Amgen Incv.AbbVie Biotechnology Ltd.

Patent Trial and Appeal Board

Jan 14, 2016

14453461 (P.T.A.B. Jan. 14, 2016)

Trials@uspto.gov Paper 9
571-272-7822 Entered: January 14, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

AMGEN, INC.,
Petitioner,

v.

ABBVIE BIOTECHNOLOGY LTD.,
Patent Owner.
____________

Case IPR2015-01514
Patent 8,916,157 B2
____________

Before RAMA G. ELLURU, TINA E. HULSE, and
ELIZABETH A. LAVIER, Administrative Patent Judges.

ELLURU, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
37 C.F.R. § 42.108

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I. INTRODUCTION
Petitioner, Amgen, Inc. (“Amgen”), filed a Petition requesting an inter
partes review of claims 1–8, 10–13, and 15–30 of U.S. Patent No. 8,916,157
B2 (Ex. 1001, “the ’157 patent”). Paper 2 (“Pet.”). Patent Owner, AbbVie
Biotechnology Ltd. (“AbbVie”), filed a Preliminary Response. Paper 8
(“Prelim. Resp.”). We have jurisdiction under 35 U.S.C. § 314, which
provides that an inter partes review may not be instituted unless the
information presented in the petition “shows that there is a reasonable
likelihood that the petitioner would prevail with respect to at least 1 of the
claims challenged in the petition.”
For the reasons set forth below, on this record, we find that Amgen
has not established a reasonable likelihood of prevailing with respect to at
least one challenged claim of the ’157 patent. Accordingly, we deny the
Petition and decline to institute an inter partes review of the ’157 patent.
A. Related Matter
Amgen concurrently filed a petition for inter partes review of U.S.
Patent No. 8,916,158 B2, which is in the same family as the ’157 patent.
Pet. 3; Paper 4, 1.
B. The ’157 patent
The ’157 patent is titled “FORMULATION OF HUMAN
ANTIBODIES FOR TREATING TNF-α ASSOCIATED DISORDERS.”
Ex. 1001, at [54]. Tumor necrosis factor alpha (“TNF-α” or “TNFα”) is a
cytokine implicated in various diseases and disorders in humans, including
sepsis, autoimmune diseases, and transplant rejection. Id. at 1:35–52. Thus,
TNFα is a target for various therapeutic strategies, including antibodies that
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bind to and neutralize TNFα, to counteract or inhibit its activity. Id. at 1:53–
57. The ’157 patent focuses especially on antibody formulations, including
the anti-TNFα antibody D2E7. See, e.g., id. at 17:19–20 (“In the most
preferred embodiment, the antibody is D2E7.”). AbbVie states that the ’157
patent covers the commercial product HUMIRA®. Prelim. Resp. 16; see
also Pet. 59 (stating the challenged claims “may encompass” HUMIRA®).
C. Illustrative Claim
Amgen challenges claims 1–8, 10–13, and 15–30 of the ’157 patent.
Of the challenged claims, claims 1 and 24 are independent. Claim 1 is
illustrative of the claimed subject matter and recites the following:
1. A stable liquid aqueous pharmaceutical formulation
comprising
(a) a human IgG1[1] anti-human Tumor Necrosis Factor alpha
(TNFα) antibody, or an antigen-binding portion thereof, at a
concentration of 20 to 150 mg/ml,
(b) a tonicity agent,
(c) a surfactant, and
(d) a buffer system having a pH of 4.0 to 8.0,
wherein the antibody comprises the light chain variable region
and the heavy chain variable region of D2E7.
Ex. 1001, 39:1–10.

1 Immunoglobulin G1 (IgG1) is a subclass of antibodies found in humans.
See Ex. 2031, 5–7.
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D. Asserted Grounds of Unpatentability
Amgen asserts the following grounds of unpatentability (Pet. 5):
Challenged Claims Basis References
1–8, 10–13, 15–30 § 103(a) Lam2 and Barrera3
1–8, 10–13, 15–30 § 103(a) Salfeld4 and Heavner5

II. ANALYSIS
A. 35 U.S.C. § 325(d)
As a preliminary matter, we briefly address AbbVie’s request that we
reject the Petition pursuant to 35 U.S.C. § 325(d) on the basis that the
Petition presents “the same or substantially the same prior art or arguments”
as were previously presented to USPTO. See Prelim. Resp. 55–58. Under
§ 325(d), the Director, and by extension the Board, has broad discretion to
deny a petition that raises substantially the same prior art or arguments
previously presented to the Office. See Unilever, Inc. v. Procter & Gamble
Co., Case IPR2014-00506, slip op. at 6 (Paper 17) (PTAB July 7, 2014)
(informative). Specifically, AbbVie contends that the Examiner advanced
substantially the same prior art combinations during the prosecution of the
’157 patent and its parent patents, but nonetheless found the claims of the
’157 patent patentable. Prelim. Resp. 55 (stating the four asserted references

2 Lam et al., US 6,171,586 B1, issued January 9, 2001 (Ex. 1003).
3 Barrera et al., Effects of Treatment with a Fully Human Anti-Tumour
Necrosis Factor α Monoclonal Antibody on the Local and Systemic
Homeostasis of Interleukin 1 and TNFα in Patients with Rheumatoid
Arthritis, 60 ANN. RHEUM. DIS. 660–69 (2001) (Ex. 1004).
4 Salfeld et al., US 6,090,382, issued July 18, 2000 (Ex. 1005).
5 Heavner et al., US 7,250,165 B2, issued July 31, 2007 (Ex. 1006).
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were “cited and considered” in an Information Disclosure Statement
submitted during prosecution of the ’157 patent). AbbVie further asserts
that “during prosecution of claims in parent patents, the PTO expressly
raised the same arguments Petitioner now advances.” Id. at 55–56. Because
AbbVie alleges that the “same arguments” advanced by Amgen in its
Petition were advanced against claims in related patent applications, not the
challenged claims of the ’157 patent, we decline to exercise our discretion to
apply § 325(d) to deny the Petition.
B. Claim Construction
In an inter partes review, the Board interprets claim terms in an
unexpired patent according to the broadest reasonable construction in light
of the specification of the patent in which they appear. See In re Cuozzo
Speed Techs., LLC, 793 F.3d 1268, 1278–79 (Fed. Cir. 2015); 37 C.F.R.
§ 42.100(b). Under that standard, and absent any special definitions, we
give claim terms their ordinary and customary meaning, as would be
understood by one of ordinary skill in the art at the time of the invention.
See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any
special definitions for claim terms must be set forth with reasonable clarity,
deliberateness, and precision. See In re Paulsen, 30 F.3d 1475, 1480 (Fed.
Cir. 1994). “Absent some clear intent to the contrary,” examples from a
patent’s specification are not to be imported into the claims. In re
Omeprazole Patent Litig., 483 F.3d 1364, 1372 (Fed. Cir. 2007).
Whether a term appearing in the claim’s preamble is limiting “is a
determination ‘resolved only on review of the entire[ ] . . . patent to gain an
understanding of what the inventors actually invented and intended to
encompass by the claim.’” Catalina Mktg. Int’l, Inc. v. Coolsavings.com,
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Inc., 289 F.3d 801, 808 (Fed. Cir. 2002) (quoting Corning Glass Works v.
Sumitomo Elec. U.S.A., Inc., 868 F.2d 1251, 1257 (Fed. Cir. 1989)).
Generally, however, “a preamble limits the invention if it recites essential
structure or steps, or if it is ‘necessary to give life, meaning, and vitality’ to
the claim,” id. (quoting Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d
1298, 1305 (Fed. Cir. 1999)), but not “‘where a patentee defines a
structurally complete invention in the claim body and uses the preamble only
to state a purpose or intended use for the invention,’” id. (quoting Rowe v.
Dror, 112 F.3d 473, 478 (Fed. Cir. 1997)).
1. “stable”
“[S]table” appears in the preamble of claims 1 and 24, and modifies
“liquid aqueous pharmaceutical formulation.” The Specification expressly
states that “[a] ‘stable’ formulation is one in which the antibody therein
essentially retains its physical stability and/or chemical stability and/or
biological activity upon storage.” Ex. 1001, 7:20–22.
Amgen argues that “stable” bears no patentable weight, solely on the
basis that “stable” appears only in preamble language. Pet. 10–11. But this
factor is not dispositive. See Catalina, 289 F.3d at 808 (designating
“guideposts,” not a “litmus test,” in preamble analysis). We are not
persuaded that this factor alone outweighs the consistent focus in the
Specification on stability, including the express definition of “stable,” Ex.
1001, 7:20–22. Likewise, we do not consider “stable” as stating merely an
intended use or purpose of the claimed invention; rather, it describes a
mandatory characteristic thereof. Accordingly, based on our review of the
’157 patent as a whole and on this record, we conclude that “stable,” as used
in the preambles of claims 1 and 24, breathes life and meaning into claims 1
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and 24 and, therefore, limits its scope.
Having determined “stable” is limiting, we turn to its broadest
reasonable construction. Amgen argues that if “stable” is limiting, then a
formulation is “stable” under the definition given in the Specification.
According to Amgen, a formulation is “stable” if it retains its physical,
chemical, and/or biological stability upon storage “for any period of time, no
matter how short,” but does not require storage at a specific temperature or
for a specific time. Pet. 11. In support, Amgen argues the Specification
only expresses preferences (not requirements) for certain time and
temperature conditions, and that there is “no evidence that the broadly
disclosed and claimed formulations . . . are stable for any particular time
under any particular conditions.” Id.
AbbVie counters that such an interpretation would “define ‘stable’ to
encompass formulations stable . . . only for a fraction of a second—which is
to say, not stable at all.” Prelim. Resp. 8. Although AbbVie does not
attempt to define “stable” quantitatively, AbbVie points to the Summary of
the Invention of the ’157 patent, which focuses on the need for a formulation
“‘with an extended shelf life.’” Prelim. Resp. 7 (quoting Ex. 1001, 3:9–10).
AbbVie further asserts that “stable” should be read in context of the phrase it
modifies, i.e., “pharmaceutical formulation,” and, thus, necessitates a
preparation that is biologically effective and not significantly toxic. Id. at 7–
8 (citing Ex. 1001, 7:10–15 (defining “pharmaceutical formulation”)). Thus,
AbbVie contends, and we agree, that one of skill in the art “would have
understood that a formulation would need to be stable for storage and use.”
Id. at 7. A more specific threshold is unnecessary to understand the broadest
reasonable interpretation of “stable” with sufficient clarity to further analyze
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the claims in light of the cited prior art. See Vivid Techs., Inc. v. Am. Sci. &
Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (noting claim terms require
construction “only to the extent necessary to resolve the controversy”).
2. “a human IgG1 anti-human Tumor Necrosis Factor alpha (TNFα)
antibody, or an antigen-binding portion thereof, . . . wherein the
antibody comprises the light chain variable region and the heavy chain
variable region of D2E7”
This language is recited in claim 1. Amgen breaks this phrase into
several separate terms in need of construction, see Pet. 12–13, whereas
AbbVie considers it as a whole, see Prelim. Resp. 9–11. We begin with the
component parts, as necessary, building to an understanding of the entire
phrase.
The first portion, “a human IgG1 anti-human Tumor Necrosis Factor
alpha (TNFα) antibody,” is further defined at the end of the claim, by the
language “wherein the antibody comprises the light chain variable region
and the heavy chain variable region of D2E7.” As both parties recognize,
(see Pet. 13; Prelim. Resp. 10–11), “D2E7” refers to an antibody disclosed
in Salfeld,6 incorporated by reference in the ’157 patent. See Ex. 1001,
9:54–55. Salfeld provides amino acid sequences for the light chain variable
region (SEQ ID NO: 1), light chain CDR37 domain (SEQ ID NO: 3), heavy
chain variable region (SEQ ID NO: 2), and heavy chain CDR3 domain (SEQ
ID NO: 4) for the D2E7 antibody. See Ex. 1005, 2:59–67.

6 In addition to the Salfeld patent relied on as prior art by Amgen in this
inter partes review, the ’157 patent also identifies a second patent to Salfeld,
US 6,258,562 B1. Ex. 1001 9:54–55.
7 “CDR” stands for “complementarity determining regions.” CDRs are
hypervariable sub-regions of the variable regions of the heavy and light
chains of an antibody. Ex. 1001, 9:45–49.
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The parties dispute, however, how the phrase “or an antigen-binding
portion thereof” affects the scope of the claim. As Amgen notes (Pet. 12),
the Specification defines “antigen-binding portion” as “one or more
fragments of an antibody that retain the ability to specifically bind to an
antigen (e.g., hTNFα).” Ex. 1001, 9:56–59. Amgen argues that the phrase
“antigen-binding portion” thus “encompasses an antibody fragment that can
be as small as one CDR (5 to 17 amino acids).” Pet. 12.
In contrast, AbbVie argues that claim 1 is limited to an antibody, or
antibody fragment, that “includes the complete light chain variable (VL)
region and the heavy chain variable (VH) region of the antibody D2E7.”
Prelim. Resp. 9. Thus AbbVie contends that the clamed “antigen-binding
portion” includes the complete light chain variable region and the heavy
chain variable region of the antibody D2E7. AbbVie presumably relies on
the language of the “wherein” clause as support for further limiting the term
“an antigen-binding portion.” As explained above, however, the “wherein”
clause is modifying the “antibody” term, and not the term “an antigen-
binding portion thereof.” Thus, although we agree that the claimed
“antibody” must include the light chain variable region and the heavy chain
variable region of D2E7, we do not agree that the claimed “an antigen-
binding portion” must include the complete light chain and heavy chain
variable regions of D2E7, as AbbVie asserts. This is particularly true given
the claim’s use of a “(TNFα) antibody, or an antigen-binding portion
thereof” (emphasis added), which is disjunctive.
Accordingly, on the present record, we find that the broadest
reasonable interpretation of the entire phrase allows for either an antibody
comprising the light chain variable region and the heavy chain variable
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region D2E7, or one or more fragments of D2E7 that retain the ability to
specifically bind TNFα.
C. Obviousness
A claim is unpatentable for obviousness if, to one of ordinary skill in
the pertinent art, “the differences between the subject matter sought to be
patented and the prior art are such that the subject matter as a whole would
have been obvious at the time the invention was made.” 35 U.S.C. § 103(a)
(2006); see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406–07 (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) objective evidence of nonobviousness.
Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). The level of ordinary
skill in the art may be reflected by the prior art of record. See Okajima v.
Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001); In re GPAC Inc.,
57 F.3d 1573, 1579 (Fed. Cir. 1995); In re Oelrich, 579 F.2d 86, 91 (CCPA
1978).
If all the claimed elements are taught or suggested by the prior art
references, the obviousness inquiry turns to the combination of those
references:
[P]roper analysis under § 103 requires, inter alia, consideration
of two factors: (1) whether the prior art would have suggested
to those of ordinary skill in the art that they should make the
claimed composition or device, or carry out the claimed
process; and (2) whether the prior art would also have revealed
that in so making or carrying out, those of ordinary skill would
have a reasonable expectation of success.
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Par Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1196 (quoting
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1164 (Fed. Cir. 2006)).
Although obviousness does not require absolute predictability, In re
Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986), there must be “some
articulated reasoning with some rational underpinning to support the legal
conclusion of obviousness,” KSR, 550 U.S. at 418 (quoting In re Kahn, 441
F.3d 977, 988 (Fed. Cir. 2006)). An explicit teaching of a motivation to
combine is not required, however, as a tribunal “can take account of the
inferences and creative steps that a person of ordinary skill in the art would
employ.” Id. Nonetheless, “[t]o the extent an art is unpredictable . . . KSR’s
focus on these ‘identified, predictable solutions’ may present a difficult
hurdle because potential solutions are less likely to be genuinely
predictable.” Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359
(Fed. Cir. 2008).
1. General State of the Art
Before considering the specific grounds of unpatentability asserted by
Amgen, we begin with a discussion of the state of the art, both for
background purposes and because Amgen relies in part on the general state
of the art to support its rationale for combining the proffered references. See
Pet. 14–17; cf. Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359,
1365 (Fed. Cir. 2015) (“Art can legitimately serve to document the
knowledge that skilled artisans would bring to bear in reading the prior art
identified as producing obviousness.” (citation omitted.)). For example, the
parties refer to commercialized prior art antibody formulations that were
available at the time of the invention, and on what we refer to as “the Wang
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article,” a journal article from 1999 (Ex. 1017).8 See, e.g., Pet. 15–16, 29;
Prelim. Resp. 24–26, 56.
a. Commercially Available Antibody Formulations
By 2002,9 various parenteral antibody formulations had been
approved by the United States Food and Drug Administration (USFDA),
including REMICADE™ (infliximab), a prior art IgG1 anti-TNFα antibody
product, “formulated at pH 7.2 with sucrose (a tonicity agent) and
polysorbate 80 (a surfactant).” Pet. 16.
Amgen maintains that the formulation of antibodies was generally
known at that time, Pet. 14 (citing Ex. 1002 ¶¶ 45, 72–73), and that the
ordinarily skilled artisan would have been motivated to optimize different
parameters such as pH, and components such as surfactants and polyols, see
id. at 14–16. Because D2E7 was of the same antibody class (IgG) as other
known antibody formulations, Amgen concludes that the skilled artisan
“would have understood that the formulation components of an antibody
formulation could be applied to a new formulation of a structurally similar
antibody.” Pet. 16–17 (citing Ex. 1002 ¶¶ 74–77).
AbbVie counters that “development of stable liquid antibody
formulations, especially those at a concentration high enough to be suitable
for [subcutaneous] administration, was far from routine.” Prelim. Resp. 20
(citing Ex. 2005 at 1906). AbbVie maintains that the commercial antibody

8 Wang, Instability, Stabilization, and Formulation of Liquid Protein
Pharmaceuticals, 185 INT’L J. PHARMACEUTICS 129–188 (1999) (Ex. 1017).
For consistency, we refer to pages in Wang by their exhibit page numbers,
not their publication page numbers.
9 The ’157 patent claims priority to an application filed on August 16, 2002.
Ex. 1001, at [63].
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formulations on which Amgen relies, see Pet. 14–17 (citing Ex. 1002 ¶ 74,
Table 2), were either: (1) low-concentration (10 mg/ml or less) liquid
formulations, or (2) lyophilized (i.e., freeze-dried) formulations. See Prelim.
Resp. 16–19. As AbbVie notes, REMICADE™ was lyophilized, and
included instructions to use within three hours after liquid reconstitution.
Prelim. Resp. 35–36 (citing Ex. 1002 ¶74; Ex. 1035 at 10). In its
reconstituted liquid form, REMICADE™’s concentration was 10 mg/ml. Id.
at 17 (citing Ex. 1035).
b. The Wang Article
Both parties cite the Wang article as evidence of the state of the art at
the time of the invention. See Pet. 15–16, 29; Prelim. Resp. 24–26, 56. The
Wang article begins: “One of the most challenging tasks in the development
of protein pharmaceuticals is to deal with physical and chemical instabilities
of proteins.” Ex. 1017, 1.
Amgen asserts that the Wang article acknowledges the challenges, but
then “teaches all of the excipient components recited in the challenged
claims of the ’157 patent, and how to optimize those features to develop a
stable formulation.” Pet. 29 (citing Ex. 1002 ¶ 74). Amgen does not quote
or cite specific portions of the Wang article for this proposition, but instead
relies on further discussion in the Randolph Declaration. See id. at 29.10

10 AbbVie asserts that Amgen’s “extensive reliance” on the Randolph
Declaration throughout the Petition constitutes improper incorporation by
reference and amounts to a page limit violation. Prelim. Resp. 6 (citing,
inter alia, 37 C.F.R. §§ 42.24(a)(1)(i), 42.6(a)(3)). Instead of denying the
Petition on this basis, as AbbVie urges, we consider only those arguments
Amgen presents squarely in its Petition. For example, as is relevant to our
analysis regarding the general state of the art, Amgen cites to the Randolph
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AbbVie responds that the Wang article demonstrates unpredictability,
not predictability, in the art of formulating proteins: “‘[v]ery often, proteins
have to be evaluated individually and stabilized on a trial-and-error basis.’”
Prelim. Resp. 24 (quoting Ex. 1017, 2). AbbVie further points to Amgen’s
prior reliance on Wang as evidence of unpredictability in the art during
prosecution of Amgen’s own protein formulation patent applications, as well
as to Dr. Randolph’s prior published statements regarding the complexities
of protein folding and instability. See id. at 24–28.
c. Analysis
Upon consideration of the parties’ arguments regarding commercially
available antibody formulations including REMICADE™, the Wang article,
and other evidence presented regarding the general state of the art at the time
of the invention, we are not persuaded by Amgen’s evidence and argument.
Specifically, on this record, we are not persuaded that the prior art provided
sufficient guidance such that a skilled artisan would have had a reasonable
expectation of success in arriving at the formulation of stable, liquid
pharmaceutical compositions comprising antibodies at a concentration of 20
to 150 mg/ml.
For example, Amgen fails to direct us to a commercially available
antibody product that was available in liquid form, within the claimed
antibody concentration range. As noted above, REMICADE™ was sold in
lyophilized form, and its product information indicated it should be used

Declaration’s discussion of various other background references (in addition
to the Wang article), without any additional argumentation or explanation in
the Petition. See Pet. 15. We decline to consider further these other
background references.
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within three hours of liquid reconstitution. Prelim. Resp. 35–36 (citing Ex.
1002 ¶ 74; Ex. 1035, 10). In other words, REMICADE™ was not a stable
liquid antibody formulation.
Further, Amgen does not persuade us that the Wang article
“provide[d] guidance on how to formulate such compositions,” Pet. 29, to a
sufficient degree to have provided a skilled artisan at the time with a
reasonable expectation of success to arrive at the claimed composition.
Although the Wang article indeed provides general guidance, the Wang
article also underscores the unpredictability of the undertaking. See
Ex. 1017, 2 (noting that “the structural differences among different proteins
are so significant that generalization of universal stabilization strategies has
not been successful”). Amgen asserts that “[j]ust because each new
formulation must be optimized on a case-by-case basis does not mean that
the formulation development is complex or not routine.” Pet. 29. Although
this is true to an extent, Amgen’s statement flips the burden on its head.
Amgen, as the Petitioner in these proceedings, bears the burden of proving
(at this stage) a reasonable likelihood of prevailing in its assertion that one or
more of the claims is unpatentable. Thus, as is relevant here, Amgen also
bears the burden of persuasion as to the teachings of the prior art as used to
bolster the rationale for combining the cited references. As far as the Wang
article is concerned, Amgen has not persuaded us that Wang provides a
reasonable expectation of success in making stable liquid antibody
formulations as a general matter. In contrast, we agree with AbbVie that, on
the whole, Wang suggests a high degree of unpredictability in the antibody
formulation art.
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d. Conclusion
On this record, Amgen has not persuaded us that “[t]he skilled person
would have had a reasonable expectation of success in applying the
formulations commercially available and taught in the literature to D2E7.”
Pet. 17.
2. Obviousness over Lam and Barrera
Amgen asserts that claims 1–8, 10–13, and 15–30 are unpatentable under
35 U.S.C. § 103(a) as having been obvious over Lam and Barrera. Pet. 17–
32. In support, Amgen relies on a Declaration of Theodore W. Randolph,
Ph.D. Ex. 1002. AbbVie counters that one of ordinary skill in the art would
not have combined the references as arranged in the challenged claims, nor
would have had a reasonable expectation of success in doing so. Prelim.
Resp. 31–40. AbbVie makes additional arguments with respect to the
dependent claims. See id. at 40–45.
a. Lam
Lam describes “a stable aqueous pharmaceutical formulation
comprising a therapeutically effective amount of an antibody not subjected
to prior lyophilization, a buffer maintaining the pH in the range from about
4.5 to about 6.0, a surfactant and a polyol.” Ex. 1003, 2:25–29. Lam’s
examples involve formulations comprising anti-CD18 and anti-CD20
antibodies. Id. at 24:28–40:26 (anti-CD18), 40:29–46:32 (anti-CD20). Lam
lists TNFα among various exemplary target antigens. See id. at 10:5–52
(specifically at 10:19).
b. Barrera
Barrera describes administering a single dose of D2E7 to study short-
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term effects in rheumatoid arthritis patients, using a preparation of “25
mg/ml D2E7 mAb in 1.2% mannitol, 0.12% citric acid, 0.02% sodium
citrate” in an intravenous infusion. Ex. 1004, 1, 3. Amgen characterizes
Barrera’s formulation as “short-term . . . appropriate for phase I clinical
trials.” Pet. 20. Barrera, however, does not expressly discuss the stability of
its formulation. Barrera also is silent as to pH and whether it includes a
surfactant. Id. at 21.
c. Analysis
Amgen argues that the combination of Lam and Barrera teaches each
of the limitations of the challenged claims, and that a skilled artisan would
have had reason to combine them in either of two ways. Both of these
combinations rely on the references themselves as well as on Amgen’s
characterization of the state of the art at the time of the invention.
Amgen’s first proposed rationale for combining Lam and Barrera is
that because “the Lam patent discloses every feature recited in the ’157
patent claims except the particular anti-TNFα antibody, D2E7,” Pet. 19, the
successful trial with “a short-term formulation” of D2E7 reported in Barrera
would have provided the skilled artisan a reason to “select D2E7 as the anti-
TNFα antibody included in the Lam formulation, resulting in the same
formulation recited in the challenged claims.” Id. at 20. Amgen maintains
that there would have been a reasonable expectation of success “because the
Lam patent taught formulations for anti-TNFα antibodies and D2E7 was an
anti-TNFα antibody, and because the art provided guidance on formulating
antibodies.” Id. at 20–21. In support of these statements, Amgen offers no
additional explanation in its brief, but rather relies on the Randolph
Declaration (Ex. 1002). See, e.g., id.
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Second, because Barrera “discloses everything recited in claim 1 of
the ’157 patent except the pH range and surfactant,” Amgen maintains that
the skilled artisan “would have been motivated to build off [Barrera’s]
success by designing a stable formulation for long-term storage” as shown in
Lam, including a pH between about 4.5 and 6.0 and a surfactant such as
polysorbate 80. Pet. 21–22. Amgen further maintains, and refers to the
Randolph Declaration in support, that “nearly all commercially available
protein formulations, including antibody formulations, had a pH within that
range,” and that “surfactants were known to prevent antibodies from
aggregating,” thus increasing formulation stability, and were included in
“many” commercial formulations. Id. at 21–22 (citing Ex. 1002).
Both of these arguments, as presented in the Petition, are too general
to be persuasive. As AbbVie points out, Lam primarily relates to anti-CD18
and anti-CD20 antibodies; TNFα is but one of many other antigens listed in
Lam, for which there is no additional disclosure regarding sequence or
formulation. Prelim. Resp. 31 (discussing Ex. 1003, 10:5–63, 24:29–46:20).
We are unpersuaded that the inclusion of TNFα in a laundry-list of untested
potential targets in Lam would have provided sufficient direction to one of
ordinary skill in the art to select TNFα, much less combine Lam’s
formulation with the teachings regarding D2E7 in Barrera, to achieve the
claimed formulation (whether starting with Lam, or starting with Barrera).
This is not a situation in which “there are a finite number of identified,
predictable solutions,” KSR, 550 U.S. at 421, such as might render
combining the references “obvious to try.” Instead, the proffered
combinations seem to be exercises in impermissible hindsight
reconstruction. See Grain Processing Corp. v. Am.-Maize Prods. Co., 840
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F.2d 902, 907 (Fed. Cir. 1988) (“Care must be taken to avoid hindsight
reconstruction by using ‘the patent in suit as a guide through the maze of
prior art references, combining the right references in the right way so as to
achieve the result of the claims in suit.’” (quoting Orthopedic Equip. Co. v.
United States, 702 F.2d 1005, 1012 (Fed. Cir. 1983))).
Nor is Amgen’s reliance on the general state of the art persuasive to
shore up either rationale for combining the references. As discussed supra
in § II.C.1, Amgen has not persuaded us that either the commercially
available antibody formulations (e.g., REMICADE™) or the
contemporaneous literature (e.g., the Wang article) would have provided the
skilled artisan with a reasonable expectation of success in formulating the
claimed invention. To the contrary, the difficulty of formulating liquid
antibodies as described in the Wang article and the dearth of high-
concentration, stable liquid antibody formulations available at the time of the
invention together appear to paint a prior art landscape of unpredictability.
d. Conclusion
Amgen has not persuaded us, on this record, that it is reasonably
likely to prevail in establishing that one of ordinary skill in the art would
have had a reasonable likelihood of success in combining Lam and
Barrera.11 Accordingly, on this record, we conclude that Amgen has not
established a reasonable likelihood of prevailing with respect to its challenge
of claims 1 and 24 based on Lam and Barrera.

11 Accordingly, we need not address the parties’ arguments with respect to
secondary considerations of non-obviousness. See Pet. 45–58; Prelim. Resp.
54–55.
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As the other challenged claims depend on claims 1 and 24,
respectively, and Amgen has not established a reasonable likelihood of
prevailing with respect to claims 1 and 24, it follows that Amgen likewise
has not established a reasonable likelihood of prevailing with respect to the
remaining challenged claims.
3. Obviousness over Salfeld and Heavner
Amgen also asserts that claims 1–8, 10–13, and 15–30 are
unpatentable under 35 U.S.C. § 103(a) as having been obvious over Salfeld
and Heavner, again relying on Dr. Randolph’s Declaration for support. Pet.
32–45. AbbVie disagrees. Prelim. Resp. 45–54.
a. Salfeld
As noted supra in § II.B.2, Salfeld discloses the D2E7 antibody. See
Ex. 1005, 2:59–67. Salfeld further teaches incorporating the antibody or
antibody-portions into pharmaceutical compositions, including, inter alia,
liquid dosage forms that may comprise buffers and/or surfactants. See id. at
20:59–21:49. Salfeld identifies a preferred antibody dosage range of 1–10
mg/kg. Id. at 23:13–15. Salfeld does not expressly disclose a pH range, but
includes “phosphate buffered saline” among other pharmaceutically-
acceptable carriers. Id. at 21:2.
b. Heavner
Heavner teaches anti-TNF antibodies and therapeutic formulations
thereof. Ex. 1006, at [57]. The “TNV” antibodies and fragments thereof
specifically disclosed in Heavner differ in sequence from D2E7. See Pet.
42; Prelim. Resp. 46; see also Ex. 1006 (sequence listing). Heavner’s
sprayer-suitable aqueous formulations include antibody concentrations in the
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range of about 0.1 mg/mL to about 100 mg/mL, and can include a surfactant,
a buffer, and a polyol. Ex. 1006, 44:43–61. Heavner discloses a “wide
range of pHs,” from about 4 to about 10, and preferably between about 6.8
and about 7.8. Id. at 32:28–33.
c. Analysis
Amgen argues that Salfeld alone expressly or implicitly (as to
concentration and pH) discloses all the limitations of the challenged claims,
and that even if Salfeld does not teach the claimed antibody concentration
and pH ranges, Heavner does. Pet. 33–35. AbbVie disputes the alleged
implicit teachings of Salfeld, Prelim. Resp. 48–49, and argues more
generally that “Heavner or Salfeld, alone or in combination, do not disclose
any specific antibody formulation at all, but only broad sweeping lists of
possible components leading to an endless number of possible
combinations,” id. at 47.
i. Salfeld: Antibody Concentration
In arguing that the asserted combination teaches the claimed
concentration, Amgen refers to a 1 mg/kg “effective dose” (instead of the
disclosed 1–10 mg/kg preferred range), presumes an average patient size of
70 kg and a “practical injection volume for a subcutaneous administration”
of about 0.3–1.5 ml, to arrive at an antibody concentration of about 50–90
mg/ml. Pet. 34 (citing Ex. 1002 ¶¶ 52, 119; Ex. 1005, 23:12–15).
We are not persuaded, on this record, that Salfeld’s dose information
teaches an antibody concentration range within the scope of claims 1 and 24.
At the very least, Amgen’s calculations make too many assumptions and are
not explained in sufficient detail for us to rely on them. As AbbVie notes,
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one factor that could skew Amgen’s concentration calculations is whether a
single-dose or a multi-dose therapy is assumed. See Prelim. Resp. 48.
Because Heavner expressly teaches the claimed antibody concentration
range, however, this deficiency in Salfeld is not dispositive of this asserted
ground of unpatentability.
ii. Salfeld: pH Range
In arguing that the asserted combination teaches the claimed pH
range, Amgen asserts that Salfeld teaches phosphate buffered saline, which
“buffers at a pH that falls within the claimed range,” and that Salfeld’s
“physiologically compatible” carrier likewise would have indicated a pH
between 4 and 8 to one of ordinary skill in the art. Pet. 34–35 (citing Ex.
1002 ¶ 118). AbbVie responds that this analysis amounts to “making
conclusory statements” (Prelim. Resp. 48–49), but we find Amgen’s position
to be sufficiently persuasive, on this record, regarding an implicit teaching of
pH within the claimed range.
iii. Combination of Salfeld and Heavner
According to Amgen, a skilled artisan would have had reason to
combine Salfeld and Heavner “because both focus on anti-TNFα antibodies,
both focus on IgG antibodies, and both teach how to formulate these
antibodies.” Pet. 35 (citing Ex. 1002). Amgen notes that the parameters
taught in Heavner are “consistent” with the state of the antibody formulation
art. Id. Again, in support of its rationale to combine, Amgen offers little
additional explanation in its brief, but rather relies on the Randolph
Declaration (Ex. 1002).
AbbVie responds that Salfeld provides wide-ranging formulation
information “merely as a general approach” and offers no stability data.
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Prelim. Resp. 46–47. Further, AbbVie contends that Heavner provides only
“bulk recitations of potential formulation ingredients” covering “virtually
every imaginable route of administration,” and “offers no guidance at all on
how to actually select from this massive number of possible combinations to
prepare any antibody—much less a D2E7 antibody—as a stable liquid
antibody formulation.” Id. at 46 (discussing Ex. 1006, 42:59–48:4).
Although Heavner’s antibody concentration range overlaps with that
of claims 1 and 24, we agree with AbbVie that the lack of teachings
regarding specific pharmaceutical formulations in Heavner would have left
one of ordinary skill in the art “with an utter lack of guidance as to which of
the many combinations would work.” Prelim. Resp. 46; see generally Ex.
1006, 28:30–39:28 (compositions, formulations, and therapeutic
applications); 71:5–74:17 (in vivo murine studies). And, as with the other
asserted ground, see supra § II.C.2.c, Amgen’s proffered rationale for
combining Salfeld and Heavner finds no additional support in the general
state of the art at the time of the invention, as we are unconvinced that the art
was sufficiently predictable to offer the ordinarily skilled artisan a
reasonable chance of success in combining the references as claimed.
d. Conclusion
Amgen has not persuaded us, on this record, that it is reasonably
likely to prevail in establishing that a skilled artisan would have had a
reasonable likelihood of success in combining Salfeld and Heavner to arrive
at the claimed antibody formulation.12 Accordingly, on this record, we

12 As with the challenge based on Lam and Barrera, see supra § II.C.2.d, our
conclusion here obviates the need to analyze secondary considerations of
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conclude that Amgen has not established a reasonable likelihood of
prevailing with respect to its challenge of claims 1 and 24 on this basis. We
are likewise unpersuaded of Amgen’s likelihood of prevailing with respect
to the other challenged claims, which depend on claims 1 and 24.
III. CONCLUSION
For the foregoing reasons, we determine, based on the Petition and the
accompanying evidence, that Amgen has not shown a reasonable likelihood
of prevailing on any of its challenges to claims 1–8, 10–13, and 15–30 of the
’157 patent.
IV. ORDER
For the foregoing reasons, it is
ORDERED that the Petition is denied, and no trial is instituted.

nonobviousness.
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PETITIONER:

Sandip H. Patel
Li-Hsien Rin-Laures
Marshall, Gerstein & Borun LLP
SPatel@marshallip.com
LRinLaures@marshallip.com

PATENT OWNER:
David P. Frazier
Robert Steinberg
Michael A. Morin
Latham & Watkins LLP
david.frazier@lw.com
bob.steinberg@lw.com
michael.morin@lw.com
Tamera M. Weisser
J. Patrick Elsevier
Anthony M. Insogna
Jones Day
tweisser@jonesday.com
jpelsevier@jonesday.com
aminsogna@jonesday.com