Sandoz Inc. v. AbbVie Biotechnology Ltd.

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Trials@uspto.gov
Entered:
Paper No. 11
571-272-7822 	June 5, 2018
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
SANDOZ INC.,
Petitioner,
v.
ABBVIE BIOTECHNOLOGY LTD.,
Patent Owner.
Case IPR2018-00156
Patent 9,187,559 B2
Before SUSAN L. C. MITCHELL, TINA E. HULSE, and
MICHELLE N. ANKENBRAND, Administrative Patent Judges.
ANKENBRAND, Administrative Patent Judge.
DECISION
Denying Institution of Inter Partes Review
35 U.S.C. § 314(a)
Dismissing as Moot Petitioner’s Motions for Pro Hac Vice Admission
37 C.F.R. § 42.10

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I. 	INTRODUCTION
Sandoz Inc. (“Petitioner”) requests an inter partes review of claims 1–
30 of U.S. Patent No. 9,187,559 B2 (“the ’559 patent,” Ex. 1001). Paper 1
(“Pet.”). AbbVie Biotechnology Ltd. (“Patent Owner”) filed a Preliminary
Response. Paper 10 (“Prelim. Resp.”).
We have authority to determine whether to institute an inter partes
review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
inter partes review “unless . . . there is a reasonable likelihood that the
petitioner would prevail with respect to at least 1 of the claims challenged in
the petition.” 35 U.S.C. § 314(a). Applying that standard, and upon
consideration of the information presented in the Petition and the
Preliminary Response, we deny the Petition and do not institute an inter
partes review.1
II. 	BACKGROUND
Related Matters
The parties do not identify any litigation, interference proceedings, or
reexamination proceedings involving the ’559 patent. See Pet. 5–7; Paper 5,
1. Petitioner identifies litigation involving two patents that Petitioner
contends are related to the ’559 patent because all three patents claim
priority to the same application. Pet. 5 (identifying AbbVie Inc. v. Amgen
Inc., No. 1:16-cv-00666-MSG (D. Del. Aug. 4, 2016)).
Petitioner further identifies several inter partes review proceedings in
which the Board previously found claims of certain of Patent Owner’s
1 Because we deny the Petition, we dismiss as moot Petitioner’s pending
motions for Daniel L. Reisner and Abigail Langsam to appear pro hac vice
in this proceeding (Papers 3 and 7, respectively).
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patents unpatentable, but acknowledges that those patents and the ’559
patent do not claim priority to any of the same applications. Pet. 5–7.
Petitioner explains that it previously filed additional petitions requesting an
inter partes review of certain other patents assigned to Patent Owner:
IPR2017-01823 (challenging U.S. Patent No. 8,802,100), IPR2017-01824
(challenging U.S. Patent No. 9,512,216), IPR2017-01987 (challenging
U.S. Patent No. 8,911,737), IPR2017-01988 (challenging U.S. Patent No.
8,974,790), IPR2017-02105 (challenging U.S. Patent No. 9,090,689),
IPR2017-02106 (challenging U.S. Patent No. 9,067,992), and IPR2018-
00002 (challenging U.S. Patent No. 9,512,216). Id. at 7. According to
Petitioner some of those patents and the ’559 patent claim priority to the
same applications. Id.
Finally, Patent Owner identifies a number of United States patent
applications and patents that claim the benefit of priority to the ’559 patent,
or to which the ’559 patent claims the benefit of priority. Paper 4, 1–2.
The ’559 Patent
The ’559 patent, titled “Multiple-Variable Dose Regimen for Treating
Idiopathic Inflammatory Bowel Disease,” issued on November 17, 2015.
Ex. 1001, [45], [54]. The ’559 patent relates to methods for treating tumor
necrosis factor α (“TNFα”) related disorders, including Crohn’s disease,
comprising administering a TNFα inhibitor in an induction or loading phase,
followed by administering the inhibitor in a maintenance or treatment phase,
wherein a higher dose is administered in the induction phase. Ex. 1001,
Abstract, 28:64–66. In one embodiment, the TNFα inhibitor D2E7, or
adalimumab, is administered as a multiple-variable dose regimen comprising
an induction phase to induce remission of Crohn’s disease and a treatment
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phase. Id. at 4:47–53. According to the ’559 patent, an “induction dose” or
“loading dose” is the “first dose of TNFα inhibitor, which is larger in
comparison to the maintenance or treatment dose.” Id. at 11:62–65. The
induction dose can be administered as a single dose or a set of doses, “is
often used to bring the drug in the body to a steady state amount[,] and may
be used to . . . achieve maintenance drug levels quickly.” Id. at 11:65–12:1.
The “treatment dose” or “maintenance dose,” as described in the ’559 patent,
is “the amount of TNFα inhibitor taken . . . to maintain or continue a desired
therapeutic effect.” Id. at 12:16–18. Like the induction dose, the
maintenance or treatment dose can be administered as a single dose or a set
of doses. Id. at 12:19–20. Treatment doses, however, “are smaller than the
induction dose.” Id. at 12:23.
The ’559 patent describes several efficacy studies involving the
multiple-variable dose regimen, including studies in which patients with
Crohn’s disease received multiple-variable doses of adalimumab. Id. at
73:40–76:20. In a first study in patients with Crohn’s disease, “multiple,
variable doses of [adalimumab] significantly increased the frequency of
remission of disease in Crohn’s disease subjects.” Id. at 75:9–11. In a
second study involving patients with Crohn’s disease “who had previously
received and responded to infliximab [Remicade], but who no longer had a
sustained response to or could not tolerate infliximab[,]” the multiple-
variable dose treatment “was well tolerated and was clinically beneficial.”
Id. at 76:16–20.
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Illustrative Claim
Of the challenged claims, claims 1 and 4 are independent. Claim 1 is
illustrative of the claimed subject matter and recites:
1. 	A multiple-variable dose method for treating idiopathic
inflammatory bowel disease in a human subject in need thereof,
comprising subcutaneously administering to the human subject:
a first dose of 160 mg of adalimumab administered to the
human subject within a day; and
a second dose of 80 mg of adalimumab administered to the
human subject within a day, wherein the second does is
administered two weeks following administration of the first
dose.
Ex. 1001, 93:56–65.
The Asserted Ground of Unpatentability
Petitioner asserts claims 1–30 of the ’559 patent are unpatentable
under 35 U.S.C. § 103(a) over the combination of 2003 Humira Package
Insert2 and WO ’330,3 in view of Goodman & Gilman,4 2002 Remicade
Package Insert,5 and Hanauer.6 Petitioner supports its assertions with the
testimony of Ingvar Bjarnason, M.D. (Ex. 1002) and John Posner, Ph.D.
(Ex. 1025).
2 Humira (adalimumab) Label (Abbott Laboratories) (Ex. 1026).
3 WO 02/100330 A2, published December 19, 2002 (Ex. 1020).
4 GOODMAN & GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS
25–27 (Joel G. Hardman et al. eds., 10th ed. 2001) (Ex. 1030).
5 PHYSICIANS’ DESK REFERENCE, Remicade entry 1178–1182 (57th ed. 2003)
(Ex. 1068).
6 Stephen B. Hanauer & Themistocles Dassopoulos, Evolving Treatment
Strategies for Inflammatory Bowel Disease, 52 ANNUAL REVIEW MED. 299–
318 (2001) (Ex. 1027).
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III. 	ANALYSIS
We organize our analysis into four sections. First, we address the
level of ordinary skill in the art. Second, we turn to claim construction.
Third, we provide an overview of the asserted references. Fourth, taking
account of the information presented, we consider whether Petitioner’s
asserted ground meets the threshold showing for instituting an inter partes
review based on obviousness.
Level of Ordinary Skill in the Art
We consider the asserted ground of unpatentability in view of the
understanding of a person of ordinary skill in the art. Petitioner and its
experts contend that, as of April 9, 2004 (and one year prior), a person of
ordinary skill in the art would have the skill sets of a team comprising a
pharmacologist having experience with TNFα inhibitors and a physician
treating patients for Inflammatory Bowel Disease (IBD), including Crohn’s
disease and ulcerative colitis. Pet. 13; Ex. 1002 ¶¶ 38–39; Ex. 1025 ¶¶ 34–
35. Dr. Bjarnason testifies that the physician on the team “would have an
M.D. and at least three years’ post-residency experience treating patients
having IBD.” Ex. 1002 ¶ 40. Dr. Posner testifies that the pharmacologist on
the team “would have a Ph.D. in pharmacology, pharmacokinetics, or a
related field and at least three years of experience working on the
pharmacokinetics/pharmacodynamics of biologic drugs.” Ex. 1025 ¶ 36.
At this stage of the proceeding, Patent Owner does not dispute
Petitioner’s proposed level of ordinary skill, which we adopt for purposes of
this decision. See generally Prelim. Resp. We also find, for purposes of this
decision, that the prior art itself is sufficient to demonstrate the level of
ordinary skill in the art at the time of the invention. See Okajima v.
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Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art, itself, can
reflect the appropriate level of ordinary skill in art). Further, based on
Dr. Bjarnason’s and Dr. Posner’s statements of qualifications and curriculum
vitae, for the purposes of this decision, we find that they are qualified to
opine from the perspective of a person of ordinary skill in the art at the time
of the invention. See Ex. 1002 ¶¶ 3–8 (Dr. Bjarnason’s qualifications),
App’x A (Dr. Bjarnason’s curriculum vitae); Ex. 1025 ¶¶ 3–14 (Dr. Posner’s
qualifications), App’x A (Dr. Posner’s curriculum vitae).
Claim Construction
The Board interprets claims in an unexpired patent using the “broadest
reasonable construction in light of the specification of the patent.” 37 C.F.R.
§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
(2016). “Under a broadest reasonable interpretation, words of the claim
must be given their plain meaning, unless such meaning is inconsistent with
the specification and prosecution history.” Trivascular, Inc. v. Samuels, 812
F.3d 1056, 1062 (Fed. Cir. 2016).
Petitioner “does not assert that any special meanings apply to claim
terms in the ’559 patent,” but does contend that the preambles to
independent claims 1 and 4 are non-limiting statements of intended use.
Pet. 18. Petitioner argues, alternatively, that if we conclude the preambles
should be construed, “the term ‘treating’ in claims 1 and 4 should be given
its broadest reasonable interpretation of ‘reducing the signs and/or symptoms
of idiopathic inflammatory bowel disease,” without requiring any specific
level of therapeutic effect. Id. Patent Owner disagrees (Prelim. Resp. 25–
26), but asserts that we need not determine whether the preambles are
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limiting to resolve the parties’ dispute at this stage of the proceeding.
Prelim. Resp. 24–25.
We agree with Patent Owner that the parties’ dispute at this stage of
the proceeding does not turn on whether the preambles are limiting or, if
assumed limiting, the proper construction of the preambles. Thus, we
determine that no claim term requires construction for purposes of this
decision. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
(Fed. Cir. 1999) (“only those terms need be construed that are in
controversy, and only to the extent necessary to resolve the controversy”).
Asserted References
Before turning to Petitioner’s asserted ground, we provide a brief
summary of the asserted references. First, however, we address a threshold
argument Patent Owner raises with respect to whether Petitioner shows
sufficiently that 2003 Humira Package Insert is a prior art printed
publication.
1. 2003 Humira Package Insert (Ex. 1026) as “Printed Publication”
Prior Art Under 35 U.S.C. § 102(b)
Under 35 U.S.C. § 311(b), a petitioner in an inter partes review may
only challenge the claims of a patent based on “prior art consisting of patents
or printed publications.” Petitioner has the initial burden of production to
establish that there is prior art that renders the challenged claims
unpatentable. See Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800
F.3d 1375, 1379 (Fed. Cir. 2015) (citing Tech. Licensing Corp. v. Videotek,
Inc., 545 F.3d 1316, 1327 (Fed. Cir. 2008)). For institution purposes,
Petitioner has the burden to establish a reasonable likelihood that it will
prevail on the merits, which includes, inter alia, making a sufficient showing
in the Petition that 2003 Humira Package Insert qualifies as a “printed
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publication” within the meaning of 35 U.S.C. §§ 102 and 311(b). 35 U.S.C.
§ 314(a); see 37 C.F.R. § 42.108(c); see also, e.g., Symantec Corp. v. Trs. of
Columbia Univ., Case IPR2015-00371, slip op. at 5, 9 (PTAB June 17,
2015) (Paper 13) (denying institution where the Petition failed to include
discussion or cite to evidence sufficient to show that the asserted reference
was a prior art printed publication). Petitioner is not required at this stage of
the proceeding to establish by a preponderance of the evidence that 2003
Humira Package Insert was publicly accessible before the effective filing
date of the ’559 patent7 and, therefore, qualifies as a printed publication. To
meet the initial burden of production under Dynamic Drinkware, however,
the Petition must include argument and direct us to evidence sufficient to
show that Petitioner would establish such public accessibility by a
preponderance of the evidence during the course of the trial.
Whether a reference qualifies as a “printed publication” involves a
case-by-case inquiry into the facts and circumstances surrounding the
reference’s disclosure to members of the public. In re Klopfenstein, 380
F.3d 1345, 1350 (Fed. Cir. 2004). The key inquiry is whether the reference
was made “sufficiently accessible to the public interested in the art” before
the effective filing date. In re Lister, 583 F.3d 1307, 1311 (Fed. Cir. 2009)
(quoting In re Cronyn, 890 F.2d 1158, 1160 (Fed. Cir. 1989)). A reference
is considered “publicly accessible” upon a satisfactory showing that the
document has been “disseminated or otherwise made available to the extent
that persons interested and ordinarily skilled in the subject matter or art
exercising reasonable diligence[] can locate it.” Kyocera Wireless Corp. v.
7 For purposes of the Petition, Petitioner asserts that the effective filing date
of the challenged claims is April 9, 2004. See Pet. 8.
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ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008) (citation and internal quotation
marks omitted). A party seeking to introduce a reference, therefore, “should
produce sufficient proof of its dissemination or that it has otherwise been
available and accessible to persons concerned with the art to which the
document relates and thus most likely to avail themselves of its contents.”
In re Wyer, 655 F.2d 221, 227 (CCPA 1981) (quoting Philips Elec. &
Pharm. Indus. Corp. v. Thermal & Elecs. Indus., Inc., 450 F.2d 1164, 1171
(3d Cir. 1971)).
Petitioner identifies 2003 Humira Package Insert as prior art under
§ 102(b). Pet. 10 (Table). Petitioner asserts that 2003 Humira Package
Insert was publicly available on the Food and Drug Administration’s
(“FDA”) website “no later than March 31, 2003[,] as demonstrated by the
Internet Archive and the Wayback Machine service which it provides.” Id.
As support, Petitioner provides a screenshot of the webpage
https://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_02_B-Abbott-
Humira Prescribing Info.pdf, as shown on the Internet Archive for March
31, 2003 (Ex. 1031) and the September 27, 2017, Affidavit of Christopher
Butler, Office Manager of the Internet Archive (“Butler Affidavit,”
Ex. 1032), which includes as Exhibit A “true and accurate copies of
printouts of the Internet Archive’s records of the HTML files for the URLs
and the dates specified in the footer of the printout.” Id. ¶ 6, Ex. A.
Petitioner also directs us to Dr. Bjarnason’s testimony regarding the
accessibility of drug product inserts (or labels) on the FDA website. Pet. 11
(citing Ex. 1002 ¶¶ 10, 77).
Patent Owner responds that Petitioner fails to make a threshold
showing that 2003 Humira Package Insert was available as a printed
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publication before the priority date of the ’559 patent, because Petitioner
provides insufficient evidence that the insert was publicly accessible in
March 2003. Prelim. Resp. 53–56. Patent Owner acknowledges that the
screenshot of 2003 Humira Package Insert from the Wayback Machine and
the Butler Affidavit “establish the existence of the Humira[] Label on an
FDA website on March 31, 2003.” Prelim. Resp. 53–54. Patent Owner
argues, however, that “[e]xistence on an FDA website . . . is insufficient to
establish public accessibility.” Id. at 54 (citing Celltrion, LLC v. Biogen,
Inc., Case IPR2017-01230, slip op. at 11–14 (PTAB Oct. 12, 2017) (Paper
10)). Patent Owner further argues that Petitioner fails to establish whether
the FDA website indexed drug information in 2003 and how such
information would have been categorized, whether the FDA website had a
search capability in 2003, what search would have identified 2003 Humira
Package Insert, and whether the FDA website had “any ‘tools for customary
and meaningful research’ in 2003.” Id. at 55 (quoting SRI Int’l, Inc. v.
Internet Sec. Sys., Inc., 511 F.3d 1186, 1194–97 (Fed. Cir. 2008)).
Although we agree with Patent Owner that evidence of indexing is
probative of public accessibility, such evidence is not necessarily required in
all cases. See Voter Verified, Inc. v. Premier Election Sols., Inc., 698 F.3d
1374, 1381 (Fed. Cir. 2012); Klopfenstein, 380 F.3d at 1350 (“distribution
and indexing are not the only factors to be considered in a § 102(b) ‘printed
publication’ inquiry”). Rather, absent evidence of indexing, testimony
indicating that the particular online publication or website on which the
reference was published was well-known to the community interested in the
subject matter of the reference, and that, upon accessing the website, those
interested would have found the reference using the website’s own search
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functions can support the ultimate determination that a given reference was
publicly accessible. Id. at 1380–81. If such evidence is sufficient to
establish public accessibility, then the same evidence necessarily is
sufficient to satisfy the threshold showing of public accessibility for
purposes of institution. Indeed, when determining whether a petitioner’s
arguments and evidence are sufficient for purposes of institution we are
cognizant that:
[t]he reasonable likelihood standard for instituting inter partes
review is . . . not a lower standard of proof than a preponderance
of 	the 	evidence, 	but 	instead 	asks 	whether 	the 	same
preponderance standard is reasonably likely to be met at a later
time. 	We must assess the persuasiveness of the petitioner’s
evidence while “recognizing that [we are] doing so without all
evidence that may come out at trial.” As such, we have required
only a “threshold showing” of public availability in order to
institute trial. When petitioners have not come forward with any
credible evidence establishing a key aspect of public availability,
we have denied institution.
ServiceNow, Inc. v. Hewlett-Packard Co., Case IPR2015-00707, slip op. at 2
(PTAB Aug. 26, 2015) (Paper 12) (Crumbley, APJ, dissenting).
Here, Petitioner directs us to not only the Wayback Machine
screenshot and Butler Affidavit, which evidence that 2003 Humira Package
Insert was available on the FDA website as of March 31, 2003, but also to
Dr. Bjarnason’s testimony regarding how persons interested and ordinarily
skilled in the art exercising reasonable diligence could have located 2003
Humira Package Insert on the FDA website. In particular, Dr. Bjarnason
testifies that: (1) 2003 Humira Package Insert is a label for a commercially
marketed prescription drug (Ex. 1002 ¶ 10); (2) physicians would have
known in 2003 that labels for drugs they prescribe were available for review
from a number of sources including the FDA website (id.); (3) physicians
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could and did access such labels from the FDA website, as he “ha[s] done
personally many times” (id.); and (4) a person interested in the art “would
have accessed the FDA’s website and easily found the 2003 Humira[]
Package Insert using that website’s own search capabilities, as physicians
regularly did” (id. ¶ 77). At this stage of the proceeding, we credit
Dr. Bjarnason’s testimony, which is unrebutted and based on his personal
experience with accessing labels from the FDA website.8 Thus, we find that
Petitioner provides adequate evidence to make a threshold showing that
2003 Humira Package Insert was accessible to the extent required to
establish it as a “printed publication” for purposes of institution.
8 Patent Owner contends that Dr. Bjarnason’s testimony is entitled to no
weight because Dr. Bjarnason fails to cite objective evidence to support his
opinions, establish personal knowledge of 2003 Humira Package Insert’s
public availability on the FDA website, or cite any evidence establishing that
2003 Humira Package insert was actually disseminated to the interested
public. Prelim. Resp. 54. Initially, we note that actual dissemination is not
required to show that a reference was publicly accessible. Kyocera, 545
F.3d at 1350 (A reference is considered “publicly accessible” upon a
satisfactory showing that the document has been “disseminated or otherwise
made available to the extent that persons interested and ordinarily skilled in
the subject matter or art exercising reasonable diligence[] can locate it.”
(emphasis added) (citation and internal quotation marks omitted)). Further,
although not based on personal experience with 2003 Humira Package
Insert, we find that Dr. Bjarnason’s testimony is evidence of the methods
those interested in the art generally would have used to search and locate
labels such as 2003 Humira Package insert on the FDA website—a well-
known government website that was open and accessible to the public in
March 2003.
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2. 2003 Humira Package Insert (Ex. 1026)9
2003 Humira Package Insert provides that the recommended dose of
Humira for adult patients with rheumatoid arthritis (“RA”) is “40 mg
administered every other week as a subcutaneous injection.” Ex. 1026, 9.10
2003 Humira Package Insert also discloses that although the maximum
tolerated dose of Humira “has not been established in humans[,] [m]ultiple
doses up to 10 mg/kg have been administered to patients in clinical trials
without evidence of dose-limiting toxicities.” Id.
3. WO ’330 (Ex. 1020)
WO ’330 discloses “[m]ethods of treating disorders in which TNFα
activity is detrimental via biweekly, subcutaneous administration of human
antibodies, preferably recombinant human antibodies.” Ex. 1020, Abstract.
WO ’330 describes D2E7 (adalimumab) as “[t]he most preferred
recombinant antibody of the invention.” Id. at 4:27. WO ’330 identifies a
number of disorders in which TNFα is detrimental, including RA and IBD
(including Crohn’s disease and ulcerative colitis), and states that the
antibodies of the invention can be used to treat the identified disorders. See
id. at 28:35–38, 29:21–25, 29:33–35, 31:19–26. According to WO ’330,
“[a]n exemplary, non-limiting range for a therapeutically or prophylactically
effective amount of an antibody . . . of the invention is 10-100 mg, more
preferably 20-80 mg and most preferably about 40 mg.” Id. at 26:37–39.
9 Unless otherwise noted, we cite to the original page numbers of each
exhibit, not the page numbers that Petitioner added to the particular exhibit.
10 Because 2003 Humira Package Insert does not include page numbers, we
cite to the page numbers that Petitioner added to the exhibit.
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4. Goodman & Gilman (Ex. 1030)
Goodman & Gilman describes the concepts of loading or induction
doses and maintenance or treatment doses. Maintenance dosing involves,
inter alia, a series of repetitive doses given “to maintain a steady-state
concentration of drug associated with the therapeutic window.” Ex. 1030,
26. A loading dose “is one or a series of doses that may be given at the
onset of therapy with the aim of achieving the target concentration rapidly.”
Id. at 27.
Goodman & Gilman provides an equation for calculating the
appropriate magnitude of the loading dose:
Loading dose = target Cp x (Vss/F)
Id. In the equation, target Cp refers to the target plasma concentration, Vss
refers to the distribution volume at steady-state, and F refers to the
bioavailability of the drug. Id. at 22–24, 27. Goodman & Gilman further
discloses that a “loading dose may be desirable if the time required to attain
steady state by the administration of a drug at a constant rate is long relative
to the temporal demands of the condition being treated.” Id. at 27. The use
of a loading dose, however, “also has significant disadvantages” with respect
to toxicity and it is “usually advisable to divide the loading dose into a
number of smaller fractional doses that are administered over a period of
time.” Id.
5. 2002 Remicade Package Insert (Ex. 1068)
2002 Remicade Package Insert discloses the chimeric antibody
infliximab for “inducing and maintaining clinical remission in patients with
moderately active to severe Crohn’s disease.” Ex. 1068, 1179. The
recommended dose is “5 mg/kg given as an induction regimen at 0, 2 and 6
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weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks
thereafter.” Id. at 1181.
6. Hanauer (Ex. 1027)
Hanauer describes “approaches to the medical therapy of ulcerative
colitis and Crohn’s disease” (collectively, IBD). Ex. 1027, 299 (Abstract).
Hanauer explains that treatment for IBD “consists of inducing remission of
active disease and then maintaining remission to prevent relapse.” Id. at
300. According to Hanauer, many conventional approaches to treating IBD
required certain drugs for inducing remission and different drugs for
maintaining remission. See, e.g., id. at 300–301 (Tables 1 and 2 showing
different therapies for inducing and maintaining remission of IBD), 303
(describing corticosteroids as “the current mainstay of inductive therapy” for
IBD, but “ineffective as maintenance therapies”), 304 (explaining that 6-
mercaptopurine and azathioprine “are effective maintenance therapies” for
IBD).
“A series of pivotal clinical trials[,]” however, “have begun to define
a role for infliximab as both an inductive and maintenance agent for
[Crohn’s disease].” Id. at 306. In one study, 108 patients received a single
intravenous infusion of placebo or infliximab at doses of 5, 10, or 20 mg/kg.
Id. Hanauer reports that 33% of the infliximab-treated patients achieved
clinical remission versus 4% of the placebo-treated patients at 4 weeks. Id.
“The trial confirmed the efficacy of infliximab in the treatment of moderate
to severe [Crohn’s disease], with the 5 mg/kg dose showing the best results.”
Id. at 307.
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Asserted Obviousness over 2003 Humira Package Insert and WO
’330, in view of Goodman & Gilman, 2002 Remicade Package Insert,
and Hanauer
Petitioner asserts that claims 1–30 of the ’559 patent are unpatentable
under 35 U.S.C. § 103(a) because the subject matter of those claims would
have been obvious over the combination of 2003 Humira Package Insert and
WO ’330, in view of Goodman & Gilman, 2002 Remicade Package Insert,
and Hanauer. Pet. 20–24, 35–50, 55–59 (claim charts). Petitioner argues
that the asserted references expressly disclose all elements of independent
claims 1 and 4, except “the precise 160 mg/80 mg induction dosing regimen
required by the claims.” Pet. 20. In particular, Petitioner contends that 2003
Humira Package insert discloses that the FDA-approved method for
maintaining remission of RA symptoms was the subcutaneous injection of
40 mg adalimumab every other week, which WO ’330 also described as the
preferred dosing regimen for treating IBD. Id. at 21, 25. Thus, Petitioner
argues that a person of ordinary skill in the art would have reasonably
expected a 40 mg subcutaneous injection of adalimumab every other week to
maintain remission of IBD symptoms. Id. at 21, 24 (citing Ex. 1002 ¶ 80;
Ex. 1026, 3, 9), 26 (citing Ex. 1002 ¶ 90).
Petitioner further contends that Hanauer and 2002 Remicade Package
Insert teach treating IBD by first inducing remission of symptoms, and then
administering therapy to maintain remission. Id. at 21, 27–29 (citing
Ex. 1002 ¶¶ 62, 66; Ex. 1027, 300–301; Ex. 1068, 1179). In that regard,
Petitioner directs us to 2002 Remicade Package Insert’s approved dosing
regimen of administering 5 mg/kg infliximab at weeks 0, 2, and 6 for
inducing Crohn’s disease remission, followed by 5 mg/kg every 8 weeks for
maintaining remission. Id. at 29 (citing Ex. 1068, 1181). Petitioner also
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points to knowledge in the art that higher induction doses could be used for
other disorders. Id. at 30–32. According to Petitioner, such prior art
disclosures would have led a person of ordinary skill in the art to design an
appropriate IBD induction dosing regimen and would have provided a
reasonable expectation that “an adalimumab dosing regimen greater than the
40 mg [every other week] maintenance dose would induce IBD remission.”
Id. at 21, 36–37.
To arrive at an adalimumab induction dosing regimen, Petitioner first
points to WO ’330’s disclosure of using higher doses of adalimumab to treat
TNFα disorders, including 80 mg every other week. Id. at 22, 37 (citing
Ex. 1020, 3:34–4:2, 26:37–39, 33:14–34:26). Petitioner asserts that an
ordinarily skilled artisan would have reasonably expected an 80 mg every
other week dosing regimen to provide some efficacy in inducing IBD
remission, i.e., the 80 mg every other week would have served as a good
basis for selecting an IBD induction or loading dose. Id. at 22 (citing
Ex. 1002 ¶ 95), 37, 39. Petitioner further asserts that the skilled artisan
would have been led to modify an 80 mg every other week induction dose
into “the claimed 160 mg/80 mg dosing regimen” based on a number of
teachings in the prior art, including: (1) the knowledge that IBD is a
debilitating and potentially life-threatening disease; (2) administering
infliximab using an induction regimen achieved remission of Crohn’s
disease in 4 weeks; (3) using an 80 mg every other week induction regimen
would require 10 weeks to reach steady state blood levels and treating the
severe symptoms of IBD required more rapid relief; (4) well-known dosing
rules and equations and the known pharmacokinetics of adalimumab dictated
that a 160 mg dose would achieve the desired blood levels more rapidly than
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an 80 mg every other week dose; and (5) an 80 mg dose administered
2 weeks after the 160 mg dose would maintain heightened blood levels for 4
weeks, at which time the 40 mg every other week maintenance dosing would
begin. Id. at 22–23 (citing id. §§ VI.B.4–VI.B.5, VI.C.1; Ex. 1025 ¶¶ 49,
62, 82–83; Ex. 1026, 2; Ex. 1027, 306), 32–33, 38–42. More specifically,
Petitioner contends that the skilled artisan would have used 80 mg every
other week “as the basis for an IBD induction therapy” based on the prior art
disclosures, and would have doubled that basis dose in accordance with the
known general rule for determining an appropriate induction dose and
Gilman & Goodman’s equation. Id. at 39–40 (citing Ex. 1003, 352–353;
Ex. 1029, 285; Ex. 1025 ¶ 50).
Having considered the arguments and evidence, we are not persuaded
that Petitioner shows a reasonable likelihood of prevailing in its assertion
that the 160 mg/80 mg dosing regimen that the claims of ’559 patent require
would have been obvious over the cited prior art. Although we agree with
Petitioner that it was known in the art to use a loading or induction dose for
drugs with a long half-life, we determine that Petitioner does not show
sufficiently on this record that an ordinarily skilled artisan—without the
benefit of hindsight—would have had a reason to use 160 mg as an
induction dose, or would have had a reason to select an intermediate dose to
serve as a “basis” or “baseline” for calculating an induction dose.
As Petitioner acknowledges, the prior art discloses that, as a general
rule, the loading dose of a drug is twice the size of the maintenance dose, if
the maintenance dosing interval corresponds to the biological half-life of the
drug. Pet. 34–35, 40 (applying the loading dose general rule set forth in the
prior art); Ex 1003, 353 (Table 28-1) (“If the dosing interval . . . is equal to
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or somewhat shorter than the elimination half-life . . ., then the dose ratio [of
loading dose to maintenance dose] should be 2:1”); Ex. 1025 ¶ 50
(Dr. Posner’s testimony regarding the general rule); Ex. 1029, 285.
According to Petitioner, such a loading dose allows a patient to achieve
blood levels that are close to steady-state from the induction dose alone. Pet.
35 (citing Ex. 1025 ¶¶ 50, 72; Ex. 1029, 285 (Fig. 19.8)).
Petitioner consistently identifies 40 mg every other week as the
maintenance dosing regimen for adalimumab. See, e.g., Pet. 3, 20–21, 24–
25, 36–37. Likewise, Dr. Bjarnason testifies that a person of ordinary skill
in the art “would have understood that [2003 Humira Package Insert’s]
recommended dosing regimen of 40 mg adalimumab [every other week] was
an acceptable, long-term maintenance therapy” based on the clinical study
data in 2003 Humira Package Insert and, therefore, would have selected a
higher dose to use for induction therapy. Ex. 1002 ¶¶ 80, 94; see id. ¶ 86
(“[T]he ‘most preferabl[e]’ 40 mg [every other week] regimen disclosed in
WO ’330 is a maintenance dosing regimen, for maintaining remission of
IBD and controlling flare ups, rather than an induction dosing regimen.”).
Petitioner and Dr. Posner also point out that the half-life of adalimumab is
approximately 2 weeks. See Pet. 38 (citing Ex. 1026, 2); Ex. 1025 ¶ 41
(“adalimumab ha[s] an approximately 2 week half-life”). Thus, the present
record demonstrates that the adalimumab every other week maintenance
dosing interval corresponds to adalimumab’s half-life. Applying the general
rule for determining an appropriate loading dose, therefore, results in an
adalimumab loading dose of 80 mg (i.e., a doubling of the 40 mg dose that
Petitioner identifies as the maintenance dose), not a dose of 160 mg as
recited in the claims. Accordingly, we are not persuaded on this record that
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the general rule for determining an appropriate loading dose would have led
the ordinarily skilled artisan to a dose of 160 mg of adalimumab (see Pet.
40)—a dose that is quadruple the dose that Petitioner identifies as the
maintenance dose.
Petitioner further argues, however, that the person of ordinary skill in
the art would have arrived at a 160 mg adalimumab dose by first selecting an
80 mg adalimumab dose as the “basis” for an induction regimen, then
doubling that dose in accordance with the general rule set forth in the prior
art for determining a loading dose. Pet. 40–42. But the record at this stage
of the proceeding does not support Petitioner’s argument. For example, the
references Petitioner cites do not disclose or suggest using a basis or
baseline dose to calculate an appropriate induction dose for a drug with a
dosing regimen that corresponds to its half-life. Rather, as explained above,
those references disclose the maintenance dose—not some other basis or
baseline dose—as the appropriate dose for determining the induction dose.
And neither Dr. Bjarnason nor Dr. Posner identifies sufficient factual
support for arriving at a loading dose by first selecting a basis or baseline
intermediate dose. See Ex. 1002 ¶ 95; Ex. 1025 ¶ 62 (Dr. Posner adopting
Dr. Bjarnason’s bare conclusion that 80 mg adalimumab every other week
“would be an appropriate choice as the basis for an induction regimen to
induce remission of IBD”). Thus, we determine that Petitioner does not
show sufficiently on this record that a skilled artisan would have been
prompted to combine and modify the disclosures of the prior art to achieve
the claimed multiple-variable dose method of treatment that all of the
challenged claims require. See Grain Processing Corp. v. Am. Maize Prods.
Co., 840 F.2d 902, 907 (Fed. Cir. 1988) (“Care must be taken to avoid
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hindsight reconstruction by using ‘the patent in suit as a guide through a
maze of prior art references, combining the right references in the right way
so as to achieve the result of the claims in suit.’” (quotation omitted)).
Given the foregoing, we are not persuaded the record before us
establishes a reasonable likelihood that Petitioner will prevail in showing
that the subject matter of claims 1–30 would have been obvious over the
combination of 2003 Humira Package Insert and WO ’330, in view of
Goodman & Gilman, 2002 Remicade Package Insert, and Hanauer.
IV. 	CONCLUSION
Taking account of the information presented in the Petition and the
Preliminary Response, and the evidence of record, we determine that
Petitioner fails to demonstrate a reasonable likelihood of prevailing at trial as
to any challenged claim. Accordingly, the Petition is denied, and no trial is
instituted.
V. 	ORDER
It is hereby
ORDERED that the Petition is denied as to all challenged claims of
the ’559 patent, and no trial is instituted;
FURTHER ORDERED that Petitioner’s Pro Hac Vice Motion to
Admit Daniel L. Reisner Pursuant to 37 C.F.R. § 42.10(c) (Paper 3) is
dismissed as moot; and
FURTHER ORDERED that Petitioner’s Pro Hac Vice Motion to
Admit Abigail Langsam Pursuant to 37 C.F.R. § 42.10(c) (Paper 7) is
dismissed as moot.
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PETITIONER:
Deborah E. Fishman
David R. Marsh
David K. Barr
ARNOLD & PORTER KAYE SCHOLER LLP
deborah.fishman@kayescholer.com
david.marsh@apks.com
David.Barr-PTAB@apks.com
PATENT OWNER:
William B. Raich
Michael J. Flibbert
Maureen D. Queler
Jessica L.A. Marks
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP
william.raich@finnegan.com
michael.flibbert@finnegan.com
maureen.queler@finnegan.com
jessica.marks@finnegan.com
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