ViiV Healthcare UK Ltd. et al v. Lupin Ltd. et al

Filing 126

Claim Construction OPINION. Signed by Judge Richard G. Andrews on 11/16/2012. Associated Cases: 1:11-cv-00576-RGA, 1:11-cv-00688-RGA(nms)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

VIIV HEALTHCARE UK LTD. AND VIIV
HEALTHCARE CO.,
Plaintiffs,
C.A. 11-576-RGA

V.

LUPIN LTD. AND LUPIN
PHARMACEUTICALS, INC.,
Defendants.

VIIV HEALTHCARE UK LTD. AND VIIV
HEALTHCARE CO.,
Plaintiffs,

C.A. 11-688-RGA

V.

TEVA PHARMACEUTICALS USA, INC.,
Defendant.

Brian E. Farnan, Esq., Wilmington, Delaware; F. Christopher Mizzo, Esq. (argued),
Washington, D.C.; Tiffany P. Cunningham, Esq. (argued), Chicago Illinois; Attorneys for
Plaintiffs Viiv Healthcare UK Limited and and Viiv Pharmaceutical.
John C. Phillips, Jr., Esq., Wilmington, Delaware; Paul J. Molino, Esq. (argued),
Chicago, Illinois; Deanne M. Mazzochi, Esq. (argued), Chicago, Illinois; Attorneys for
Defendants Lupin Ltd. and Lupin Pharmaceuticals, Inc.
David E. Moore, Esq., Wilmington, Delaware; Ira J. Levy, Esq. (argued), New York,
New York; Eric H. Yecies, Esq. (argued), New York, New York; Attorneys for
Defendant Teva Pharmaceuticals USA, Inc.

November /

fn

2012

Wilmingto~elaware

This is a claim construction opinion. Plaintiffs Viiv Healthcare UK Ltd. and Viiv
Healthcare Co. assert U.S. Patent No. 6,417,191 ('" 191 Patent") against Defendants Lupin Ltd.,
Lupin Pharmaceuticals, Inc., and Teva Pharmaceuticals, USA, Inc. 1 The '191 Patent relates to
therapeutic combinations of anti-HIV drug compounds.

I.

Agreed Upon Term
The parties have agreed to the construction of the term "simultaneously" as follows:

Agreed Upon Construction

Undisputed Claim Term

at the same time, either in the same or separate
pharmaceutical formulations

"simultaneously"
(claims 8, 21, 27, 36)

II.

Disputed Terms
This brings the Court to the disputed terms. The disputed terms "animal,"

"physiologically functional derivative," and "symptoms or effects of an HIV infection" are
construed as follows:

Disputed Claim
Term
"animal" (claims I,

Court's Construction
Plain and ordinary meaning.

11,20,24,30,32,39)

1

Viiv filed suit against the Lupin entities and Teva separately. The claim construction briefing and hearing were
conducted jointly for purposes of efficiency.

2

"physiologically
functional derivative"
(claims 1, 2, 13, 15,
48, 51)

"symptoms or effects
of an HIV infection"
(claims 1, 20, 32)

Any physiologically acceptable salt, ether, ester, salt of such ester of
1592U89, zidovudine or 3TC; or solvates of any thereof and their
physiologically functional derivatives; or any other compound which
upon administration to the recipient, is capable of providing (directly or
indirectly) such a compound or an antivirally active metabolite or
residue thereof.
Plain and ordinary meaning.

The remaining terms present more complicated issues of claim construction and merit
written explanation.
A. "Synergism"
Disputed
Claim Term/Phrase
from Patent-in-Suit
"(IS, 4R)cis-4-[2-amino-6(cyclopropylamino)9H-purin-9-yl ]-2cyclopentene-1methanol or a
physiologically
functional derivative
thereof and (2R, cis)4-amino-1-(2hydroxymethyl1,3-oxathiolan-5-yl)( 1H)-pyrimidin-2-one
or a physiologically
functional derivative
thereof'
(claim 48)

ViiV's Proposed
Construction

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its
plain and ordinary
meaning is a
combination of (1 S,
4R)cis-4-[2-amino-6(cyclopropylamino )9H-purin-9-yl]-2cyclopentene-1methanol or a
physiologically
functional derivative
and (2R, cis )-4amino-1-(2hydroxymethyl1,3-oxathiolan-5-yl)( 1H)-pyrimidin-2-one
or physiologically
functional derivative.

[Lupin takes no
position on this term.]

Synergistic
combination of(IS,
4R)- cis-4-[2-amino6(cyclopropylamino )9H-purin-9-yl]- 2cyclopentene-1methanol or a
physiologically
functional derivative
thereof and (2R, cis)4-amino-1-(2hydroxymethyl-1 ,3oxathiolan-5-yl)-( 1H)pyrimidin-2-one or a
physiologically
functional derivative
thereof

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Disputed Claim
Term/Phrase from
Patent-in-Suit
"combination"
(claims 1, 8, 10, 20,
21,23,27,29,32,36,
38)

Disputed Claim
Term/Phrase from
Patent-in-Suit
"pharmaceutical
formulation"
/"formulation"
(claims 10, 16, 23, 29,
38,48,51)

Disputed Claim
Term/Phrase from
Patent-in-Suit
"combination"
(claims 1, 8, 10,20,
21,23,27,29,32,36,
38)

Disputed Claim
Term/Phrase from
Patent-in-Suit
"pharmaceutical
formulation"
/"formulation"
{claims 10, 16, 23, 29,

ViiV's Proposed
Construction

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its
plain and ordinary
meaning is
combination.
ViiV's Proposed
Construction

Synergistic
combination.

Synergistic
combination

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its
plain and ordinary
meaning is a
combination of one or
more active
ingredients with one
or more
pharmaceutically
acceptable carriers or
excipients and
optionally other
therapeutic agents.

Synergistic
pharmaceutical
formulation I
Synergistic
formulation.

Teva does not seek
construction of this
claim term and
therefore does not
proffer a construction.

ViiV's Proposed
Construction

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its
plain and ordinary
meaning is
combination.
ViiV's Proposed
Construction

Synergistic
combination.

Synergistic
combination

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its

Synergistic
pharmaceutical
formulation I
Synergistic

Teva does not seek
construction ofthis
claim term and
therefore does not

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38, 48, 51)

plain and ordinary
meanmg Is a
combination of one or
more active
ingredients with one
or more
pharmaceutically
acceptable carriers or
excipients and
optionally other
therapeutic agents.

formulation.

proffer a construction.

Disputed Claim
Term/Phrase from
Patent-in-Suit
"therapeutically
effective amount"

ViiV's Proposed
Construction

Lupin's Proposed
Construction

Teva's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
construe the term, its
plain and ordinary
meaning is an amount
that will treat or
prevent symptoms or
effects of an HIV
infection in an
infected animal.

Amount sufficient to
cause a synergistic
response.

Teva does not seek
construction of this
claim term and
therefore does not
proffer a construction.

(claims 1, 20, 32)

The construction of all of these terms hinges upon the same dispute: whether the
"synergism" achieved by the drug combination functions to limit the '191 Patent's claims.
Synergism is not mentioned within any of the claims. Defendants, however, argue that the
specification and prosecution history demonstrate that synergism is an essential element of the
claimed drug combination. They argue that the patentee disavowed non-synergistic
combinations and the claims should be construed accordingly. Viiv argues that the synergistic
activity is not an element of the drug combination itself, but is an unexpected effect or result of

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the drug combination's administration, which was emphasized in order to overcome repeated
rejections for obviousness.
Claim terms should generally be given their ordinary and customary meaning. ICU

Med, Inc. v. Alaris Med Sys., Inc., 558 F.3d 1368, 1374 (Fed. Cir. 2009). That meaning is
determined by how a person of ordinary skill in the art in question would understand the terms at
the time of the invention. Id In determining this meaning, the claims must be read in view of
the specification, of which they are a part. SciMed Lifo Sys., Inc. v. Advanced Cardiovascular

Sys., Inc., 242 F.3d 1337, 1340 (Fed. Cir. 2001). "Where the specification makes clear that the
invention does not include a particular feature, that feature is deemed to be outside the reach of
the claims of the patent, even though the language of the claims, read without reference to the
specification, might be considered broad enough to encompass the feature in question." Id at
1341. "The patentee may demonstrate intent to deviate from the ordinary and accustomed
meaning of a claim term by including in the specification expressions of manifest exclusion or
restriction, representing a clear disavowal of claim scope." Id "Mere criticism of a particular
embodiment encompassed in the plain meaning of a claim term is not sufficient to rise to the
level of clear disavowal. ... It is likewise not enough that [all of the embodiments] contain a
particular limitation." Thorner v. Sony Computer Entm't Am. LLC, 669 F.3d 1362, 1366 (Fed.
Cir. 2012). Any disclaimer must be clear and unmistakable. Id at 1366-67.
Defendants begin their disavowal argument with reliance on the specification.
Defendants point to the title of the '191 Patent itself, which emphasizes the synergistic aspect of
the invention: "Synergistic Combinations ofZidovudine, 1592U89, and 3TC." Defendants then
refer to description that explains the synergistic anti-viral activity achieved by the invention:

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Unexpectedly, it has now been found that by combining 1592U89, zidovudine and 3TC a
synergistic anti-HIV effect is achieved. The result is surprising since all three drugs act
upon the same molecule, HIV Reverse Transcript use. It is a feature of this invention that
the use ofthis drug combinations [sic] will provide synergistic antiviral effects, more
complete viral suppression over a longer period, limit the emergence of drug resistant
HIV mutants and allow better management of drug-related [toxicity].
Patent '191, 11. 2:08-15. Defendants particularly emphasize the language describing "synergistic
antiviral effects" as a "feature of the invention." Defendants argue that this statement speaks to
the scope of the invention itself as requiring synergism and the claims should be limited
accordingly.
Defendants next cite another passage from the specification: "If there is sequential
administration, the delay in administering the second and third active ingredients should not be
such as to lose the benefit of a synergistic therapeutic effect of the combination of the active
ingredients." !d. at 3:62-65. Defendants argue that these directions explicitly mandate a
particular method of administration to ensure that the synergistic drug activity is not lost.
Defendants also point to the description of specific drug ratios aimed at ensuring synergism?
According to Defendants, these are additional pieces of evidence that synergism is an essential
part of the invention and that non-synergistic drug combinations have been disclaimed by the
patentee.
The Court does not find that the specification evinces "manifest statements of exclusion
or restriction" giving rise to clear and unmistakable disclaimer. Disclaimer of claim scope most
2

The ratios are explained as follows:
The synergistic effects ofthe combination of 1592089, zidovudine and 3TC (or, alternatively to 3TC,
FTC), or a physiologically functional derivative of any thereof are seen over a ratio, for example, of 1 to
20:1 to 20:1 to 10 (by weight), preferably 1 to 10:1 to 10: 1 to 5 (by weight), particularly 1 to 3: 1 to 3: 1 to 2
(by weight)[.] Conveniently each compound will be employed in the combination in an amount at which it
exhibits antiviral activity when used alone.

!d. at4:17-25.

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typically occurs through a patentee's differentiation of prior art. Here, at no point does the
patentee criticize a prior art for lacking synergism and then distinguish the drug combination for
its synergistic aspect. To the contrary, the patentee differentiates her invention by emphasizing
the novelty of combining the drugs in the first place. 3 Further, when the specification explains
what the "present invention" consists of, it describes the drug combination. 4 Synergism or
synergistic effects are only discussed insofar as they constitute unexpected results. The
description of "synergistic anti-viral effects" as a "feature of the invention" does not give rise to
disavowal of non-synergism. The discussion just preceding this description makes clear that this
synergism feature came along "unexpectedly" and that the "result [was] surprising." 5 This
confirms the nature of synergism as an incident of the claimed drug combination, but not as a
component or property of the combination itself. 6
Despite Defendants' arguments, the specification's detailing of preferred drug
combination ratios for the delivery of synergy is not persuasive evidence of disclaimer.

3

The specification describes the prior art in relation to the present invention as follows:
To date the treatment ofHIV infection has relied to a large extent upon monotherapy with
nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine (ddl), zalcitabine (ddC) and
stavudine (D4T). However, these drugs eventually become less effective due either to the emergence of
HIV resistant mutants [or] because of toxicity. Thus, new therapies are needed.
The combination of zidovudine with either ddC or ddl has shown promising results in HIV
infected patients[.]

Id at 1:59-67.
4

For example, the specification states, "[T]he present invention provides a combination comprising 1592U89 or a
physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof and 3TC
(or, alternatively to 3TC, FTC) or a physiologically functional derivative thereof." Jd at 2:18-23.
5

"Unexpectedly, it has now been found that by combining 1592U89, zidovudine and 3TC a synergistic anti-HIV
effect is achieved. This result is surprising since all three drugs act upon the same molecule, HIV Reverse
Transcript use." Jd at 2:7-9.
6

1t makes sense for the patentee to have emphasized these unexpected results, as the '191 Patent's application was
repeatedly rejected for obviousness. (D.I. 67, Exhs. 37-41).

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Dependent claims 2-4 claim these same ratios. These claims are dependent to claim 1, which
does not mention any ratio. The rule of claim differentiation suggests that claim 1 should be read
more broadly than its dependent claims 2-4 and is thus not limited to the described ratios. It
therefore follows that the effects of these ratios are not limiting on the independent claim.
Finally, the specification's advice that the combination "should" be taken within a certain time
period is not strong enough language to justify finding a "clear and unmistakable" disclaimer.
Moreover, even in this context, synergism is described as an effect of the combination rather
than a property of the combination itself. In addition, the claims describe numerous distinct
methods of administration, and they are not limited to sequential administration, thus
undermining the argument that the statements should limit every claim. For all these reasons, the
Court holds that specification disclaimer does not render "synergism" as a limit on claim scope.
Defendants also argue for prosecution disclaimer. "[A] patentee may limit the meaning
of a claim term by making a clear and unmistakable disavowal of scope during prosecution."

Computer Docking Station Corp. v. Dell, Inc., 519 F.3d 1366, 1374 (Fed. Cir. 2008). This may
occur where an applicant clearly characterizes an invention in order to overcome rejections based
on prior art. Jd Prosecution disclaimer is not found where the file history is ambiguous. Id at
1375.
Defendants argue that the patentee's responses to the PTO Examiner's rejections
disclaimed non-synergistic drug combinations. The '191 Patent application was rejected
numerous times for obviousness. (D.I. 67, Exhs. 37-41). The rejections were predicated on the
rationale that "[i]t is generally considered prima facie obvious to combine two compounds each
of which is taught by the prior art to be useful for the same purpose, in order to form a
composition which is to be used for the very same purpose." (See, e.g., D.I. 67, Exh. 41 at 2-3).
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In response to these rejections, the patentee emphasized the originality of combining the drug
compounds and the unexpected results of the combination. The patentee stated the following
within a November 19, 1998 response:
Nothing in the references suggests that HIV infections can be successfully treated with
[the triple drug combination]. Figure 1 of the instant specification demonstrated that no
measurable HIV -1 mediated cytopathic effect remained upon treatment of HIV -1 infected
MT4 cells with all three compounds. Furthermore, these compounds were found to be
synergistic[.]
(D.I. 67, Exh. 26 at 2). Despite this response, the application was again rejected for obviousness.
Within the next response, dated September 14, 1999, the patentee again attempted to change the
examiner's mind, referencing proof of the drug combination's synergistic effects:
The Examiner contends that Applicants fail to illustrate the presence of unexpected
benefits. On the contrary, the specification at page 2 states the combinations of the
present invention are synergistic and data provided in Figure 1 indicates the excellent
anti-HIV effect of the combinations of the present invention.
(D.I. 67, Exh. 2 at 2). The patentee further explained why the synergism of the combination was
to be unexpected and that it rendered the drug combination non-obvious and patentable:
[D]rugs having the same mode of action would be expected to be antagonistic.
The drugs of the instant application are all inhibitors of HIV reverse transcriptase
and therefore, would be expected to be antagonistic or at best additive. This is not
the case, as illustrated in the specification and in the Daluge article. In summary,
the demonstration of synergy between [the combined drugs] is an unexpected
effect.
(!d. at 3). Despite the patentee's insistence, the Examiner again rejected the application as

obvious. Only after the patentee filed a March 14, 2001 response with the affidavit of Inventor
Martha Heider St. Clair attached was the Examiner persuaded. This response again insisted that
"the combination is synergistic." (D.I. 67, Exh. 42 at 2). It also explained that this result was
surprising and unexpected, as "[i]t would not be obvious to one skilled in the art to combine

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three drugs that have the same viral mechanism of action to achieve a synergistic effect." (/d.).
The attached St. Clair affidavit stated the following:
8.
The results of this experiment indicate that the triple combination of
zidovudine, 3TC and 1592089 was synergistic in suppression of viral replication
in lymphocytes in vitro.

9.

The synergistic effects ofzidovudine, 3TC and 1592089 was unexpected
because zidovudine, 3TC and 1592089 are all nucleoside reverse transcriptase
inhibitors, and therefore, act upon the same viral target in cells. Because of the
same mechanism of action ofzidovudine, 3TC and 1592089 it would not be
obvious to one skilled in the art that combining these three agents would result in
the synergistic effect described above.

(D.I. 67, Exh. 3 at~~ 8-9). In response to this filing, the Examiner finally allowed the
application, agreeing that "it would not be obvious for the skilled artisan to employ the claimed
compounds concomitantly and expect the therapeutic effect herein claimed." (D.I. 67, Exh. 30 at
2). The Examiner specifically cited paragraphs eight and nine of the St. Clair affidavit as support
for overcoming the rejections for obviousness. (!d.).
Defendants argue that this file history makes clear that the applicants only intended to
claim synergistic combinations of the drug compounds and disavowed all non-synergistic
combinations. Classic prosecution disclaimer occurs when an applicant escapes rejection for
anticipation through narrowing statements to the examiner differentiating the application from
the prior art. The claimant then attempts to "recapture" the disclaimed scope by submitting a
final patent application with claims covering the scope of the prior art that was previously
distinguished. This is not what occurred here. The '191 application was never rejected as
anticipated by prior art, as the Examiner agreed that nothing in the prior art disclosed the
combined use of the drug compounds. 7 It was thus not necessary for the patentee to narrow

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"That the prior art failed to employ one, or another prior art antiviral compound concomitantly in the prior art
medicament composition fails to reduce the prior art's obviation power." (D.I. 67, Exh. 38 at 2).

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claim scope in order to defeat the Examiner's rejections. Instead, the patentee was required to
prove that it would not be obvious to administer a combination of drugs known to be individually
effective against the HIV virus for that same effective purpose. The patentee eventually proved
the nonobvious nature of the invention by successfully arguing that the combined use of the drug
compounds would not be expected to be as effective as proven. This was because the drug
compounds have the same "mode of action" in fighting the HIV virus, and typically drugs with
the same mode of action have antagonistic rather than synergistic therapeutic effects. These
arguments were accepted by the Examiner. They should not be considered clear and
unmistakable disclaimer, because they did not require the claims to be narrowed, distinguished,
or amended. Had the patentee proved the existence of synergistic effects (and thus nonobviousness) via responses that altered the chemical or physical characteristics of the drug
combination itself, those responses would arguably limit the scope of the claims, as the invention
itself would have been re-characterized. Instead, the properties of the drug combination never
needed to be altered or narrowed in order to prove the existence of synergism, as synergism was
maintained as an intended result from the beginning of the application process. Statements
during prosecution that purely concern the intended results of the administration of drug
compounds do not limit the patent's claims. See Bristol-Myers Squibb Co. v. Ben Venue
Laboratories, Inc., 246 F.3d 1368, 1375 (Fed. Cir. 2001). For these reasons, Defendants have

failed to show clear and unmistakable disclaimer of non-synergistic combinations.
The Court thus adopts the plain and ordinary meaning for each term in this group.

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2.

"A single combined formulation"

The Court next construes "a single combined formulation." The parties' proposed
constructions are as follow:
Disputed Claim
Term/Phrase
"a single combined
formulation"

Viiv's Proposed
Construction

Plain and ordinary
meaning. If the Court
wishes to further
(claims 10, 23, 29, 38) construe the term, its
plain and ordinary
meanmg 1s one
formulation.

Lupin's Proposed
Construction

Teva's Proposed
Construction

A dosage form
wherein the 1592U89,
zidovudine and 3TC
are mixed together in
the same admixture.
(Claims 10 and 23).

No position, as none
of the claims asserted
against Teva contain
this term.

A dosage form
wherein the 1592U89
and 3TC are mixed
together in the same
admixture. (Claims 29
and 38).

"A single combined formulation" is used within claims 10, 23, 29, and 38 ofthe '191
Patent. The claim construction dispute hinges on whether the word "combined" within this
phrase requires the drug compounds to be mixed together within the same admixture. Viiv
argues that "combined" only requires that the individual drug compounds be contained within
one formulation and places no restrictions on how the drugs are physically composed within that
formulation. "A single combined formulation" is thus arguably due its plain and ordinary
meaning. In the alternative, Viiv offers "one formulation." Lupin argues that Viiv' s
construction fails to give "combined" any meaning. Lupin points to claim 6, which claims a
"unit dosage form." According to Lupin, a "unit dosage form" already claims Viiv's
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construction, i.e., a single formulation of the drug compounds with no restriction on how the
drugs are physically composed within the formulation. Lupin argues that the presence of the
word "combined" within the phrase "single combined formulation" necessarily makes the scope
of that phrase narrower than "unit dosage form." Lupin concludes that "combined" can only be
construed faithfully with the specification if it requires the drug compounds to be uniformly
mixed in the same admixture.
I do not agree with Lupin. It is not the case that the word "combined" within "a single
combined formulation" makes that phrase narrower than "unit dosage form." The specification
states, "The formulations may be presented in unit-dose or multi-dose sealed containers, for
example, ampoules and vials[.]" '191 Patent, 11. 7:27-29. This indicates that a single
formulation is not equivalent to a "unit-dosage form," as a single formulation may encompass
both "unit-dose" and "multi-dose" containers. The fact that a "single formulation" is not
equivalent to a "unit dosage form" defeats the inference that a "single combined formulation"
must be more narrowly construed than "unit dosage form." This undermines Lupin's argument
that "combined" necessarily gives rise to the admixture limitation. Further consideration of the
claims reveals that "combined" simply requires that the drug compounds are contained within a
single pharmaceutical formulation, regardless of admixture. Claim 1 broadly covers the
administration of the claimed combination and places no limits on the methods of administration.
This means that drugs that can be administered at the same or separate times, whether in separate
formulations (one compound per formulation) or combined formulations (at least two
compounds combined in the same formulation). Various dependent claims then narrow the
scope of the "methods" of "administ[ration]" of the claimed "combination." Dependent claim 21
refers to methods "wherein the combination is administered simultaneously," dependent claim 22

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refers to methods "wherein the combination is administered sequentially," and dependent claim
23 refers to methods with a "single combined formulation." Claim 21's use of"simultaneously"
would cover the scenario where the drug combination is taken all at once, but not necessarily in
the same pill. Claim 22's use of"sequentially" would cover the scenario where pills are given
over a period of time as opposed to all at once. Finally, claim 23's use of "single combined
formulation" would cover the scenario where all the drugs are administered within a single pill.
Thus, it is not accurate to say that "combined" restricts the claim to require admixing, when its
most naturally reading in comparison with the other claims merely requires that the drugs are
administered in one formulation. For these reasons, the Court adopts Viiv's proposal and
construes "a single combined formulation" according to its plain and ordinary meaning.

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