Apotex Inc.v.Wyeth LLC

Patent Trial and Appeal Board

Apr 20, 2015

11374330 (P.T.A.B. Apr. 20, 2015)

Trials@uspto.gov Paper 94
571-272-7822 Date: April 20, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
_____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

APOTEX INC.,
Petitioner,

v.

WYETH LLC,
Patent Owner.
____________

Case IPR2014-00115
Patent 7,879,828 B2
____________

Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
JO-ANNE M. KOKOSKI, Administrative Patent Judges.

KOKOSKI, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

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I. INTRODUCTION
Apotex Inc. (“Petitioner”) filed a Petition (Paper 1, “Pet.”) to institute
an inter partes review of claims 1–23 of U.S. Patent No. 7,879,828 B2 (Ex.
1001, “the ’828 patent”). Wyeth LLC (“Patent Owner”) did not file a
preliminary response. We determined that the information presented in the
Petition demonstrated that there was a reasonable likelihood that Petitioner
would prevail in challenging claims 1–23 as unpatentable under 35 U.S.C.
§ 103 as obvious over the combination of CN ’550,
1
Pawelczyk,
2
and
Naggar.
3
Pursuant to 35 U.S.C. § 314, we instituted this proceeding on
April 21, 2014. Paper 10 (“Dec. to Inst.”), 2, 9.
Patent Owner filed a Patent Owner Response (Paper 36, “PO Resp.”),
and Petitioner filed a Reply (Paper 60, “Reply”). Petitioner filed a Motion to
Exclude (Paper 62) portions of the Declarations of Dr. Henry Grabowski
(Ex. 2010) and Mr. Christian L. Ofslager (Ex. 2011), as well as a number of
Patent Owner’s other exhibits. Patent Owner filed an Opposition to the
Motion to Exclude (Paper 73), and Petitioner filed a Reply (Paper 75).
Patent Owner filed a Motion to Exclude (Paper 66) CN ’550 and its
accompanying translations and declarations (Exs. 1003–1005, 1046, 1047),
and portions of the cross examinations of Dr. Lester Mitscher (Ex. 2175) and

1
Chinese Patent Publication No. CN 1390550A, published January 15, 2003
(Ex. 1003 and Exs. 1004 and 1046 (English translations)).
2
E. Pawelczyk et al., Kinetics of Drug Decomposition. Part 74. Kinetics of
Degradation of Minocycline in Aqueous Solution, 34 POL. J. PHARMACOL.
PHARMA. 409–421 (1982) (Ex. 1006).
3
V. Naggar et al., Effect of Solubilizers on the Stability of Tetracycline,
29(2) PHARMAZIE 126–129 (1974) (Ex. 1007).

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Dr. Robert Williams (Ex. 2176). Petitioner filed an Opposition (Paper 70),
and Patent Owner filed a Reply (Paper 76).
Petitioner supports its Petition with a Declaration by Mark L. Nelson,
Ph.D. (Ex. 1002, “Nelson Decl.”). Patent Owner relies on Declarations by
Lester A. Mitscher, Ph.D. (Ex. 2008, “Mitscher Decl.”), Robert O. Williams
III, Ph.D. (Ex. 2009, “Williams Decl.”), Harry Grabowski, Ph.D. (Ex. 2010,
“Grabowski Decl.”), and Christian L. Ofslager (Ex. 2011, “Ofslager Decl.”).
An oral hearing was held on January 23, 2015. A transcript of the
hearing is included in the record. Paper 89 (“Tr.”).
We have jurisdiction under 35 U.S.C. § 6(c). This Final Written
Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
For the reasons that follow, we determine that Petitioner has not shown by a
preponderance of the evidence that claims 1–23 of the ’828 patent are
unpatentable.
A. The ’828 Patent
The ’828 patent relates generally to compositions comprising
tigecycline, a suitable carbohydrate, and an acid or buffer. Ex. 1001, 1:8–
12. Tigecycline, a chemical analog of minocycline, is a tetracycline
antibiotic used to treat drug-resistant bacteria. Id. at 1:22–25. Due to poor
oral bioavailability, tigecycline typically is formulated as an intravenous
solution that is prepared from a lyophilized tigecycline powder immediately
prior to administration. Id. at 1:45–50. In solution, tigecycline undergoes
oxidation at slightly basic pH, causing the tigecycline to degrade relatively
rapidly. Id. at 2:24–26, 33–40. When the pH of the solution is lowered,
however, oxidative degradation decreases, and degradation by epimerization
predominates. Id. at 2:43–49. The tigecycline epimer lacks antibacterial
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effect, and is, thus, an undesirable degradation product. Id. at 3:19–22.
According to the ’828 patent, the claimed compositions reduce tigecycline
degradation, because the acidic pH of the solution comprising tigecycline
and a suitable carbohydrate minimizes oxidative degradation, while the
carbohydrate stabilizes the tigecycline against epimerization in the acidic
solution. Id. at 4:49–59.
The Specification of the ’828 patent discloses various embodiments,
such as compositions comprising tigecycline, lactose, and hydrochloric acid,
at pH values between 3.0 and 7.0. Id. at 7:63–10:35, 11:15–12:53. The
Specification further discloses embodiments where the molar ratio of
tigecycline to lactose varies between 1:0.24 and 1:4.87. Id. at 13:40–14:33.
Claims 1 and 12 of the ’828 patent are independent. Claims 2–11
depend, directly or indirectly, from claim 1, which is reproduced below:
1. A composition comprising tigecycline, lactose, and an
acid selected from hydrochloric acid and gentisic acid,
wherein the molar ratio of tigecycline to lactose is
between about 1:0.2 and about 1:5 and the pH of the
composition in a solution is between about 3.0 and about
7.0.
Id. at 14:36–40.
Claims 13–23 depend, directly or indirectly, from claim 12, which is
reproduced below:
12. A composition comprising tigecycline, lactose, and
hydrochloric acid, wherein the molar ratio of tigecycline
to lactose is between about 1:0.2 and about 1:5 and the
pH of the composition in a solution is between about 3.0
and about 7.0.
Id. at 14:62–65.
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II. ANALYSIS
A. Claim Interpretation
In an inter partes review, “[a] claim in an unexpired patent shall be
given its broadest reasonable construction in light of the specification of the
patent in which it appears.” 37 C.F.R. § 42.100(b); In re Cuozzo Speed
Techs., LLC., 778 F.3d 1271, 1279–80 (Fed. Cir. 2015). Under this
standard, claim terms are given their ordinary and customary meaning in
view of the specification, as would be understood by one of ordinary skill in
the art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d
1249, 1257 (Fed. Cir. 2007).
For purposes of our Decision to Institute, we determined that the
terms in the challenged claims did not need to be construed expressly, and
we see no reason to modify that determination in light of the record
developed at trial.
B. Obviousness of Claims 1–23 over
CN ’550, Pawelczyk, and Naggar
To prevail on its patentability challenge, Petitioner must establish
facts supporting its challenge by a preponderance of the evidence. 35 U.S.C.
§ 316(e); 37 C.F.R. § 42.1(d). We instituted review based upon Petitioner’s
contention that the combination of CN ’550, Pawelczyk, and Naggar
rendered claims 1–23 obvious under 35 U.S.C. § 103. Upon consideration
of the parties’ arguments and evidence before us now, we determine that
Petitioner has not demonstrated by a preponderance of the evidence that
those claims would have been obvious over the combination of CN ’550,
Pawelczyk, and Naggar for the reasons explained below.
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1. Overview of CN ’550
CN ’550 is a Chinese-language patent application. Ex. 1003. In
support of the Petition, Petitioner relied on a certified English translation of
CN ’550 (Ex. 1004,
4
“the first translation”) that described lactose, and other
ingredients, as excipients. See, e.g., Ex. 1004, 1:32–33 (“[The formulation]
is made of minocycline hydrochloride, an excipient, and a pH adjusting
agent.”), 3:35–37 (“The excipient is . . . selected from mannitol, glucose,
NaCl, dextran, lactose, and hydrolyzed gelatin.”); Pet. 26–30. After the
Decision to Institute issued, but before the Patent Owner Response was filed,
Patent Owner objected to the first translation on the basis that “excipient”
should have been translated as “lyophilized powder supporting agent,” and
that lactose was included in a list of excipients on page 3 of the translation,
when it did not appear in the original text. Transcript of Teleconference, Ex.
2172, 16:6–22; Paper 66, 3.
In response to Patent Owner’s objections, Petitioner submitted a
corrected certified translation of CN ’550 (Ex. 1046,
5
“the corrected
translation”). In the corrected translation, the characters originally translated
as “excipient” are translated as “lyophilized powder supporting agent,” and
lactose no longer appears in the list on page 3. See, e.g., Ex. 1046, 1 (“[The
formulation] is made of minocycline hydrochloride, a lyophilized powder
supporting agent, and a pH adjusting agent.”), 3 (“The lyophilized powder
supporting agent is . . . selected from mannitol, glucose, NaCl, dextran, and

4
The cited page numbers in Exhibit 1004 refer to the numbers at the bottom
of each page, rather than those at the top.
5
The cited page numbers in Exhibit 1046 refer to the numbers at the bottom
of each page, rather than those at the top.
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hydrolyzed gelatin.”). Patent Owner does not object to the content of the
corrected translation, but did file a motion to exclude both translations,
which we address below. Ex. 2172, 28:5–15; Paper 66, 1–13.
Although we relied upon the first translation in the Decision to
Institute, we rely on the corrected translation in rendering this Final
Decision. As such, the following discussion of CN ’550 with respect to
Petitioner’s contention that the ’828 patent would have been obvious over
the combination of CN ’550, Pawelczyk, and Naggar is based on the
corrected translation.
CN ’550 is directed to lyophilized minocycline hydrochloride powder
injections. Ex. 1046, 1. The lyophilized powder is comprised of 0.05–10
parts (by weight) minocycline hydrochloride, 0–100 parts lyophilized
powder supporting agent, and a suitable amount of a pH adjusting agent. Id.
at 3. The lyophilized powder supporting agent can be selected from
mannitol, glucose, sodium chloride, dextran, lactose, and hydrolyzed gelatin.
Id. at 2 (claim 5), 3. The pH adjusting agent is an inorganic acid, such as
hydrochloric acid. Id. at 3. The pH of the lyophilized powder is 0–7.5, most
preferably 2–3.5. Id. CN ’550 discloses an embodiment in Example 1 that
contains 108 g minocycline hydrochloride, 210 g mannitol, and a suitable
amount of 0.1 M hydrochloric acid. Id. at 4. Example 2 discloses an
embodiment containing 108 g of minocycline hydrochloride, 210 g of
dextran, and a suitable amount of acetic acid. Id. Example 3 describes an
embodiment containing 108 g minocycline hydrochloride, 210 g hydrolyzed
gelatin, and a suitable amount of phosphoric acid. Id. at 5.
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2. Overview of Pawelczyk
Pawelczyk reports the results of studies investigating the stability of
minocycline in aqueous solutions over a broad pH range. Ex. 1006, 409.
Pawelczyk discloses aqueous minocycline solutions at pH 4.38, 4.86, and
5.42. Id. at 413, Table 1. Pawelczyk teaches that oxidation is the
predominant minocycline degradation process above pH 5. Id. at 417.
3. Overview of Naggar
Naggar details an investigation of the rate of tetracycline
epimerization under various experimental conditions. Ex. 1007, 126.
Naggar teaches that, at a pH of 2–6, tetracycline undergoes a reversible
epimerization at the C4 dimethylamino group. Id. The epimerization occurs
most rapidly at a pH of 3–4. Id. Naggar teaches that solubilizers (such as
polysorbate 20, PEG 6000, urea, and thiourea) interact with tetracycline and
act as deprotonating agents, thus inhibiting epimerization by deterring the
rearrangement of tetracycline ring A. Id. at 127. Naggar reports that
tetracycline and a solubilizer in solution with a pH of 3–5 is “chemically
stable over a long period of time.” Id.
4. Analysis
Petitioner contends that CN ’550 discloses a lyophilized composition
that is stabilized against light, heat, oxygen, and water, and contains (1)
minocycline (an analog of tigecycline), (2) lactose, glucose, or dextran, and
(3) hydrochloric acid. Pet. 31–40. Petitioner contends that a person skilled
in the art “would find reason to substitute tigecycline for minocycline in the
lyophilized formulation of CN ’550” because tigecycline was known to
work where other antibiotics, including other tetracyclines had failed, and
because minocycline and tigecycline are tetracycline antibiotics that have
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identical A and B rings, and undergo epimerization at the C4 dimethylamino
group by the same reaction. Id. at 31–32. Petitioner also contends that
because Naggar teaches that tetracyclines are stabilized against
epimerization by hydrogen bonding between a saccharide (such as lactose)
and a tetracycline, “a person of ordinary skill in the art would understand
and expect that lactose disclosed in CN ’550 would also be effective to
stabilize tigecycline against epimerization.” Id. at 44.
Patent Owner asserts that CN ’550 does not teach or suggest the use
of lactose to minimize or prevent epimerization. PO Resp. 24–27. Patent
Owner asserts that CN ’550 describes lactose as a “lyophilized powder
supporting agent,” which “provides physical support to a lyophilized powder
formulation” so that it does not collapse, not as “an ingredient that engages
in chemical interactions such as deprotonating the active ingredient to avoid
epimerization.” Id. at 24. Therefore, according to Patent Owner, a person
having ordinary skill in the art would have understood that lyophilized
powder supporting agents “play a very specific role in maintaining physical
structure,” and “would never have looked” at the disclosure of lactose in
CN ’550 to enhance chemical stability of a tigecycline formulation. Id. at
26. Patent Owner notes that other lyophilized powder supporting agents
named in CN ’550, such as mannitol, sodium chloride, and hydrolyzed
gelatin, do not “suggest a common chemical interaction or bonding
potential” or have similar structures that would suggest, to a person having
ordinary skill in the art, a common interaction between each named
lyophilized powder supporting agent and a tetracycline derivative. Id. at 25.
Patent Owner also asserts that there is no indication, in any event, that the
compositions described in CN ’550 were epimerically stable. Id. at 28–30.
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Patent Owner further asserts that Naggar does not teach an ordinary
artisan that lactose can be used to stabilize tetracyclines against
epimerization. PO Resp. 31–36. Patent Owner notes that Naggar does not
disclose lactose, and the disclosed compound noted by Petitioner—
polysorbate 20—is not as effective against epimerization as other disclosed
solubilizers, such as PEG 6000 and thiourea. Id. at 31–32. There is
therefore no reason, Patent Owner asserts, for a person having ordinary skill
in the art to choose lactose to stabilize tigecycline against epimerization
based on the disclosures in Naggar. Id. at 32–36.
We agree with Patent Owner that Petitioner has not shown, by a
preponderance of the evidence, that a person having ordinary skill in the art
would have had reason to substitute tigecycline for minocycline in the
lyophilized formulation of CN ’550, or to make the compositions recited in
the challenged claims in particular in any event. Pet. 31–33. As discussed
in more detail below, none of CN ’550, Pawelczyk, or Naggar discloses or
discusses tigecycline. PO Resp. 19. Petitioner does not explain adequately
why an ordinary artisan, reading such references, would have had reason to
use tigecycline in the formulation of CN ’550 when the references
themselves lack any teaching or suggestion about the use or specific
chemistry of tigecycline in particular. In addition, we also agree with Patent
Owner that Petitioner has not shown sufficiently that a person having
ordinary skill in the art would have considered it obvious to include lactose
in a tigecycline composition in the amounts recited in the ’828 patent claims,
for example, to stabilize the composition against epimerization.
A claim is unpatentable under 35 U.S.C. § 103 if the differences
between the subject matter sought to be patented and the prior art are such
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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 the
subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
(2007). Prior art references must be “considered together with the
knowledge of one of ordinary skill in the pertinent art.” In re Paulsen, 30
F.3d 1475, 1480 (Fed. Cir. 1994). Moreover, an obviousness analysis “need
not seek out precise teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” KSR, 550 U.S.
at 418. A patent claim composed of several elements is not proved obvious
merely by demonstrating that each of its elements was known,
independently, in the prior art. Id. A party that petitions the Board for a
determination of obviousness must show that “a skilled artisan would have
been motivated to combine the teachings of the prior art references to
achieve the claimed invention, and that the skilled artisan would have had a
reasonable expectation of success in doing so.” Procter & Gamble Co. v.
Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009) (quoting Pfizer,
Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007)).
a. Substituting Tigecycline for Minocycline
Petitioner states that a person of ordinary skill in the art would have
found reason to substitute tigecycline for minocycline in the CN ’550
compositions because it was known to work where other antibiotics failed,
and that it was active against specific viruses that show tetracycline
resistance. Pet. 31. Petitioner cites Dr. Nelson’s testimony in support of this
contention:
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A person of ordinary skill in the art in 2005 would find
reason to substitute tigecycline for minocycline in the
lyophilized formulation of CN ’550, because the ’828 Patent
states that it was known that tigecycline “has been shown to
work where other antibiotics have failed” and “it has been
active against methicillin-resistant Staphylococcus aureus,
penicillin-resistant Streptococcus pneumoniae, vancomycin
resistant enterococci…and against organisms carrying either of
the two major forms of tetracycline resistance: efflux and
ribosomal protection.”
Nelson Decl., Ex. 1002 ¶ 84 (citing Ex. 1001, 1:23–44).
Dr. Nelson does not explain, however, why the knowledge that
tigecycline is effective “where other antibiotics have failed” would lead a
person having ordinary skill in the art to substitute tigecycline for
minocycline in the CN ’550 compositions. Neither Petitioner nor Dr. Nelson
provides information demonstrating that a person of ordinary skill in the art
would correlate the therapeutic effectiveness of tigecycline as an antibiotic
to the properties of tigecycline that must be considered when preparing a
lyophilized formulation of tigecycline. Moreover, Petitioner does not
provide any evidence or explanation why a person having ordinary skill in
the art would have expected reasonably that the substitution tigecycline for
minocycline in the CN ’550 compositions would have resulted in a stabilized
tigecycline composition. Petitioner, therefore, has not provided sufficient
rationale to explain why a person having ordinary skill in the art would have
substituted tigecycline for minocycline in the CN ’550 compositions for any
reason, much less in an attempt to make a lyophilized tigecycline
composition that was stable against epimerization on this basis, as Petitioner
contends.
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Petitioner also argues that a person having ordinary skill in the art
“would understand and expect that lactose would be effective to stabilize
minocycline and tigecycline against C4 epimerization in a solution having a
pH from 0.1–7.5, including an acid pH of 2.0–3.5, as taught by CN ’550,
based on the exact structural identity of the A and B rings in these analogs.”
Pet. 32 (citing Nelson Decl., Ex. 1002 ¶ 88). Petitioner goes on to conclude:
A person of ordinary skill in the art would expect each of
the saccharide excipients disclosed in CN ’550 to be effective to
stabilize minocycline and tigecycline against C4 epimerization
in a solution having a pH from 0.1–7.5, including an acid pH of
2.0–3.5, because of the structural similarities of glucose (a
monosaccharide), lactose (a disaccharide), and dextran (a
polysaccharide). It was known in the prior art, including CN
’550, that suitable carbohydrates including disaccharides such
as lactose, monosaccharides such as glucose, and
polysaccharides such as dextran, are effective to stabilize
tetracyclines against epimerization at acid pHs.
Id. (citing Nelson Decl., Ex. 1002 ¶¶ 42–50, 56–59, 86–87).
Petitioner’s contentions in this regard are insufficient because they
presume that a person of ordinary skill in the art would have recognized that
the compositions disclosed in CN ’550 were stable against epimerization.
As is discussed below, Petitioner has not established that a person of
ordinary skill in the art would have known from the CN ’550 disclosure that
the described minocycline compositions were stable against epimerization.
In its Reply, Petitioner argues that whether a person having ordinary
skill in the art would have recognized that the CN ’550 compositions were
epimerically stable is irrelevant to the obviousness inquiry:
Contrary to [Patent Owner]’s fundamental argument, the ’828
patent claims do not relate to a method for stabilizing
tigecycline against epimerization, or indeed, any method of
stabilizing tigecycline. The claims recite a lyophilized
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composition, containing tigecycline, lactose and hydrochloric
acid, having a specified pH “in a solution” that is not limited to
any one of the 3 solutions that are disclosed in the specification.
The issue is whether a [person having ordinary skill in the art]
would have found it obvious to make the claimed composition,
by substituting tigecycline for minocycline in the composition
disclosed in CN ’550, for any reason, not just to reduce
epimerization.
Reply 3 (citations omitted).
Petitioner also argues that a person having ordinary skill in the art
would have expected, from CN ’550’s disclosure of minocycline
compositions that are stabilized against degradation by light, heat, oxygen,
and water that also have good therapeutic effectiveness, that similar benefits
would result if tigecycline were simply substituted for minocycline. Id. at 4;
see also Pet. 39 (“[a] person of ordinary skill in the art would recognize that
the technique for stabilizing minocycline disclosed in CN ’550 by using
lactose, would similarly stabilize and improve a composition containing the
analog antibiotic tigecycline”). As noted above, however, Petitioner does
not establish adequately that an ordinary artisan would have had reason to
believe that tigecycline, rather than minocycline, would have been similarly
stable in the formulation disclosed in CN ’550.
Petitioner is correct that the claims do not recite epimeric stability and
therefore obviousness of the claims can be demonstrated without a showing
of epimeric stability in the prior art. We are not persuaded, however, that
Petitioner has established that a person having ordinary skill in the art would
have found it obvious to substitute tigecycline for minocycline in the
composition disclosed in CN ’550.
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b. Using Lactose to Stabilize a
Lyophilized Tigecycline Composition
Petitioner relies on CN ’550’s disclosure of “stable” minocycline
compositions as motivation for a person having ordinary skill in the art to
combine CN ’550 with Pawelczyk and Naggar to address the problem of
tigecycline’s instability due to epimerization. Pet. 40. In urging that a
person having ordinary skill in the art would have used lactose to stabilize a
lyophilized tigecycline composition against epimerization, Petitioner also
points to Naggar’s teaching that (1) tetracycline antibiotics undergo
epimerization at pH conditions between 2 and 6, (2) the epimerization
occurs at the C4 dimethylamino group, and (3) polysorbate 20 stabilizes
tetracycline against epimerization. Pet. 42–44. Based on these disclosures
in CN ’550 and Naggar, and Pawelczyk’s teaching that “a pH range below 5
is preferable to avoid oxidative degradation of minocycline,” Petitioner
concludes that “a person of ordinary skill in the art would understand and
expect that lactose disclosed in CN ’550 would also be effective to stabilize
tigecycline against epimerization in solutions having a pH in the range from
4 to 6 taught as optimal by Naggar.” Id. at 41, 44.
As Patent Owner points out, however, neither CN ’550, Pawelczyk,
nor Naggar discloses tigecycline, Naggar and Pawelczyk do not disclose
lactose, and CN ’550 only discloses lactose as one of a list of lyophilized
powder supporting agents in a dependent claim. PO Resp. 19–20. In
addition, although CN ’550 states that the disclosed formulations are stable
against light, heat, oxygen, and water (Ex. 1046, 1, 3), there are no
statements from which a person skilled in the art would understand that the
CN ’550 formulations were epimerically stable. PO Resp. 23–24. Indeed,
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neither CN ’550 nor Pawelczyk mention epimerization at all. As discussed
above, the ’828 patent, but none of the cited prior art references, discloses
that compositions having the claimed ingredients and pH are stabilized
against oxidative degradation and epimerization of tigecycline.
In support of its contention regarding the epimeric stability of the
compositions disclosed in CN ’550, Petitioner relies on Dr. Nelson’s
testimony in which he asserts that “CN ’550 discloses that the lyophilized
powder is stabilized under acidic conditions, and a person of ordinary skill in
the art would readily appreciate that stabilization would include prevention
of C4 epimerization in an acidic solution by the disclosed excipients, which
include the carbohydrates lactose, glucose and dextran.” Nelson Decl., Ex.
1002 ¶ 78. Dr. Nelson concedes that CN ’550 does not mention
epimerization explicitly (Complete Deposition Transcript of Mark L.
Nelson, Ph.D., Ex. 2012, 38:6–39:15), but argues that a person skilled in the
art would understand that because epimerization affects stability, and CN
’550 discloses stable formulations, those formulations must be epimerically
stable. Id. at 47:11–23.
Dr. Nelson’s statements regarding what a person skilled in the art
would have understood about the epimeric stability of the CN ’550
compositions, however, are not supported by any objective evidence or
analysis. Dr. Nelson simply states the skilled artisan would “readily
appreciate” that the CN ’550 compositions are epimerically stable, without
providing any explanation as to why that would be the case. Dr. Nelson
relies on CN ’550’s teaching that the disclosed compositions feature stable
light, thermal, oxygen, and water properties, but does not expound upon the
reasons why a person skilled in the art would understand that statement to
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include epimeric stability. See, e.g., Nelson Decl., Ex. 1002 ¶ 78.
Dr. Nelson’s unsupported and unexplained opinions are not persuasive. See
37 C.F.R. § 42.65(a) (“Expert testimony that does not disclose the
underlying facts or data on which the opinion is based is entitled to little or
no weight.”); Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776
F.2d 281, 294 (Fed. Cir. 1985) (stating a lack of objective support for an
expert opinion “may render the testimony of little probative value in [a
patentability] determination”).
Patent Owner, in contrast, provides reasoning as to why a person
having ordinary skill in the art would not have understood CN ’550 to
address epimeric stability. PO Resp. 22–24. For example, Patent Owner
notes that CN ’550 does not include data, studies, or any explicit indication
that epimeric stability was a part of the disclosure. Id. at 23; see also
Williams Decl., Ex. 2009 ¶ 69 (“A [person of ordinary skill in the art]
simply would not believe that a reference solves an epimerization problem if
it neither mentions epimerization, nor provides any analytical data relating to
epimerization.”). Dr. Mitscher also testified that a person having ordinary
skill in the art would not understand that the compositions described in
CN ’550 reduced epimerization:
Nor does the bare statement that CN ’550 that the goal of
the study was “to provide a lyophilized minocycline
hydrochloride powder injection that features stable light,
thermal, oxygen, and water properties; is non-polluting and
easy to manipulate, transport, and store” teach or suggest that
the formulations reduced epimerization. To the contrary, if the
invention were targeted at preventing epimerization as well, a
[person of ordinary skill in the art] would have expected
epimerization to be included in this list or otherwise mentioned.
The fact that it is absent would lead a [person of ordinary skill
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in the art] to believe that either the formulations do not work to
solve an epimerization problem, or that the authors did not test
or otherwise have reason to believe that the disclosed
formulations were solutions to the epimerization problem.
Mitscher Decl., Ex. 2008 ¶ 110 (internal citations omitted). We find Patent
Owner’s arguments, that a person having ordinary skill in the art would not
have looked to a reference that does not mention epimerization in order to
solve the problem of epimeric instability of tigecycline compositions, to be
persuasive. PO Resp. 22–24; see Yorkey v. Diab, 601 F.3d 1279, 1284 (Fed.
Cir. 2010) (holding that Board has discretion to give weight to one item of
evidence over another “unless no reasonable trier of fact could have done
so”).
Dr. Nelson also relies on the following statement in CN ’550
regarding the therapeutic effectiveness of the disclosed lyophilized
minocycline compositions as further support of Petitioner’s contention that
the disclosed lyophilized powder supporting agents are stabilizing the
formulations against epimerization (Ex. 2012, 91:3–93:16; PO Resp. 26–27):
This disclosure is a lyophilized powder for injection with
a pH level of 0–7.5, with the most suitable level being 2–3.5.
Its uses are as follows: It has a very good therapeutic effect on
a variety of infections caused by drug-resistant Staphylococcus
aureus, Chlamydia, and Acinetobacter, and can be administered
extravascularly. The lyophilized powder supporting agent is a
soluble support easily dissolved in water and fast-dissolving in
clinical applications, selected from mannitol, glucose, NaCl,
dextran, and hydrolyzed gelatin.
Ex. 1046, 3.
Dr. Nelson does not provide any objective evidence explaining how
the stated therapeutic effectiveness of the compositions in CN ’550
correlates to epimeric stability. The mere fact that the CN ’550
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compositions are therapeutically effective does not necessarily mean that
they are stable against epimerization. Patent Owner, however, provides
evidence that stability testing does not correlate to the activity of a
compound, which is determined using different testing methods. PO Resp.
29. Dr. Mitscher testified that “stability testing is distinct from the test of
the activity of a compound, typically performed by assessing the minimum
inhibitory concentration (‘MIC’) at which a compound inhibits growth of
bacteria,” and that “an MIC test is not intended to convey information
regarding a compound’s stability and does not do so.” Mitscher Decl., Ex.
2008 ¶ 65 (emphasis in original).
Dr. Mitscher also explained that a person of ordinary skill in the art
would not have relied on MIC testing to reach a conclusion about the degree
of a compound’s stability for a number of reasons, including that (1) MIC
testing is performed on the active pharmaceutical ingredient, not on the
formulation, and (2) there is no standard or accepted way of substituting
MIC test results for stability test results. Id. ¶ 123. Dr. Williams agrees
with Dr. Mitscher, and points out that a person of ordinary skill in the art “in
2005 would not have interpreted a statement about microbiological activity
as indicative of the stability of a formulation, particularly a statement
involving an active ingredient in the tetracycline class that is known to be
susceptible to degradation.” Williams Decl., Ex. 2009 ¶ 39.
Moreover, Dr. Nelson’s testimony regarding the therapeutic
effectiveness of the CN ’550 compositions and the ability of lactose to
stabilize minocycline against epimerization is based on an admittedly
incorrect translation of CN ’550. PO Resp. 25. Dr. Nelson’s reliance on the
statement of therapeutic effectiveness in CN ’550 was premised on the first
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translation’s erroneous inclusion of lactose in the sentence “[t]he lyophilized
powder supporting agent is a soluble support easily dissolved in water and
fast-dissolving in clinical applications, selected from mannitol, glucose,
NaCl, dextran, and hydrolyzed gelatin” that immediately followed the
sentence describing therapeutic effectiveness. Id. at 26–27. According to
Dr. Nelson, it was important that lactose appeared in the same paragraph as
the statement of therapeutic effectiveness of the disclosed embodiments
because “I would try the same experiment, just supplanting lactose for
hydrolyzed gelatin because they’d mentioned that it works the same as the
hydrolyzed gelatin.” Ex. 2012, 91:3–25. Dr. Nelson further testified that
this disclosure would provide motivation for a person skilled in the art to use
lactose. Id. at 93:5–16. Although Dr. Nelson also testified that his
conclusions are not changed by the corrected translation, neither he nor
Petitioner provide any analysis or evidence as to why this is the case. Id. at
426:17–23.
Additionally, to the extent that Petitioner argues that a person having
ordinary skill in the art would have been motivated to combine CN ’550,
Pawelczyk, and Naggar because they each teach stabilization of tetracyclines
by saccharides (Tr. 31:4–7), that argument is similarly unpersuasive.
Specifically, Petitioner argues that Naggar’s disclosure of the
saccharide polysorbate 20 as being effective to stabilize tetracycline against
epimerization “informs a person skilled in the art that the stabilization of
tetracyclines including minocycline and tigecycline by saccharides involves
a hydrogen bond between an excipient such as lactose and a tetracycline
such as minocycline or tigecycline that may result from hydrogen bonding.”
Pet. 44. Dr. Nelson then explains that “polysorbate is a carbohydrate based
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polymer having primary and secondary hydroxyl groups that are
characteristic of saccharides,” and further describes that “[c]arbohydrates
including monosaccharides such as glucose and mannose; disaccharides
exemplified by lactose and sucrose; and poly-saccharides such as dextran,
have the ability” to stabilize epimerization “via an intramolecular
interaction.” Nelson Decl., Ex. 1002 ¶¶ 43, 45. At no point does Dr. Nelson
or Petitioner explain adequately, however, why a person having ordinary
skill in the art would have focused on Naggar’s disclosure of polysorbate 20
over other solubilizers disclosed therein (when Naggar indicates that other
solubilizers worked better), nor why one would have used lactose instead of
polysorbate 20 in any event, when the reference does not mention other
polysaccharides, much less lactose in particular.
Dr. Nelson’s testimony is unpersuasive. Dr. Nelson opines that all of
the elements of the claims disparately existed in the prior art, but fails to
provide sufficient reason why one of ordinary skill in the art at the time of
filing would have combined the different elements, some disclosed and some
not, in the different references. See, e.g., InTouch Techs., Inc. v. VGO
Commc’ns, Inc., 751 F.3d 1327, 1348–49 (Fed. Cir. 2014) (holding expert
testimony to be impermissible hindsight for failing to explain what reason or
motivation one of ordinary skill in the art at the time of the invention would
have had to place the prior art together).
In an obviousness determination, we must avoid analyzing the prior
art through the prism of hindsight. Instead, we must “cast the mind back to
the time the invention was made” and “occupy the mind of one skilled in the
art who is presented only with the references, and who is normally guided by
the then-accepted wisdom in the art.” W.L. Gore & Assoc., Inc. v. Garlock,
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Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983). Here, Petitioner attempts to
imbue one of ordinary skill in the art with knowledge of the claimed
invention, when no prior art reference or references of record conveys or
suggests that knowledge. Rather, Petitioner’s argument that CN ’550 is
combinable with Pawelczyk and Naggar appears to be premised on
Petitioner’s knowledge of the ’828 patent’s disclosure of lyophilized
compositions of tigecycline and lactose that are stable against epimerization.
See, e.g., Tr. 28:6–12 (“The same saccharides are disclosed in the claims of
the Chinese ’550 patent . . . . The ’828 patent says all disaccharides are
expected to work. Saccharides are generally expected to work. And here
are three that are expected to work. One of them is lactose, one of them is
glucose, and one of them is dextran.”).
c. Conclusion
Petitioner bears the burden of showing by a preponderance of the
evidence that an ordinary artisan would have had reason to combine
elements in the asserted prior art references to achieve the recited
compositions. On the record before us, we find that Petitioner has not
shown that the combination of CN ’550, Pawelczyk, and Naggar renders the
challenged claims unpatentable. Therefore, we conclude Petitioner has not
demonstrated by a preponderance of the evidence that claims 1–23 of the
’828 patent would have been obvious over the combination of CN ’550,
Pawelczyk, and Naggar.
C. Secondary Considerations of Non-Obviousness
Patent Owner contends that Petitioner fails to meet its burden of
showing unpatentability because objective indicia of nonobviousness
indicate that the claimed subject matter would not have been obvious. PO
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Resp. 57–60. As discussed above, we find that Petitioner has not
demonstrated that claims 1–23 would have been obvious over the
combination of CN ’550, Pawelczyk, and Naggar. Thus, we need not
address Patent Owner’s evidence regarding secondary considerations of
nonobviousness.
III. MOTIONS TO EXCLUDE
A. Petitioner’s Motion to Exclude
Petitioner moves to exclude Exhibits 2010 (Grabowski Declaration),
2011 (Ofslager Declaration), 2026, 2037–2151, and 2153–2168. Paper 62,
1, 4, 5, 8, 11. Because our Decision does not rely on any of the challenged
exhibits, we dismiss Petitioner’s Motion to Exclude as moot.
B. Patent Owner’s Motion to Exclude
Patent Owner moves to exclude CN ’550 and its accompanying
translations and declarations (Exs. 1003–1005, 1046, 1047), and portions of
the cross examinations of Dr. Mitscher and Dr. Williams (Exs. 2175, 2176).
Paper 66, 1.
1. Exhibits 1004, 1005, 2175, and 2176
Because we do not rely on Exhibits 1004, 1005, nor Dr. Mitscher’s or
Dr. William’s testimony on cross-examination in reaching the Final Written
Decision, we dismiss as moot Patent Owner’s Motion to Exclude as to
Exhibits 1004, 1005, 2175, and 2176.
2. Exhibits 1003, 1046, and 1047
Patent Owner argues that Exhibit 1047 (Declaration of Jennifer
Brooks filed in support of the corrected translation of CN ’550 (Ex. 1046))
includes materially inaccurate statements regarding the errors in the first
translation of CN ’550 (Ex. 1004). Paper 66, 11–13. According to Patent
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Owner, the declaration cannot support the corrected translation of CN ’550
(Ex. 1046) because it does not comply with 37 C.F.R. § 42.63(b), and in the
absence of a properly supported translation, CN ’550 (Ex. 1003) is
inadmissible. Id. at 13. Patent Owner does not object to the content of the
corrected translation (Ex. 1046). See Paper 70, 1–2.
Rule 42.63(b) states:
When a party relies on a document or is required to produce a
document in a language other than English, a translation of the
document into English and an affidavit attesting to the accuracy
of the translation must be filed with the document.
37 C.F.R. § 42.63(b); see also § 42.2 and §1.68 (defining “affidavit”). The
Brooks Declaration (Ex. 1047) was signed by the translator of CN ’550,
states that the translation is true and accurate, and includes an
acknowledgement that the statements are made of the declarant’s own
knowledge and with the “knowledge that willful false statements and the like
so made are punishable by fine or imprisonment, or both under section 1001
of Title 18 of the United States Code, and that such willful false statement
may jeopardize the validity of the involved patent/application.” Ex. 1047 ¶
11. Therefore, Exhibit 1047 complies with § 42.63(b), and Exhibit 1046 is
supported by a proper declaration.
Patent Owner further argues that the Brooks Declaration is misleading
because it states that the inclusion of lactose in the first translation was an
inadvertent error, and “that ‘excipient’ is merely a less literal translation, and
there is no mention of the first declaration being submitted under Ms.
Brooks’ name without her knowledge or consent.” Paper 66, 11–12. Patent
Owner argues that Petitioner submitted the misleading declaration in order
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to comply with Rule 42.123 regarding the filing of supplemental
information. Id. at 10–11, 13.
Rule 42.123(b) states:
A party seeking to submit supplemental information more than
one month after the date the trial is instituted, must request
authorization to file a motion to submit the information. The
motion to submit supplemental information must show why the
supplemental information reasonably could not have been
obtained earlier, and that consideration of the supplemental
information would be in the interests-of-justice.
37 C.F.R. § 42.123(b). According to Patent Owner, Petitioner could not
show that the corrected translation could not have been obtained earlier
without including the alleged misleading statements in the declaration.
Paper 66, 13.
Here, the record reflects that Petitioner provided the corrected
translation in response to Patent Owner’s objections to the first translation,
and that Patent Owner does not object to the translation itself. Patent Owner
does not identify any reason why we would be unable to weigh this evidence
without prejudice or confusion.
In addition, as the moving party, Patent Owner does not persuade us
that Exhibit 1047 does not comply with § 42.63(b). Accordingly, we deny
Patent Owner’s Motion to Exclude in relation to Exhibits 1003, 1046, and
1047.

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IV. CONCLUSION
For the reasons given, we are not persuaded that Petitioner has shown
by a preponderance of the evidence that claims 1–23 of the ’828 patent
would have been obvious over the combined teachings of CN ’550,
Pawelczyk, and Naggar.

V. ORDER
In consideration of the foregoing, it is
ORDERED that Petitioner has not shown by a preponderance of the
evidence that claims 1–23 of the ’828 patent are unpatentable;
FURTHER ORDERED that Petitioner’s Motion to Exclude (Paper
62) is dismissed;
FURTHER ORDERED that Patent Owner’s Motion to Exclude
(Paper 66) is dismissed-in-part and denied-in-part; and
FURTHER ORDERED that because this is a Final Written Decision,
parties to the proceeding seeking judicial review of the decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

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PETITIONER:
Kenneth J. Burchfiel
Travis B. Ribar
SUGHRUE MION, PLLC
kburchfiel@sughrue.com
tribar@sughrue.com

PATENT OWNER:
Stanley E. Fisher
David Berl
Galina Fomenkova
WILLAIMS & CONNOLLY LLP
sfisher@wc.com
berl@wc.com
gfomenkova@wc.com