Case Information
*2 Before R ADER , Chief Judge , B RYSON , and W ALLACH ,
Circuit Judges .
W ALLACH , Circuit Judge .
Barr Laboratories, Inc., Teva Pharmaceuticals USA, Inc., and Teva Pharmaceutical Industries Ltd. (collec- tively, “Barr”), and Sandoz Inc. (“Sandoz”) appeal from the decision of the United States District Court for the District of Delaware, which held that Barr’s and Sandoz’s proposed products (described in Abbreviated New Drug Applications (“ANDA”) Nos. 91-194 and 200487, respec- tively) infringed claim 10 of Allergan, Inc.’s (“Allergan”) U.S. Patent No. 5,688,819 (“the ’819 patent”) and that the asserted claim was not invalid. Allergan, Inc. v. Barr Judge Bryson assumed senior status on Janu- ary 7, 2013. Allergan also asserted claims 1-3 of its U.S.
Patent 6,403,649 (“the ’649 patent”), and the district court likewise found the ’649 patent was not invalid and in- fringed by Barr’s and Sandoz’s ANDAs. , 808 F. Labs., Inc. , 808 F. Supp. 2d 715, 717 (D. Del. 2011). Because the district court correctly construed the relevant claim term and determined the asserted claim was not obvious, we affirm .
B ACKGROUND
Allergan markets and sells Lumigan®, which was approved by the Food and Drug Administration (“FDA”) to reduce intraocular pressure (“IOP”) in people with ocular hypertension or glaucoma. The active ingredient in Lumigan® is bimatoprost. Allergan’s ’819 patent claims bimatoprost and methods of using bimatoprost to treat ocular hypertension or glaucoma.
1. Background of the Invention
In a healthy eye, proper IOP is maintained by
aqueous humor, which is fluid between the cornea and the
lens of the eye that transports nutrients like vitamins,
sugars, and amino acids to the cornea. Too much aqueous
humor disrupts IOP and poses a substantial risk factor
for developing glaucoma. PGF α is a naturally-occurring
prostaglandin that is known to lower IOP by increasing
the outflow of aqueous humor from the eye. Prostagland-
ins are a class of naturally-occurring substances, all of
which share the following twenty-carbon basic structure:
Supp. 2d at 736. However, the ’649 patent expired on
September 21, 2012 and thus is not at issue in this ap-
peal.
,
are numbered from 1 to 20, with 1 through 7 forming an α (alpha) chain, 13 through 20 forming an ω (omega) chain, and 8 through 12 forming a five-membered (cyclopentane) ring. The C-1 position (highlighted by the box above) features carboxylic acid, which is present in all naturally- occurring prostaglandins.
As noted, it was known prior to the invention at issue
that PGF
[2]
α lowered IOP. The prior art also revealed that
certain lipid-soluble esters of PGF α lowered IOP, and
actually showed greater hypotensive effects than the
parent compound PGF α . ’819 patent col. 2 ll. 9-38. Ac-
cording to the ’819 patent’s specification, however, pros-
taglandins like PGF α and its isopropyl ester were
associated with negative side effects like “ocular surface
hyperemia” (red eye) and “foreign-body sensation.”
Id
. col.
2 ll. 41-46. The ’819 patent discloses that certain com-
pounds that replace the carboxylic acid group with a non-
acidic substituent can reduce these side effects while
retaining the desired IOP-lowering effect.
Id
. col. 3 ll. 9-
18. One such compound is bimatoprost (cyclopentane N-
ethyl heptenamide-5-cis-2-(3 α -hydroxy-5-phenyl-1-trans-
pentenyl)-3, 5-dihydroxy, [1 α ,2 β ,3 α ,5 α ]). . col. 7 ll. 44-46. Bimatoprost is PGF α , with an ethyl amide instead
of a carboxylic acid group at the C-1 position and a phenyl
ring at C-17. [J.A.10] Bimatoprost has the structure
depicted below:
,
by increasing the flow of aqueous humor leaving the eye.
2. Patent-in-Suit
The ’819 patent is related to and claims priority from U.S. Patent No. 5,352,708 (“the ’708 patent”), filed on September 21, 1992. The ’819 patent was issued on November 18, 1997, and was extended for 698 days as a result of the FDA’s regulatory review of Lumigan®. Asserted claim 10 of the ’819 patent ultimately depends from independent claim 5, which recites:
5. A method of treating ocular hypertension or glaucoma which comprises applying to the eye an amount sufficient to treat ocular hypertension or glaucoma of the formula
wherein . . . X is a radical selected from the group consisting of –OR [4] and –N(R [4] ) [2] wherein R [4] is se- lected from the group consisting o[f] hydrogen, a lower alkyl radical having from one to six carbon atoms,
wherein R [5] is a lower alkyl radical having from one to six carbon atoms . . . .
’819 patent col. 13 l. 49 – col. 14 l. 7 (emphasis added to disputed claim term). Dependent claim 10 discloses five compounds that may be used in the treatment of ocular hypertension or glaucoma in which X is –N(R ) . . col. 14 l. 55 – col. 15 l. 7. One of these compounds is bimato- prost, listed as cyclopentane N-ethyl heptenamide-5-cis-2- (3 α -hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1 α ,2 β ,3 α ,5 α ]. Id. col. 15 ll. 1-3.
3. Barr’s and Sandoz’s Abbreviated New
Drug Applications
On March 26, 2009, Barr filed an ANDA for a ge- neric version of Lumigan®, listing Allergan’s ’819 patent as one of the Orange Book-listed patents associated with Lumigan®. Barr’s ANDA contained a Paragraph IV certification stating that Barr believed each relied-upon Orange Book patent was “invalid or [would] not be in- fringed by the manufacture, use, or sale of the new drug for which the application [was] submitted.” 21 U.S.C. § 355(b)(2)(A)(iv). Sandoz likewise filed an ANDA for a generic version of Lumigan®, also with an accompanying Paragraph IV certification. Allergan filed patent in- fringement suits against Barr and Sandoz; the suits were consolidated into one action for a bench trial on patent invalidity and infringement.
4. District Court Proceedings A. Claim Construction
The only claim term disputed before the district
court was –N(R
[4]
)
[2]
as used in claim 5, on which asserted
claim 10 depends. The parties disagree whether or not
–N(R
[4]
)
[2]
requires identical R
[4]
substituents. If it does,
bimatoprost’s use of nonidentical R
[4]
substituents—
hydrogen (H) and an ethyl group (CH
[2]
CH
[3]
)—would fall
outside the protection of the ’819 patent. The district
court initially agreed with Barr and Sandoz that “the
plain and ordinary meaning” of –N(R
[4]
)
[2]
suggested that
identical R
[4]
substituents were required; however, it
ultimately found that Allergan had acted as its own
lexicographer by defining –N(R
[4]
)
[2]
to permit nonidentical
R elements. Therefore, the district court held that, as
used in the ’819 patent, the –N(R ) limitation did not
require the R substituents to be identical.
Allergan, Inc.
,
B. Invalidity
The district court found that asserted claim 10 of the ’819 patent was not invalid, and rejected Barr and Sandoz’s arguments based upon anticipation and obvi- ousness. The primary invalidity reference asserted during trial was a patent to Johan Stjernschantz, pub- lished as Patent Cooperation Treaty Application No. WO 90/02253 on March 22, 1990 and entitled “Prostaglandin Derivatives for the Treatment of Glaucoma or Ocular Hypertension” (“Stjernschantz”). Barr and Sandoz’s expert witness, Dr. Ashim Kumar Mitra, testified that asserted claim 10 was obvious over Stjernschantz, wheth- er alone or in combination with other prior art, including unexamined Japanese Patent Application No. S49-69636 (“JP ’636”). Barr and Sandoz also asserted post-trial that all of the asserted claims were obvious over Stjernschantz in combination with a chapter in the textbook “Prodrugs: Topical and Ocular Drug Delivery” entitled “Improved Ocular Drug Delivery with Prodrugs” (“Lee & Bund- gaard”).
Stjernschantz discloses IOP-reducing derivatives of certain prostaglandins. Two such derivatives are dis- closed compounds 2 and 9, which are both isopropyl esters that convert into bimatoprost-free acid upon hydrolysis in the eye. A third disclosed derivative is compound 17, bimatoprost-free acid or 17-phenyl PGF α , which features a carboxylic acid functional group at C-1. The structural difference between bimatoprost and these Stjernschantz derivatives is that bimatoprost features an ethyl amide functional group at the C-1 position, whereas compounds 2 and 9 have an isopropyl ester at C-1, and compound 17 has carboxylic acid.
However, these obviousness theories were under-
mined when “Mitra’s credibility was eviscerated on cross-
examination.” ,
Barr and Sandoz filed this timely appeal. This court has jurisdiction pursuant to 28 U.S.C. § 1295(a)(1). pound 9 became latanoprost, which is marketed as Xala- tan®, a leading antiglaucoma treatment.
D ISCUSSION
1. The District Court Correctly Held That –N(R [4] ) [2] As Used in the ’819 Patent Includes Compounds With Non-Identical R [4] Elements The district court determined that “the plain and ordinary meaning of –N(R [4] ) [2] would support [Barr and Sandoz’s] construction that the R [4] elements are identical functional groups,” but went on to find that Allergan had acted as its own lexicographer in defining –N(R [4] ) [2] con- trary to its ordinary meaning. , 808 F. Supp. 2d at 725-26. Barr and Sandoz appeal the district court’s construction of the –N(R ) [2] term, arguing that the plain and ordinary meaning of –N(R ) requires identical R elements, and that Allergan failed to make any express statement departing from that plain and ordinary mean- ing.
Claim construction is a question of law subject to
de
novo
review.
Cybor Corp. v. FAS Techs., Inc.,
138 F.3d
1448, 1456 (Fed. Cir. 1998) (en banc). Claim terms are
generally given their “ordinary and customary meaning”
as they would be understood by a person of ordinary skill
in the art.
Phillips v. AWH Corp.,
In this case, a person of ordinary skill in the art considering the entire ’819 patent would construe the disputed –N(R [4] ) [2] term to encompass nonidentical R [4] elements. The disputed claim term arises in independent claim 5, in which –N(R [4] ) [2] is used to claim one of the molecules that may be located at the C-1 position of the compound. Claim 5 further recites that R [4] must be se- lected from a Markush group [6] “consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms, wherein R [5] is a lower alkyl radical having from one to six carbon atoms.” ’819 patent col. 13 ll. 31-39. [J.A.49] Asserted claim 10 ultimately depends from claim 5 and expressly includes three compounds with nonidentical R [4] elements, including bimatoprost. [7] Specifically, bimato- prost has two different substituents at the R [4] position, both of which are claimed in the Markush group: hydro- gen (H) and an ethyl group (CH [2] CH [3] ). Id . col. 14 l. 60 - col. 15 l. 7. Two other compounds listed in claim 10 also feature differing R [4] elements. [8] Id . col. 14 ll. 65-67; col. 15 ll. 4-6. Consistently, claim 18, depending from claim 11, recites the same three compounds as having a –N(R [4] ) [2] molecule at the C-1 position. Id . col. 17 ll. 14-22. These same three compounds, all with nonidentical R [4] substitu- ents of –N(R [4] ) [2] , also appear in the specification’s list of “novel compounds [that] may be used in the pharmaceuti- cal compositions and the methods of treatment of the present invention.” . col. 7 ll. 19-21, 41-49.
Barr and Sandoz nevertheless focus on the district
court’s preliminary conclusion that the plain and ordinary
meaning of –N(R
[4]
)
[2]
required identical R
[4]
elements.
However, this preliminary conclusion was based on ex-
trinsic evidence, such as expert testimony that “[t]he (X) y nomenclature” was “commonly used” to represent identi-
cal substituents,
Allergan,
2. The District Court Correctly Held That the Asserted Claim Is Not Invalid As Obvious The district court held that Barr and Sandoz failed to prove obviousness by clear and convincing evidence. Barr and Sandoz appeal this determination. First, they argue that the district court’s adverse credibility determi- nation of Dr. Mitra did not excuse the court from its obligation to independently review the submitted prior art references. Additionally, they assert that their obvious- ness theories are supported even when considering only the testimony of Allergan’s experts and corroborating evidence.
“The ultimate judgment of obviousness is a legal
determination,”
KSR Int’l Co. v. Teleflex Inc.
, 550 U.S.
398, 427 (2007), which we review
de novo
,
Procter &
Gamble Co. v. Teva Pharm. USA, Inc.
,
A. The District Court Did Not Err In Finding Expert Testimony Was Required To Show Invalidity The district court found that Dr. Mitra’s credibility was “flawed on a fundamental level” and declined to assign any weight to his opinions. Allergan , 808 F. Supp. 2d at 735. This was a fair assessment of the testimony of Dr. Mitra, whose prevarication and inconsistency were repeatedly demonstrated during Allergan’s cross exami- nation. For instance: (1) Dr. Mitra incorrectly drew the bimatoprost molecule and utilized slides that inaccurately represented bimatoprost; (2) his previous testimony given at another trial directly contradicted his stated opinion that Stjernschantz persuasively showed the hypotensive effect of prostaglandin analogues; and (3) his previously published opinions that bimatoprost was more effective than latanoprost and acted through a “novel prostamide receptor” contradicted his trial testimony that bimato- prost was just a “delivery vehicle” for bimatoprost-free acid. . at 733-34.
The district court declined to independently “review the prior art references and weigh their import absent the guidance of an expert.” , 808 F. Supp. 2d at 736 n.21. On appeal, Barr and Sandoz challenge this refusal to consider their obviousness theories, contending that discrediting Dr. Mitra “did not then permit the [district] court to ignore all other evidence. . . .” BB.49.
This court has noted that “‘expert testimony re-
garding matters beyond the comprehension of laypersons
is sometimes essential,’ particularly in cases involving
complex technology.”
Wyers v. Master Lock Co.
, 616 F.3d
1231, 1240 n.5 (Fed. Cir. 2010) (quoting
Centricut, LLC v.
Esab Group, Inc.
, 390 F.3d 1361, 1369-70 (Fed. Cir.
2004)). Obviousness is one area in which expert testi-
mony may be required.
See Proveris Scientific Corp. v.
Innovasystems, Inc.
,
The district court appears to have found this case to
be “sufficiently complex to fall beyond [the] grasp of
ordinary layperson[s].” , 808 F. Supp. 2d at 736
n.21 (characterizing the holding of
Proveris Scientific
Corp.
,
B. Allergan’s Expert’s Testimony Does Not Support Barr and Sandoz’s Obviousness Theories On appeal, Barr and Sandoz argue that their obvi- ousness theories are supported by expert testimony: that of Allergan’s expert, Dr. Timothy L. Macdonald, whose testimony the district court found to be credible. In particular, they contend that Dr. Macdonald’s testimony supports the three facts needed to show the asserted claim is obvious in view of Stjernschantz and other refer- ences: (1) Stjernschantz taught that bimatoprost-free acid lowered IOP; (2) Stjernschantz’s compound 2 hydrolyzed into bimatoprost-free acid when placed in the eye; and (3) a skilled artisan would have known that substituting an amide for the ester at the C-1 position would result in a prodrug that hydrolyzed into bimatoprost-free acid in the eye.
Dr. Macdonald provided testimony consistent with the first two propositions. See J.A.2086 (testifying that Stjernschantz taught bimatoprost-free acid would have the effect of lowering IOP); J.A.2062-63 (testifying that Stjernschantz taught compound 2 would hydrolyze into bimatoprost-free acid once in the body). However, his testimony contradicts the third requirement. Dr. Mac- donald instead asserted that one of skill in the art would not have believed substituting an amide at the C-1 posi- tion would create a prodrug that hydrolyzed into bimato- prost-free acid once in the eye. To the contrary, Dr. Macdonald testified that an amide converts into carbox- ylic acid at such a slow rate that “one doesn’t consider it as a candidate [as a prodrug].” J.A.2065-66. He explained that “a prodrug approach relies on efficient conversion of the prodrug into the drug,” and the “500-year half life” of an amide in water was “not an efficient conversion.” J.A.2067; see also J.A.1996. Dr. Macdonald concluded that the prior art did not teach or motivate one of skill in the art to substitute an amide at the C-1 position to create a glaucoma drug. Given Dr. Macdonald’s testimony to the contrary, Barr and Sandoz can point to no credible expert testimony showing that substituting an amide at the C-1 position would have been obvious to a skilled artisan at the time of the invention. Because of this gap, we hold that Barr and Sandoz have failed to show obviousness of the ’819 patent by clear and convincing evidence.
C ONCLUSION
For the foregoing reasons, we affirm the district court’s claim construction and determination of nonobvi- ousness.
AFFIRMED
Notes
[2] Bimatoprost is a prostamide and is also known as 17-phenyl PGF
[2] α C-1 ethylamide.
[3] The FDA lists all patents protecting FDA- approved drugs in a publication titled the “Approved Drug Products With Therapeutic Equivalence Evaluations,” which is generally referred to as the “Orange Book.” Caraco Pharm. Labs., Ltd. v. Forest Labs., Ltd., 527 F.3d 1278, 1282 (Fed. Cir. 2008) (citing 21 U.S.C. § 355(b)(1), (c)(2)).
[4] Other prior art discussed by Dr. Mitra at trial included: U.S. Patent No. 4,599,353, and a chapter of a 1977 textbook (“Design of Biopharmaceutical Properties through Prodrugs and Analogs”) entitled “Physical Model Approach to the Design of Drugs with Improved Intestinal Absorption.”
[5] Compound 9 differs from compound 2 only in that it has a single bond between C-13 and C-14, whereas compound 2 has a double bond in that position. Com-
[6] “A Markush group is a listing of specified al-
ternatives of a group in a patent claim, typically ex-
pressed in the form: a member selected from the group
consisting of A, B, and C.”
Abbott Labs. v. Baxter Pharm.
Prods., Inc.
,
[7] Claim 9 ultimately depends from claim 5 and claims –N(R
[4] )
[2] as one of the molecules at the C-1 position. ’819 patent col. 14 ll. 56-57. Claim 10, in turn, depends from claim 9. . col. 14 l. 58. Therefore, although Barr and Sandoz stress that the –N(R
[4] )
[2] term does not appear in claim 10, the compounds in claim 10 plainly contain – N(R
[4] )
[2] .
[8] These compounds are: cyclopentane N- isopropyl heptenamide-5-cis-2-(3 α -hydroxy-5-phenyl-1- trans-pentenyl)-3, 5-dihydroxy, [1 α ,2 β ,3 α ,5 α ], and cyclopen- tane N- methyl heptenamide-5-cis-2-(3 α -hydroxy-5-phenyl- 1-trans-pentenyl)-3, 5-dihydroxy, [1 α ,2 β ,3 α ,5 α ]. ’819 patent col. 14 ll. 65-67; col. 15 ll. 4-6 (emphases added).
[9] Barr and Sandoz also rely on other Allergan witnesses to support their obviousness claim, but we have carefully reviewed the record and find nothing in the testimony of these additional witnesses that could over- ride Dr. Macdonald’s expert opinion of non-obviousness or establish clear and convincing evidence of obviousness.
[10] We need not determine whether the district court abused its discretion in finding that Barr and San- doz waived their post-trial obviousness theories, because, as determined above, the record contains insufficient expert testimony to support any of Barr and Sandoz’s obviousness theories.