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Parties Involved:
Apotex Inc.
Appellant
Wyeth LLC
Appellee

Document Text:

NOTE: This disposition is nonprecedential.

United States Court of Appeals 

for the Federal Circuit ______________________ 

APOTEX INC.,

Appellant

v.

WYETH LLC,

Appellee

______________________ 

2015-1871

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2014-

00115.

______________________ 

Decided: August 16, 2016

______________________ 

JOHN J. MOLENDA, Steptoe & Johnson, LLP, New 

York, NY, argued for appellant. Also represented by 

ROBERT GREENFELD; KATHERINE H. JOHNSON, Chicago, IL. 

DAVID I. BERL, Williams & Connolly LLP, Washington, DC, argued for appellee. Also represented by STANLEY 

E. FISHER, ADAM D. HARBER, THOMAS H.L. SELBY, SARA 

KAISER CREIGHTON.

______________________ 

Case: 15-1871 Document: 42-2 Page: 1 Filed: 08/16/2016
2 APOTEX INC. v. WYETH LLC

Before LOURIE, WALLACH, and HUGHES, Circuit Judges.

LOURIE, Circuit Judge. 

Apotex Inc. appeals from the U.S. Patent and Trademark Office Patent Trial and Appeal Board (“the Board”) 

final written decision in an inter partes review concluding

that claims 1–23 of U.S. Patent 7,879,828 (“the ’828 

patent”) are not unpatentable as obvious. See Apotex Inc. 

v. Wyeth LLC, No. 2014-00115, 2015 WL 1848261, at *14 

(P.T.A.B. Apr. 20, 2015). For the reasons that follow, we 

affirm. 

BACKGROUND

Wyeth LLC owns the ’828 patent, directed to a composition comprising tigecycline, a suitable carbohydrate, and 

an acid or buffer. ’828 patent col. 1 ll. 10–11. Tigecycline 

is a known antibiotic in the tetracycline family, id. col. 1 

ll. 22–23, with the following structure:

 

see, e.g., id. col. 2 (formula 1). “It may be used as a treatment against drug-resistant bacteria,” and often “work[s]

where other antibiotics have failed.” Id. col. 1 ll. 23–25. 

In solid and solution form, tigecycline experiences two 

significant forms of degradation. At basic pH, tigecycline 

primarily undergoes oxidation. See id. col. 2 ll. 25–27; id.

col. 2 ll. 31–33 (“[Tigecycline] possesses a phenol moiety, 

and it is well known in the art of organic chemistry that 

phenols are particularly prone to oxidation.”). As the pH 

decreases, however, oxidation slows down, and epimerizaCase: 15-1871 Document: 42-2 Page: 2 Filed: 08/16/2016
APOTEX INC. v. WYETH LLC 3

tion emerges as the “predominant degradation pathway.” 

See id. col. 2 ll. 45–50. Tigecycline and its epimer differ in 

one respect: “[i]n tigecycline, the N-dimethyl group at the 

4 carbon is cis to the adjacent hydrogen,” whereas in the 

epimer, the “N-dimethyl group” and the adjacent hydrogen are trans to one another. See id. col. 3 ll. 16–19. 

Because of that structural difference, the epimer lacks the 

antibacterial efficacy of tigecycline, and is thus “an undesirable degradation product.” See id. col. 3 ll. 19–22. 

The invention of the ’828 patent lessens both of the

above-mentioned degradation pathways, and provides for 

a stable tigecycline composition in solid and solution form. 

Id. col. 1 ll. 7–10; id. col. 4 ll. 49–51. In particular, “[t]he 

inventive compositions” comprise tigecycline, an acid or a 

buffer, and a suitable carbohydrate. See, e.g., id. col. 1 ll. 

10–13. According to the specification, the acid minimizes 

oxidative degradation, and the carbohydrate stabilizes the 

tigecycline against epimer formation at acidic pH. See id. 

col. 4 ll. 56–59.

 The ’828 patent contains 23 composition claims. See 

id. col. 14 l. 35–col. 16 l. 10. For purposes of this appeal, 

independent claim 1 is representative:

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. col. 14 ll. 35–39. Claim 12 is identical to claim 1 but is

limited to hydrochloric acid. See id. col. 14 ll. 62–65. The 

remaining dependent claims further require a lyophilized 

composition (claim 2); a solid form composition (claims 3 

and 18–22); narrower pH ranges (claims 4, 5, 10, 11, and 

14–17); and narrower molar ratios of tigecycline to lactose 

(claims 9 and 13). See, e.g., id. col. 14 l. 35–col. 16 l. 10. 

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4 APOTEX INC. v. WYETH LLC

In March 2013, Apotex filed a petition to institute inter partes review of the ’828 patent. The Board instituted 

review based on one ground: that claims 1–23 would have 

been obvious over the combination of Chinese Patent 

Publication No. 1390550A (“CN ’550”); V. Naggar et al., 

Effect of Solubilizers on the Stability of Tetracycline, 29 

PHARMAZIE 126 (1974) (“Naggar”); and E. Pawelczyk et 

al., Kinetics of Drug Decomposition: Part 74: Kinetics of 

Degradation of Minocycline in Aqueous Solution, 34 POL.

J. PHARMACOL. PHARM. 409 (1982) (“Pawelczyk”). 

In its final written decision, the Board evaluated the 

relevant prior art of record and made the following factual 

findings. First, the Board found that CN ’550* discloses a 

minocycline-based powder injection, acknowledging that

minocycline is a tetracycline antibiotic. Apotex, 2015 WL 

1848261, at *4. The powder injection comprises “minocycline hydrochloride, . . . [a] lyophilized powder supporting 

agent, and a suitable amount of a pH adjusting agent.” Id. 

The powder supporting agent can be lactose, and the “pH 

adjusting agent is an inorganic acid, such as hydrochloric 

acid.” Id. The composition is stable against “degradation 

by light, heat, oxygen, and water.” See id. at *8. 

Next, the Board found that Pawelczyk addresses the 

stability of minocycline in solutions over a broad range of 

pHs, specifically “teach[ing] that oxidation is the predominant minocycline degradation process above pH 5.” Id. at 

*5. Last, the Board found that Naggar addresses the rate 

 

* In its decision to institute, the Board relied on an 

incorrect translation of CN ’550. See Apotex, 2015 WL 

1848261, at *3–4. Apotex submitted a corrected translation in response to Wyeth’s objections, and the Board 

relied on that corrected translation in its final written 

decision. See id. at *4. Discrepancies between the two 

translations are not relevant to this appeal. See Appellant’s Br. 11 n.4. 

Case: 15-1871 Document: 42-2 Page: 4 Filed: 08/16/2016
APOTEX INC. v. WYETH LLC 5

of tetracycline epimerization, specifically teaching that “at 

a pH of 2–6, tetracycline undergoes a reversible epimerization at the C4 dimethylamino group.” Id. Further, the 

Board found that Naggar teaches that such epimerization 

occurs “most rapidly at a pH of 3–4,” and that solubilizers, 

such as polysorbate 20, urea, and thiourea, help stabilize 

tetracycline against epimerization. Id. 

After making those factual findings, the Board concluded that the combination of CN ’550, Naggar, and 

Pawelczyk did not render the claims of the ’828 patent 

unpatentable as obvious. It first reasoned that Apotex 

failed to explain why a skilled artisan “would have substituted tigecycline for minocycline in the CN ’550 composition for any reason, much less in an attempt to make a 

lyophilized tigecycline composition that was stable 

against epimerization.” Id. at *7. It then reasoned that 

Apotex failed to establish why a skilled artisan would 

have been motivated to combine CN ’550, Pawelczyk, and 

Naggar, and use lactose, as a means for stabilizing tigecycline against epimerization. Id. at *9. 

Apotex timely appealed; we have jurisdiction under 28 

U.S.C. § 1295(a)(4)(A). 

DISCUSSION

We review the Board’s legal determinations de novo,

In re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), and the 

Board’s factual findings underlying those determinations 

for substantial evidence, In re Gartside, 203 F.3d 1305, 

1316 (Fed. Cir. 2000). Obviousness is a question of law 

based on underlying factual findings, In re Baxter Int’l, 

Inc. 678 F.3d 1357, 1361 (Fed. Cir. 2012), such as what a 

reference teaches, In re Beattie, 974 F.2d 1309, 1311 (Fed. 

Cir. 1992), and whether a skilled artisan would have had 

a reason to combine references, see In re Hyon, 679 F.3d 

1363, 1365–66 (Fed. Cir. 2012). 

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6 APOTEX INC. v. WYETH LLC

 Apotex challenges the Board’s conclusion regarding 

obviousness in two respects. First, it contends that the 

Board imported an epimeric stability limitation into the 

claims, and thereby wrongly relied on the failure of CN 

’550 to teach the epimeric stability of its composition. 

Second, Apotex argues that the Board failed to consider 

any motivation to combine the prior art of record beyond 

the problem the patentee was trying to solve, in contravention of KSR International Co. v. Teleflex Inc., 550 U.S. 

398 (2007), and cases from this court. We address and

reject each challenge in turn. 

Regarding the first challenge, an obviousness inquiry 

must focus on the limitations in the claims, see Graham v. 

John Deere Co. of Kan. City, 383 U.S. 1, 16 (1966) (noting 

that under § 103, an obviousness inquiry involves an 

assessment of “the differences between the prior art and 

the claims at issue”); see also Senju Pharm. Co. v. Lupin 

Ltd., 780 F.3d 1337, 1346 (Fed. Cir. 2015) (“[T]he district 

court properly found that corneal permeability is not 

relevant in the discussion of composition claims 12–16 

because these claims do not contain the corneal permeability limitation found in method claim 6.”), and here, the

challenged claims do not require epimeric stability. 

The Board noted that “the claims do not recite epimeric stability,” and therefore stated that the purported 

“obviousness of the claims [could] be demonstrated without a showing of epimeric stability in the prior art,”

Apotex, 2015 WL 1848261, at *9 (emphasis added), but in 

the Board’s view, Apotex failed to do so. In any event, it 

is hard to see how, in view of that statement, the Board 

imported an epimeric stability limitation into the claims. 

To the extent the Board considered epimeric stability 

during its obviousness analysis generally, it did so in the 

context of assessing whether a skilled artisan would have 

been motivated to combine references. That is not the 

same as importing a limitation into the claims. 

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APOTEX INC. v. WYETH LLC 7

Turning to Apotex’s second argument, the Board correctly considered several purported motivations to combine the prior art beyond epimeric stability. See KSR, 550 

U.S. at 419–20; see Alcon Research, Ltd. v. Apotex Inc., 

687 F.3d 1362, 1367–68 (Fed. Cir. 2012). In its brief to us, 

Apotex argues that the Board failed to consider specific 

motivations to combine the prior art references. Apotex 

first contends that that the structural similarity of tigecycline and minocycline would have motivated a skilled 

artisan to replace minocycline with tigecycline in the CN 

’550 composition. Appellant’s Br. 20. To that end, Apotex 

invokes Senju, arguing that a skilled artisan necessarily 

would have been motivated to “make the simple substitution of generational drugs.” See Oral Arg. at 4:35–4:43. 

From the Board’s opinion, it is clear that it fully considered that potential motivation to combine and found it 

wanting. In its first paragraph of analysis, the Board 

acknowledged Apotex’s assertion that one of skill in the 

art “would find reason to substitute tigecycline for minocycline” in CN ’550 because it “was known to work where 

other antibiotics have failed,” and because “minocycline 

and tigecycline are tetracycline antibiotics” with “identical A and B rings.” Apotex, 2015 WL 1848261, at *5. In 

addressing that assertion, the Board rejected Apotex’s 

proffered expert testimony on this point as unpersuasive. 

Id. at *7 (“Dr. Nelson does not explain . . . why the 

knowledge that tigecycline is effective ‘where other antibiotics have failed’ would lead a person having ordinary 

skill” to substitute tigecycline for minocycline in CN ’550). 

And Apotex did not establish that minocycline was known 

to “have failed.” 

Moreover, the Board found that no evidence suggested 

that tigecycline would be as stable in the CN ’550 composition, as the notion of “identical A and B rings” alone was 

insufficient to show that. See id. at *8; cf. Joint App.

1729–34 (Wyeth’s expert noting that the oxidation rates 

for tigecycline and minocycline differ because of their 

Case: 15-1871 Document: 42-2 Page: 7 Filed: 08/16/2016
8 APOTEX INC. v. WYETH LLC

differing structures); ’828 patent col. 3 ll. 32–34 (“[T]he 

rate of degradation may vary depending upon the tetracycline”; “the epimerization rate of tigecycline is particularly 

fast.”); id. col. 4 ll. 4–6 (“[E]pimerization is a more serious 

problem with tigecycline than with other tetracyclines[,]

such as minocycline.”). Thus, there can be no question 

that the Board considered the structural similarities

between tigecycline and minocycline as a potential motivating factor for a skilled artisan to substitute tigecycline 

for minocycline in the CN ’550 composition. The Board 

simply found that the record did not support that finding, 

and we decline to disturb its decision on appeal. Moreover, there is not necessarily a motivation to substitute one 

antibiotic for a structurally related one when the prior-art 

antibiotic has a favorable stability profile, and there is 

nothing in the record here to show that the substitution 

would solve any other problem. 

We further find Apotex’s invocation of Senju unpersuasive. As an initial matter, Senju does not stand for the 

general proposition that a skilled artisan would always be 

motivated to try later generation compounds in an old 

composition. Rather, the conclusion of obviousness in 

Senju turned on the very specific factual findings made by 

the district court about the teachings of the prior art and 

the similarities across the quinolone family of compounds. 

See, e.g., Senju, 780 F.3d at 1343 (“The ’470 patent also 

teaches that each of the disclosed quinolones have ‘similar 

substituents,’ and that pharmaceutical formulations of 

gatifloxacin follow ‘the routes well known’ with respect to 

‘oral[] and parenteral[]’ administration.” (internal citation 

omitted)). Factual findings of that nature in Senju, 

favorable to a conclusion of obviousness, are noticeably 

absent here. 

In addition to addressing the structural similarities of 

tigecycline and minocycline, the Board addressed epimeric 

stability, and found that a skilled artisan would not have 

been motivated to combine Pawelczyk, Naggar, and CN 

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APOTEX INC. v. WYETH LLC 9

’550, and use lactose, to stabilize tigecycline against 

epimer formation. See Apotex, 2015 WL 1848261, at *7, 

*9–13. In particular, the Board found that (1) none of the 

references discloses tigecycline; (2) Naggar and Pawelczyk 

do not disclose lactose, much less disclose it as a stabilizing means against epimer formation; (3) CN ’550 teaches

lactose as a “powder supporting agent,” but does not teach

that it makes a composition stable against epimerization; 

and (4) Apotex failed to show why a skilled artisan would 

have been motivated to use lactose in view of Naggar, 

when Naggar teaches a different polysaccharide, polysorbate 20, as the least effective solubilizer in a larger list

of solubilizers, such as urea. Id. at *9, *13. Moreover, the 

Board rejected Apotex’s expert testimony as “not supported by objective evidence or analysis,” instead relying on 

Wyeth’s evidence as persuasive. Id. at *10–11. Apotex 

does not now meaningfully challenge any of those factual 

findings; we likewise decline to disturb them. 

Apotex lastly argues that the Board failed to consider 

whether a skilled artisan (1) would have been motivated 

to combine the art of record to optimize the pH ranges in

CN ’550, or (2) would have modified the pH ranges in CN 

’550 to the ranges recited in the dependent claims of the 

’828 patent “because those ranges were commonly used in 

conventional injection solutions.” See Appellant’s Br. 20, 

29. Apotex correctly asserts that the Board did not expressly address those motivations, but we find no reversible error in that omission in view of Apotex’s ultimate

failure to establish why a skilled artisan would have been 

motivated to substitute tigecycline for minocycline, the

dispositive issue here. 

In sum, while tigecycline is closely related to minocycline structurally and in terms of benefit, the Board did 

not err in concluding that there was insufficient basis in 

the record to show that it would have been obvious to a 

skilled artisan to substitute tigecycline in the prior art 

minocycline composition. 

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10 APOTEX INC. v. WYETH LLC

CONCLUSION

We have considered all of Apotex’s remaining arguments, but conclude that they are without merit. The 

Board’s decision was supported by substantial evidence 

and not erroneous as a matter of law. For the reasons set 

forth above, we affirm the Board’s decision. 

AFFIRMED

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