at positions 1 and 3 and –O–benzyl (the claimed
IPR2019-01394
Patent 7,026,440 B2
51
“–O–Gp”) at position 2 (10m) satisfies the limitations of claims 17 and 18.
Pet. 34–35 (Ex. 1084 ¶ 369). Then, once the protecting –O–Gp (OCH2C6H5
(a benzyl group)) is removed (10n), the deprotected form with –OH at
position 2 satisfies the limitations of claims 16 and 30. Id.
Patent Owner contends Petitioner’s arguments fail because Liebigs
discloses compounds promising for use as catalysts, lipophilic ionophores,
and molecular aggregates, and Petitioner does not sufficiently explain why
one of ordinary skill in the art would have looked to such disclosures when
producing the PEG polymers of Bentley. PO Resp. 32. Patent Owner
further contends that the pathway and synthesis steps set forth by Petitioner
are hypothetical, as neither Liebigs nor Bentley discloses taking these
particular steps to form the polymers of Bentley’s genus. Id. at 31–32.
Bentley does not describe how to form its PEG polymers. Thus, one
of ordinary skill in the art seeking to produce the activated PEG polymers of
Bentley would have needed to purchase or synthesize these compounds.
Given that the genus of Bentley has a three-carbon core with PEG arms
extending from positions 1 and 3, we find persuasive Petitioner’s argument
that one of ordinary skill in the art looking for suitable glycerol-based
starting materials would have looked to Liebigs’s three-carbon core
molecule, i.e., 2-benzyloxy-1,3-propanediol. Pet. 31.
Although Liebigs is focused on producing compounds for use as
phase transfer catalysts, etc., and not for use as PEG polymers, we credit the
testimony of Dr. Emrick that one of ordinary skill in the art would have
understood that Liebigs provides a three-carbon core molecule and synthesis
pathway that are particularly useful for producing the branched reactive
polymer disclosed in Bentley. Ex. 1084 ¶¶ 191–192, 362–367. We also find
that Liebigs is reasonably pertinent to one of the problems facing the
IPR2019-01394
Patent 7,026,440 B2
52
inventors of the ’440 patent, i.e., providing an appropriate starting material
for synthesis of the branched reactive polymers. Ex. 1001, 2:18–24
(disclosing the need to provide suitable aliphatic core structures for the
synthesis of the disclosed polymers), 2:34–35 (“The central core molecule is
an aliphatic hydrocarbon having a length of at least three carbon atoms.”),
17:55–58 (using the same commercially available starting core material as
disclosed in Liebigs (2-benzyloxy-1,3-propanediol)).
Having chosen the glycerol-based compound of Liebigs, Petitioner
persuasively explains both how and why one of ordinary skill in the art
following the general synthesis pathway of Liebigs would have produced the
claimed –O–Benzyl intermediate (claims 17 and 18) and the deprotected
form having an –OH group at position 2 (claims 16 and 30). Pet. 34–35.
Although the use of Liebigs’s pathway to produce the genus of Bentley is
hypothetical in the sense that it is not expressly disclosed in either Bentley or
Liebigs, Petitioner persuasively explains why one of ordinary skill in the art
would have followed the general pathway disclosed in Liebigs to produce
that activated PEG polymers disclosed in Bentley. Id. at 32–35.
In view of the foregoing, we find that Bentley and Liebigs teach or
suggest the subject matter of claims 16–18 and 30 of the ’440 patent and that
Petitioner persuasively explains why one of ordinary skill in the art would
have combined the teachings of Bentley and Liebigs to arrive at the claimed
invention. Accordingly, Petitioner demonstrates by a preponderance of the
evidence that claims 16–18 and 30 would have been obvious over Bentley
and Liebigs.
IPR2019-01394
Patent 7,026,440 B2
53
G. Obviousness of Claims 1–3, 5, 7–10, 12–16, 20, and 29–35 over
Harris
Petitioner contends the subject matter of claims 1–3, 5, 7–10, 12–16,
20, and 29–35 would have been obvious over the disclosures of Harris.
Pet. 39–53.
1. Harris
Harris discloses “[m]ulti-armed, monofunctional, and hydrolytically
stable polymers” having two polymer arms. Ex. 1016, Abstract.
A functional group on the polymer may be used to link this polymer to a
drug, protein, enzyme, or a surface. Id. at 1:36–40, 7:50–57 (“The multi-
armed polymer derivative of the invention having a single reactive site can
be used for, among other things, protein modification with a high retention
of protein activity.”).
One embodiment of the polymer of Harris is reproduced below:

The figure above depicts one embodiment of Harris that is based upon the
“hydrolytically stable coupling of mPEG to lysine” and contains a carbamate
linkage. Id. at 9:35–55, 20:34–55. In this embodiment, the mPEG arms
consist of CH3O–(CH2CH2O)nCH2CH2 and the reactive carboxyl moiety
provides a linkage to reactive sites on proteins, enzymes, nucleotides, lipids,
liposomes, and other materials. Id. at 9:20–22, 9:35–55.
IPR2019-01394
Patent 7,026,440 B2
54
Harris explains that the mPEG disubstituted lysine of the invention
may be made using a one-step method or a two-step method. Id. at 11:46–
58, 18:15–22. The mPEG disubstituted lysine made by the one-step method
typically has a molecular weight of 40,000 Da and the mPEG disubstituted
lysine made by the two-step method typically has a molecular weight of
10,000 Da. Id. at 18:11–22. Harris notes, however, that mPEG disubstituted
lysines may have molecular weights as high as about 100,000 and as low as
about 100 to 200 Da. Id. at 18:31–45.
Harris discloses that a wide variety of other hydrolytically stable
linkages may be used, including amine and thioether linkages, “although not
necessarily with equivalent results.” Id. at 18:46–48, 18:56–62, 19:12–
23:20. The formula of a polymer having a thioether linkage is reproduced
below:

In the figure above, the mPEG disubstituted lysine is depicted having two
mPEG arms, attached using thioether linkages, and a reactive carboxyl
moiety. Id. at 9:56–60, 12:10–16, 23:11–20. The amine-linked polymer of
Harris is similar in configuration to the thioether-linked polymer, but uses an
amine linkage as opposed to a thioether linkage. Id. at 21:28–45.
IPR2019-01394
Patent 7,026,440 B2
55
2. Analysis: Claim 1
Petitioner maps the structure of the thioether-linked PEG polymer to
the formula of claim 1, as follows (Pet. 40):

The figure above is an annotated and color-coded version of the thioether-
linked polymer of Harris. Dr. Emrick testifies this polymer satisfies the
claimed formula Y—(X)p-R(—X′-POLY)q, wherein R (red) is a five carbon
residue –(CH2)4CH of the branching core precursor (Ex. 1084 ¶ 376), POLY
(green) consists of two “mPEG” chains (corresponding to q=2) composed of
“poly(alkylene oxide),” a water soluble non-peptide polymer (id. ¶¶ 377,
380), X′ (grey) is a thioether linkage (–S–) (id. ¶ 378), Y (purple) is a
carboxyl group (-COOH) that is reactive with an electrophilic or
nucleophilic group (id. ¶ 381), and X is not present, such that p=0 (id.
¶ 379).
Petitioner and Dr. Emrick concede that the molecular weight of the
mPEG arms of the polymer is not shown in the annotated figure, but contend
that one of ordinary skill in the art would have formed this molecule with a
IPR2019-01394
Patent 7,026,440 B2
56
total molecular weight of either 10,000 Da or 40,000 Da based on Harris’s
express disclosures of achieving these molecular weights using its one- or
two-step methods. Pet. 40–41. Petitioner further contends that one of
ordinary skill in the art would have found it obvious to use a total molecular
weight of 10,000 Da based on Harris’s disclosure that a 10,000 Da polymer
conjugated to asparaginase provided an increase in blood circulation half-life
from 27 minutes to 2,600 minutes. Id. at 41 (citing Ex. 1016, 30:66–31:27,
31:65–32:40, 35:40–57).
Patent Owner contends that Petitioner’s evidence and arguments are
insufficient to demonstrate the unpatentability of the challenged claims
because: (1) the carboxyl group of the recited polymers is not a “functional
group” as claimed (PO Resp. 33); (2) Petitioner has failed to establish that
one of ordinary skill in the art would have selected the amine- or thioether-
linked polymers for further development (id. at 34–41); (3) Petitioner has
not shown that Harris would have supplied a reason to select a polymer
within the recited molecular weight range (id. at 41–42); and (4) Petitioner
has not shown that one of ordinary skill in the art would have had a
reasonable expectation of success in achieving the claimed invention (id. at
42–43). We address these arguments in turn.
a) “functional group”
Patent Owner contends that Petitioner’s arguments relying on the
amine- and thioether-linked polymers of Harris fail because the carboxyl
group (-COOH) of Harris “is not a functional group” as claimed. PO Resp.
33. This argument is not persuasive because Petitioner demonstrates that
Harris’s carboxyl group is a “functional group” under our construction of
that term, i.e., a distinct, definable portion of a molecule that performs some
function or activity and is reactive with other molecules. Ex. 1084 ¶ 381;
IPR2019-01394
Patent 7,026,440 B2
57
Pet. Reply 4 (citing Ex. 1001, 9:19–23, 10:55–11:61, 15:3–40), 18 (citing
Ex. 1084 ¶¶ 381, 401; Ex. 1095 ¶¶ 15–18, 253). Indeed, the ’440 patent
specifically identifies “alkanoic acids having a carbon length (including the
carbonyl carbon) of 1 to about 25 carbon atoms (e.g., carboxylic acid[)]” as
suitable functional groups for the inventive polymers. Ex. 1001, 10:59–
11:2.
b) Selection of Amine and Thioether Linkages
(1) The Parties’ Arguments
Petitioner contends one of ordinary skill in the art would have selected
and used the amine- and thioether-linked polymers of Harris in view of
Harris’s disclosure that such polymers are hydrolytically stable alternatives
to the carbamate-linked polymers discussed at length in Harris. Pet. 41.
Patent Owner contends that a “lead compound” analysis is “guided by
evidence of the compound’s pertinent properties,” and Harris does not
describe properties specific to these polymers, such as their “stability,
reactivity, toxicity” or yield. PO Resp. 34–35. According to Patent Owner,
without taking these factors into account “it cannot be said that a [person of
ordinary skill in the art] would have expected similar results for the amine-,
thioether-, and carbamate-linked polymers.” Id. at 36–37. Patent Owner
further argues that in some applications it may be desirable to have a
hydrolytically degradable molecule and not the hydrolytically stable amine-
and thioether-linked polymers of Harris. Id. at 36 (citing Ex. 1084 ¶ 87).
With respect to the properties of amine- and thioether-linked
polymers, Patent Owner asserts that these linkages would have presented
“challenges.” Id. at 37. In particular, Patent Owner contends that reacting
an amine with a haloalkane is not a “clean” reaction and thioether linkers are
a potential site of oxidation. Id. at 37–38 (citing Ex. 2036 ¶ 178; Ex. 2037,
IPR2019-01394
Patent 7,026,440 B2
58
950; Ex. 2038, 843–44 (organic chemistry textbooks)). In view of these
known disadvantages, Patent Owner contends that one of ordinary skill in
the art would have looked instead to the carbamate linkage described in
Harris, which is discussed throughout the reference and represents “the only
experimental data in Harris regarding branched PEG conjugates.” Id. at 38–
39.
Petitioner asserts that Patent Owner’s arguments are unavailing
because Harris identifies the amine and thioether linkages as suitable
alternatives to the carbamate linkages, claim 9 of Harris includes both the
amine and thioether linkages in a Markush group of only eleven members,
and the ’440 patent itself claims amine, ether, and thioether linkages as
alternatives, without any comparative data. Pet. Reply 19 (citing Ex. 1016,
7:30–65, 9:20–33, 10:55–11:7, 36:27–29, 37:18–39:57, 39:63–40:8 (Claims
1–11, 13–17); Ex. 1095 ¶¶ 86–89).
With respect to Patent Owner’s expressed concerns with over
alkylation of amine linkages, Petitioner asserts that Harris does not describe
using a haloalkane, but in any event one of ordinary skill in the art knew
how to either “suppress over-alkylation, use alternative methods (e.g.,
reductive amination) and/or separate reaction product.” Id. (citing Ex. 1095
¶¶ 81–83, 85). With respect to oxidation of thioether linkages, Petitioner
contends that one of ordinary skill in the art would have been aware of the
issue and been able to select appropriate conditions to avoid oxidation, as
evidenced by the fact that the ’440 patent specifically discloses that amine
and thioether linkages can be prepared using Harris’s technique. Id. at 19–
20 (citing Ex. 1001, 8:30–59, 13:49–53; PO Resp. 38; Ex. 1095 ¶ 84).
In its Sur-Reply, Patent Owner contends that it is undisputed that
amine linkages can result in overalkylation and that thioether linkages can
IPR2019-01394
Patent 7,026,440 B2
59
result in oxidation, whereas carbamate-linked polymers were actively and
successfully commercialized. Sur-Reply 19. Given these known problems,
Patent Owner contends that Petitioner fails to show that one of ordinary skill
in the art would have selected either an amine or thioether linkage for further
development, especially when carabamate-linked polymers were the most
promising compounds disclosed in Harris for further development. Id. at 20
(citing Takeda, 492 F.2d at 1357).
(2) Analysis
Harris expressly discloses and claims the use of carbamate-, amine-,
and thioether-linked polymers. Ex. 1016, 8:59–67, 17:61–18:2, 20:34–56,
21:28–45, 23:3–20, 37:66–38:3. These disclosures would have, at a
minimum, suggested that amine- and thioether-linked polymers could be
used successfully to achieve the benefits discussed in Harris. See KSR, 550
U.S. at 416 (“[W]hen a patent claims a structure already known in the prior
art that is altered by the mere substitution of one element for another known
in the field, the combination must do more than yield a predictable result.”).
Although the use of either amine- or thioether-linked polymers may
present overalkylation (amine) or oxidation (thioether) challenges, Petitioner
persuasively demonstrates that one of ordinary skill in the art would have
understood how to successfully overcome such challenges. Pet. Reply 19–
20. This conclusion is further supported by the fact that the ’440 patent
discloses and claims amine- and thioether-linked polymers without any
expressed concern regarding overalkylation or oxidation, and without
providing any express methods for avoiding such reactions. Thus, we find
that the overalkylation and oxidation issues identified by Patent Owner
would not have taught away from or counseled against the use of Harris’s
amine- or thioether-linked polymers.
IPR2019-01394
Patent 7,026,440 B2
60
As noted by Patent Owner, Harris focuses significant attention on
carbamate-linked polymers and provides its only experimental results with
these polymers. The fact that carbamate linkers may be preferred, or the
primary subject of focus, however, does not diminish the fact that amine-
and thioether-linked polymers are taught and claimed in Harris. And, as
discussed above, we reject Patent Owner’s contention that Petitioner must
show that such linkages were the most promising for use or further
development, as opposed to being acceptable substitutes for the carbamate-
linked polymers disclosed and tested in Harris. KSR, 550 U.S. at 417 (“[A]
court must ask whether the improvement is more than the predictable use of
prior art elements according to their established functions.”).
In view of the foregoing, we find that Harris expressly teaches or
suggests the use of amine- and thioether-linked polymers for use in its multi-
armed polymer derivatives.
c) Selection of a Molecular Weight of at Least 5,000 Da
Harris expressly discloses every limitation of claim 1 of the ’440
patent, except the molecular weight of the mPEG arms on its amine- and
thioether-linked polymers. As noted above, the record clearly demonstrates
that the molecular weight of mPEG arms is a result-effective variable, and
Harris discloses both a general range of molecular weights from 100 to
100,000 Da and a typical molecular weight range of 40,000 to 50,000 Da.
Ex. 1016, 18:31–45 (“Polymerization of ethylene oxide to yield mPEGs
usually produces molecular weights of up to about 20,000 to 25,000 g/mol.
Accordingly, two-armed mPEG disubstituted lysines of molecular weight of
about 40,000 to 50,000 can be made according to the invention.”). The
typical range falls squarely within the claimed range of “at least about 5,000
Da” and the general range significantly overlaps the claimed range,
IPR2019-01394
Patent 7,026,440 B2
61
rendering the claimed range prima facie obvious. See Peterson, 315 F.3d at
1329.
In addition, Harris discloses that a carbamate-linked polymer with two
5,000 Da mPEG arms conjugated to asparaginase provided increased blood
circulation half-life compared to unmodified asparaginase, and Dr. Emrick
persuasively testifies that one of ordinary skill in the art would have
expected similar properties would be achieved when using the alternative
amine and thioether linkers disclosed in Harris. Ex. 1016, 30:66–31:27,
31:65–32:40, 35:40–57; Ex. 1084 ¶ 387. This provides another independent
reason for selecting mPEG arms that would provide an overall molecular
weight of “at least about 5,000 Da.”
Patent Owner contends that although Harris generally contemplates
mPEG arms with molecular weights from “44 to 55,600 Da,” it also allows
for molecular weights down to 100 to 200 Da. PO Resp. 41–42. Patent
Owner further contends that Harris recognizes that “[t]ypically, mPEG
polymers are linear polymers of molecular weight in the range of from about
1,000 to 5,000.” Id. at 42 (citing Ex. 1016, 4:14–15). Thus, absent evidence
that the teachings regarding carbamate-linked polymers would have been
applied to other linkages, Patent Owner contends that “Petitioner has failed
to carry its burden to show the claims obvious in light of Harris.” Id.
The case law contemplates that an overlapping range will have some
values within and some values outside the claimed range, i.e., an
overlapping range as opposed to a fully encompassed range. See Peterson,
315 F.3d at 1329–30. Thus, it is of limited significance in this case that
Harris allows for molecular weights down to 100 to 200 Da. In addition,
Patent Owner presents no persuasive evidence to rebut the prima facie case
of obviousness presented by the overlapping molecular weight ranges. For
IPR2019-01394
Patent 7,026,440 B2
62
example, Patent Owner identifies no reference that teaches away from the
claimed molecular weight ranges or any evidence that the claimed molecular
weight ranges provide unexpected results. Accordingly, we agree with
Petitioner that the claimed molecular weight range of “about 5,000 Da”
would have been prima facie obvious over the broad range of molecular
weights recited in Harris, as well as the typical molecular weight range
disclosed in the reference. See id. at 1329.
d) Reasonable Expectation of Success
Although Harris teaches, suggests, and claims the use of amine and
thioether linkages for its disclosed multi-armed polymers, Patent Owner
contends that there is insufficient evidence of record that these polymers
would have similar properties to the carbamate-linked polymers disclosed in
Harris. PO Resp. 42–43. Patent Owner further contends that it was
understood in the art, and expressly described in the ’440 patent, that
Harris’s methods are difficult and require extensive purification. Id. at 43
(citing Endo Pharms., Inc. v. Actavis LLC, 922 F.3d 1365, 1375 (Fed. Cir.
2019) (Patent Owner asserting that technological difficulties are “relevant to
a reasonable expectation of success”)). Thus, Patent Owner contends that
one of ordinary skill in the art would not have had a reasonable expectation
of success in achieving the claimed invention. Id. at 42.
The claims of the ’440 patent do not require any particular level of
activity or purity for the claimed polymers, and the ’440 patent and Harris
both expressly disclose that the compounds claimed in Harris are useful and
could be formed successfully. Ex. 1001, 1:55–2:3 (noting that Harris
discloses “branched polymers [that] are useful for attaching a high molecular
weight polymer to a molecule at a single attachment cite,” but noting the
need in the art for easier and more flexible methods than those disclosed in
IPR2019-01394
Patent 7,026,440 B2
63
Harris); Ex. 1016, 7:33–37 (Harris disclosing that its “invention provides a
branched or ‘multi-armed’ amphiphilic polymer that is monofunctional,
hydrolytically stable, can be prepared in a simple, one-step reaction, and
possess no aromatic moieties in the linker fragments forming the linkages
with the polymer moieties”), 37:18–65 (Claims 1–8). That the process for
forming Harris’s polymers is more difficult or time consuming than the
later-disclosed methods of the ’440 patent does not suggest that the various
disclosures of Harris identified by Petitioner could not have been
implemented successfully to form the claimed polymers. Moreover, we
credit the testimony of Dr. Emrick that one of ordinary skill in the art would
have expected that the amine- and thioether-linked polymers of Harris would
have similar properties to the carbamate-linked polymers described and
tested in Harris. Ex. 1084 ¶¶ 387–388; Ex. 1095 ¶¶ 76–79, 86. Thus, we
find one of ordinary skill in the art would have had a reasonable expectation
of success in applying the express teachings of Harris to arrive at the
claimed invention.
e) Conclusion
Petitioner persuasively explains where Harris teaches or suggests
every limitation of claim 1 of the ’440 patent. Petitioner also persuasively
explains why one of ordinary skill in the art would have followed the
teachings of Harris to arrive at the invention recited in claim 1 with a
reasonable expectation of success.
As noted above with respect to the Bentley grounds, Patent Owner’s
evidence of secondary considerations is entitled to little, if any, weight.
Considering Petitioner’s obviousness arguments in combination with
Patent Owner’s evidence of secondary considerations, we determine that
IPR2019-01394
Patent 7,026,440 B2
64
Petitioner demonstrates by a preponderance of the evidence that claim 1 is
unpatentable as having been obvious over Harris.
3. Analysis: Dependent Claims 2, 3, 5, 8–10, 12–14, 20, and 29–35
With respect to claims 2, 3, 5, 8–10, 12–14, 20, and 29–35, Petitioner
persuasively demonstrates that Harris teaches or suggests: (1) a thioether
(–S–) linkage (claim 2) (Pet. 42 (citing Ex. 1084 ¶ 390)); (2) two mPEG
arms (q=2) (claim 3) (id. (citing Ex. 1084 ¶ 391)); (3) an aliphatic
hydrocarbon core (R) with five carbon atoms (claim 5) (id. (citing Ex. 1084
¶ 392)); (4) POLY arms that are covalently attached to a methoxy capping
group (claims 8, 9, and 10) (id. at 44–45 (citing Ex. 1084 ¶¶ 398–400));
(5) activating the carboxyl functional group to form active carbonates, etc.
(claim 12) (id. at 45–46 (citing Ex. 1084 ¶¶ 401–402)); (6) two linear
poly(ethylene glycol) (mPEG) arms (claims 13 and 14) (id. at 46 (citing
Ex. 1084 ¶¶ 404–405)); (7) using the disclosed polymers to form a
biologically active conjugate (claim 20) (id. at 48–49 (citing Ex. 1084
¶ 413)); (8) a branched reactive polymer having the structure –HO–R[–X′ –
POLY]q (claim 30) (id. at 49–50 (citing Ex. 1084 ¶¶ 416–418)); and
(9) a range of molecular weights that fall within or overlap with the claimed
ranges of “at least about 5,000 to about 100,000 Da” (claim 32), “at least
about 5,000 to about 60,000 Da” (claim 33), “at least about 8,000 to about
40,000 Da” (claim 34), and “about 2,500 to about 30,000 Da” (claim 35) (id.
at 51–52 (citing Ex. 1084 ¶¶ 420–426)).
Petitioner also persuasively demonstrates that Harris teaches or
suggests every limitation of claim 29, including wherein X′ = (–S–) (id. at
49 (citing Ex. 1084 ¶¶ 414–415)), as well as every limitation of claim 31,
wherein the thioether-linked polymer of Harris is conjugated to a
biologically active material (id. at 50 (citing Ex. 1084 ¶ 419)).
IPR2019-01394
Patent 7,026,440 B2
65
Patent Owner does not dispute Petitioner’s arguments with respect to
claims 2, 3, 5, 8–10, 12–14, and 29–35, apart from its arguments with
respect to independent claim 1 discussed above.
Upon review of Petitioner’s arguments and supporting evidence, we
find that Petitioner demonstrates by a preponderance of the evidence that the
subject matter of claims 2, 3, 5, 8–10, 12–14, 20, and 29–35 would have
been obvious over Harris. Pet. 42, 44–46, 48–53.
4. Dependent claims 7, 15, and 16
Petitioner also contends that claims 7, 15, and 16 would have been
obvious over Harris. Pet. 42–44, 46–48. Patent Owner disputes Petitioner’s
arguments with respect to these claims. PO Resp. 44–47. We address the
parties’ arguments below.
a) Analysis: Claims 7 and 16
Claim 7 depends from claim 1 and further requires “wherein each
POLY and the Y functional group are attached to different carbon atoms of
R.” Ex. 1001, 24:41–43. Claim 16 depends from claim 1 and further
requires “wherein p is 0 and Y is a hydroxyl.” Id. at 25:10–11.
Petitioner contends that Harris teaches substitution of diamino alcohol
linkers in place of lysine linkers and that such linkers may be disubstituted at
the amines with activated mPEG. Pet. 42–43 (citing Ex. 1016, 23:66–25:3,
25:52–61). Petitioner contends such a heteroatom branched polymer would
have the following structure:
IPR2019-01394
Patent 7,026,440 B2
66

The figure above is Petitioner’s depiction of the diamino heteroatom of
Harris. Id. at 43. Petitioner maps this structure to the limitations of claims
1, 7, and 16, as follows:

The figure above is annotated by Petitioner to identify the X′, R, Y, and
POLY limitations of claims 1, 7, and 16. As shown in the figure, Petitioner
contends Harris discloses a diamino polymer with two (q=2) POLY
(poly(alkylene glycol)) arms (green), a X′ (-NH-) heteroatom linkage (grey),
no linker (p=0), and a Y functional group in the form of a hydroxyl group
(-OH) (purple). Id. at 43, 47. With respect to molecular weight, Petitioner
repeats its arguments set forth above for claim 1, i.e., that the molecular
weight ranges expressly disclosed and used in Harris either fall entirely
IPR2019-01394
Patent 7,026,440 B2
67
within or substantially overlap the range recited in claim 1. Id. In view of
these disclosures, Petitioner contends the subject matter of claims 7 and 16
would have been obvious over the diamino heteroatom branched polymer of
Harris. Id. at 42–44, 47–48.
Patent Owner contends Petitioner’s arguments “start[] from scratch”
to build a new molecule off a completely different linker moiety, yet
“Petitioner fails to explain why a [person of ordinary skill in the art] would
have pursued the diamino alcohol polymer over a disubstituted lysine,” or
pursued a synthesis that would produce amine linkages versus the
carbamates depicted by Harris. PO Resp. 44–45.
Harris expressly discloses the use of disubstituted, diamino alcohol
polymers and the use of amine linkages, and Petitioner explains sufficiently
why the combined polymer renders claims 7 and 16 obvious. Although we
agree with Patent Owner that Harris does not disclose that diamino alcohol-
linked polymers are preferred or superior to carbamate-linked polymers,
Petitioner need not show that a disclosed alternative is the most preferred
embodiment in order to render the claimed polymers obvious. See Fulton,
391 F.3d at 1200 (“Thus, a finding that the prior art as a whole suggests the
desirability of a particular combination need not be supported by a finding
that the prior art suggests that the combination claimed by the patent
applicant is the preferred, or most desirable, combination.”). Accordingly,
Petitioner demonstrates by a preponderance of the evidence that claims 7
and 16 would have been obvious over Harris.
b) Analysis: Claim 15
Claim 15 depends from claim 1 and further requires “wherein p is 1
and X is selected from the group consisting of a heteroatom, -alkylene, –O-
IPR2019-01394
Patent 7,026,440 B2
68
alkylene-O–, -alkylene-O-alkylene, -aryl-O–, –O-aryl, (–O-alkylene-)m, and
(-alkylene-O-)m, wherein m is 1–10.” Ex. 1001, 25:5–9.
Petitioner contends that the diamino alcohol polymer described above
with respect to claim 7 is a polymer wherein p is 1 and the heteroatom X is
an alkylene. Pet. 46–47. In mapping the diamino alcohol polymer structure
to the limitations of claim 15, Petitioner alters its identification of (X)p and
R, as follows:

The annotated and color coded figure above depicts Petitioner’s mapping of
the diamino alcohol structure of Harris to the limitations of claim 15. As
shown in the figure above, Petitioner identifies five carbons (red) as R and
CH2 (blue) as the (X)p linker. Id. at 47. This mapping differs from that for
claims 7 and 16 in that Petitioner does not identify the CH2 group (blue) as
part of the aliphatic carbon core (R), but instead as a linker moiety wherein
p=1.
Patent Owner contends that Petitioner arbitrarily identifies the linker
as CH2 in its arguments against claim 15, and asserts that one of ordinary
skill in the art “would have been wary of adding such a linker due to the
IPR2019-01394
Patent 7,026,440 B2
69
possibility for antigenicity, toxicity, loss of activity, and hydrophilicity.”
PO Resp. 45 (citing Ex. 2036 ¶ 220; Ex. 2040, 80:17–81:17).
Contrary to Patent Owner’s argument, Petitioner does not seek to add
an additional CH2 to the diamino alcohol polymer taught or suggested in
Harris. Pet. Reply 21–22. Rather, Petitioner simply notes that one can
change the claim mapping to identify CH2 as a linker instead of as part of the
aliphatic carbon R. As such, Patent Owner’s arguments regarding the
addition of a linker are unavailing.
Upon review of the parties’ arguments and supporting evidence, we
determine that Petitioner demonstrates by a preponderance of the evidence
that claim 15 would have been obvious over Harris.
c) Conclusion
For the reasons set forth above, we find that Petitioner demonstrates
by a preponderance of the evidence that claims 7, 15, and 16 would have
been obvious over Harris.
H. Anticipation of Claims 29 and 31 by Harris
Claim 29 is independent and differs from claim 1 in relevant part in
that “X′ is –NH–, –O–, or –S–,” no molecular weight is recited for the
branched reactive polymer, and each POLY is “covalently attached to a
methoxy capping group.” Ex. 1001, 26:14–35. Claim 31 is similar to claim
29 but requires a “biologically active conjugate, comprising a biologically
active molecule covalently attached to a branched reactive polymer,” and the
POLY need not include a methoxy capping group. Id. at 26:54–27:8.
In addition to its arguments with respect to claim 1, Petitioner
contends that claim 29 is anticipated by Harris because Harris’s mPEG arms
have methoxy capping groups. Pet. 54 (citing Ex. 1016, 3:62–4:3, 8:37–49,
11:50–53, 18:11–37). Petitioner further contends that claim 31 is anticipated
IPR2019-01394
Patent 7,026,440 B2
70
by Harris because Harris is directed to branched polymers that are intended
“for attachment to biologically active molecules such as proteins.” Id. at 55
(citing Ex. 1016, 9:10–33, 10:48–64, 11:66–12:16, 25:26–51, 28:31–29:12,
Abstract).
Patent Owner contends that claim 29 is not anticipated by Harris
because Petitioner has not demonstrated that the carboxyl moiety of Harris
(–COOH–) will react readily with another chemical moiety. PO Resp. 46.
Patent Owner’s counter-argument is unavailing because the claims do not
require that the functional group “react readily” with another chemical
moiety. Thus, because Harris’s mPEG arms have a methoxy capping group,
we determine that Petitioner demonstrates by a preponderance of the
evidence that claim 29 is anticipated by Harris.
With respect to claim 31, Patent Owner argues that Harris fails to
teach or disclose conjugating either amine- or thioether-linked polymers to a
biologically active molecule, and the general statements of Harris referring
to biologically active conjugates are not sufficient to show that the cited
polymers “necessarily existed as conjugates to a biologically active
molecule.” PO Resp. 46–47.
Although we are directed to no express disclosure or description of
the specific amine- or thioether-linked polymers of Harris being attached to
a biologically active molecule, this is one of the primary intended purposes
for Harris’s polymer derivatives. Ex. 1016, 7:50–54 (“The multi-armed
polymer derivative of the invention having a single reactive site can be used
for, among other things, protein modification with a high retention of protein
activity.”), 9:27–31 (“The invention includes biologically active conjugates
comprising a biomolecule, which is a biologically active molecule, such as a
protein or enzyme, linked through an active moiety to the branched polymer
IPR2019-01394
Patent 7,026,440 B2
71
derivative of the invention.”). Harris also provides an express disclosure of
attaching one disclosed multi-armed polymer to a biologically active
material. Id. at 30:64–35:23. As such, we agree with Petitioner that one of
ordinary skill in the art would immediately understand that the amine and
thioether linkages of Harris were intended for conjugation to a biologically
active molecule. Accordingly, claim 31 is anticipated by Harris. See Blue
Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1344 (Fed. Cir. 2016)
(noting that a reference need not “include an express discussion of the actual
combination to anticipate . . . if that reference teaches that the disclosed
components or functionalities may be combined and one of ordinary skill in
the art would be able to implement the combination.”); In re Graves, 69 F.3d
1147, 1152 (Fed. Cir. 1995).
I. Remaining Grounds
Having determined that all challenged claims of the ’440 patent would
have been obvious over, or are anticipated by, one or more of Bentley,
Harris, and JP-542, we do not address Petitioner’s arguments that claims 1–
15, 17, 19–20, 29 and 31–35 would also have been obvious over the
combination of JP-542 and MDD or the combination of JP-542 and Bentley.
Pet. 53–55, 75–80. See SAS Inst., 138 S. Ct. at 1359; Boston Sci., 2020
WL 2071962, at *4.
III. CONSTITUTIONAL CHALLENGE
Patent Owner contends subjecting the ’440 patent to inter partes
review violates its constitutional rights. In particular, Patent Owner
contends (1) that subjecting a patent effectively filed before September 16,
2012 to inter parties review “is an impermissibly retroactive,
unconstitutional taking”; (2) subjecting a pre-AIA patent to inter partes
review “violates the Due Process Clause of the Fifth Amendment by
IPR2019-01394
Patent 7,026,440 B2
72
eviscerating the Patent Owner’s substantive vested rights”; and (3) inter
parties review violates the “Appointments Clause, rendering it
constitutionally impermissible for the PTAB to order the cancellation of any
patent claims.” PO Resp. 60–64.
Patent Owner’s arguments are foreclosed by the decisions in Celgene
Corp. v. Peter, 931 F.3d 1342, 1362–63 (Fed. Cir. 2019) and United States
v. Arthrex, Inc., 141 S. Ct. 1970, 1986–87, 1997 (2021). As such, we do not
further consider or address Patent Owner’s arguments.
IV. CONCLUSION18
Petitioner has shown by a preponderance of the evidence that claims
1–8, 11–15, 17, 19, 20, 29, 31–33, and 35 are anticipated by JP-542 and
claims 29 and 31 are anticipated by Harris. Petitioner has also shown by a
preponderance of the evidence that the subject matter of claims 1–20 and
29–35 would have been obvious over one or more of Bentley, Harris, and
Bentley in view of Liebigs.

18 Should Patent Owner wish to pursue amendment of the challenged claims
in a reissue or reexamination proceeding subsequent to the issuance of this
decision, we draw Patent Owner’s attention to the April 2019 Notice
Regarding Options for Amendments by Patent Owner Through Reissue or
Reexamination During a Pending AIA Trial Proceeding. See 84 Fed. Reg.
16,654 (Apr. 22, 2019). If Patent Owner chooses to file a reissue application
or a request for reexamination of the challenged patent, we remind Patent
Owner of its continuing obligation to notify the Board of any such related
matters in updated mandatory notices. See 37 C.F.R. § 42.8(a)(3), (b)(2).
IPR2019-01394
Patent 7,026,440 B2
73
In summary:

V. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–20 and 29–35 of U.S. Patent
No. 7,026,440 B2 are unpatentable; and

19 For the reasons discussed above, we do not address obviousness of claims
16, 20, and 29–31 over Bentley.
20 For the reasons discussed above, we do not address obviousness of claims
1–15, 17 19, 20, 29, 31–35 over JP-542 and MDD.
21 For the reasons discussed above, we do not address obviousness of claims
16–18, 30 over JP-542 and Bentley.
Claims

35
U.S.C.
§
Reference(s)/Basis Claims
Shown
Unpatentable
Claims
Not shown
Unpatentable
1–15, 19,
32–35
103(a) Bentley 1–15, 19, 32–
35

16, 20, 29–
31
103(a) Bentley19
16–18, 30 103(a) Bentley, Liebigs 16–18, 30
1–3, 5, 7–
10, 12–16,
20, 29–35
103(a) Harris 1–3, 5, 7–10,
12–16, 20,
29–35

29, 31 102(b) Harris 29, 31
1–15, 17,
19, 20, 29,
31–33, 35
102(b) JP-542 1–8, 11–15,
17, 19, 20, 29,
31–33, 35
9, 10
1–15, 17
19, 20, 29,
31–35
103(a) JP-542, MDD20
16–18, 30 103(a) JP-542, Bentley21
Overall
Outcome
1–20, 29–35
IPR2019-01394
Patent 7,026,440 B2
74
FURTHER ORDERED that, because this is a Final Written Decision,
parties to this proceeding seeking judicial review of our decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.
IPR2019-01394
Patent 7,026,440 B2
75
FOR PETITIONER:
Thomas Donovan
Mark Hagedorn
Vincent Liptak
BARNES & THORNBURG LLP
Thomas.donovan@btlaw.com
mhagedorn@btlaw.com
Vincent.liptak@btlaw.com
FOR PATENT OWNER:
Edgar Haug
Brian Murphy
Angus Chen
Andrew Wasson
Kaitlin Abrams
Erika Selli
Andrew Roper
HAUG PARTNERS LLP
ehaug@haugpartners.com
bmurphy@haugpartners.com
achen@haugpartners.com
awasson@haugpartners.com
kabrams@haugpartners.com
eselli@haugpartners.com
aroper@haugpartners.com