Petition for Writ of Certiorari — Vanderbilt University v. ICOS Corp.

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Supreme Court, US.

\‘)) ()) 10-412 SEP 21 7010

No. ‘OFFICE OF THE CLERK

Hn the

Supreme Court of the Gnited States

VANDERBILT UNIVERSITY,

Petitioner :

ICOS CORPORATION

Respondent

On Petition for Writ of Certiorar: to the

United States Court of Appeals for the Federal Curcuit

PETITION FOR WRIT OF CERTIORARI

Kurt C. Rommel Robert S. Brennen

James 'T. Carmichael! Counsel of Record

MILES & STOCKBRIDGE — Donald It. English, Jr.

¢e MILES & STOCKBRIDGE

1751 Pinnacle Drive rt.

suite 500 10 Light Street

McLean, Virginia 22102 Baltimore, Maryland 21202

(703) 903-9000 (410) 727-6464

rbrennen@milesstockbrndge.com

Counsel for Petitioner

September 21, 2010

Beckers Gallagher - Cincinnati, OH + Washington, D.C. - 800.890.5001

QUESTIONS PRESENTED

Whether the Court of Appeals can impose a clear

and convincing evidence burden on a statutory civil

action where there 1s no indication in the statute or

its legislative history that Congress intended a

burden of proof higher than the preponderance of

evidence standard normally imposed upon. civil

actions

Whether the Court of Appeals’ failure to remand

the case to the District Court conflicts with the

United States Supreme Court’s decision — in

Pullman Standard v. Swint, 456 US. 273 (1982)

RULE 14.1(b) STATEMENT

A list of all parties to the proceeding in the Court

whose judgment is the subject of this petition is as

follows

The Petitioner, and the Plaintiff! Appellant below, is

Vanderbilt University

The Respondent, and the Defendant-Appellee

below, is ICOS Corporation

There were no additional parties to the proceedings

below

RULE 29.6 STATEMENT

Vanderbilt University is an independent, privately

supported university incorporated on August 6, 1872

under the laws of the State of Tennessee with its

principal place of business located at. 805 Kirkland

Hlall, Nashville, Tennessee 37240 Vanderbilt

University has no parent corporations and there is no

publicly held company owning ten percent (10%) or

more of Vanderbilt University’s stock

TABLE OF CONTENTS

QUESTIONS PRESENTED .

RULE 14.1(b) STATEMENT

RULE 29.6 STATEMENT ....

TABLE OF CONTENTS ...

TABLE OF AUTHORITIES

PETITION FOR WRIT OF CERTIORART.....

RPE GUO AG EES SPRAIN ce csacksvcwesccnesvesecss

JURISDICTION

RELEVANT STATUTORY PROVISIONS ..............

STATEMENT OF THE CASE .........

REASONS FOR GRANTING THE PETITION ......

THE COURT OF APPEALS SHOULD NOT

IMPOSE A CLEAR AND CONVINCING

EVIDENCE BURDEN ON A STATUTORY

CIVIL ACTION WHERE THERE IS NO

INDICATION IN THE STATUTE OR ITS

LEGISLATIVIs HISTORY THAT

CONGRESS INTENDED A BURDEN OF

PROOF HIGHER THAN THE

PREPONDERANCE OF KVIDENCE

STANDARD NORMALLY IMPOSED UPON

Cee aie Fs FI lineslereeiscssccniee eee

oe 44

ll. THE DECISION OF THE COURT OF

APPEALS NOT TO REMAND THE CASE

CONTRADICTS THIS COURTS DECISION

IN PULLMAN-STANDARD V. SWINT.........23

CONCLUSION 26

APPENDIX

Appendix A: Opinion, United States Court

of Appeals for the Federal

Circuit

(Revised April 9, 2010). we

Appendix B: Opinion, In the United States

District Court for the District

of Delaware

(January 27, 2009) ................ d18

Appendix C: Judgment in a Civil Case, In

the United States District

Court for the District of

Delaware

(January 29, ZOO) ........050s.60. 84a

Appendix D: Order derying ~ rehearing,

United States Court of Appeals

for the Federal Circuit

Oe Rae's |) |) re 86a

Vv)

TABLE OF AUTHORITIES

Cases

Addington v. Texas,

441 U.S. 418 (1979) cf, was Oe

Alaska Dept. of Envtl. Conservation v. EPA,

940 U.S. 461 (2004)

Amax Fly Ash Corp. v. United States,

514 F.2d 541 (Ct. Cl. 1975) 19, :

BJ Servs. Co. v. Halliburton Energy Servs.,

Ine.,

338 F.3d 1368 (Fed. Cir. 2003) ..

Bd. of Educ. of the Bd. of Trustees of Fe orida

State Univ. v. Am. Bioscience, Ine.,

333 F.3d 1830 (Fed. Cir. 2008). is,

Chen v. Bouchard,

347 F.3d 1299 (Fed. Cir. 2008) ..

Chen v. Gen. Accounting Office,

821 F.2d 732 (D.C. Cir. 1987)...

eBay, Inc. v. Mercexchange, LLC,

547 U.S. 388 (2006)

Beli Lilly v. Aradigm Corp.,

376 F.3d 1352 (Fed. Cir. 2004)... RE, YS

Fina Oil and Cherm. Co. v. Ewen,

123 F.3d 1466 (Fed. Cir. 1997)...... - ae

Vii

llarman & MacLean v. Huddleston.

459 U.S. 375 (1983) 1’

Hess v. Advanced Cardiovascular Sys.. Ince

106 F.3d 976 (Fed. Cir. 1997) 17. 18, 20

Impax Labs., Inc. v. Aventis Pharm., Inc

468 F.3d 1366 (Fed. Cir. 2006) DA

Medichem, S.A. v. Rolabo, S.L..

437 F.8d 1157 (Fed. Cir. 2006) 2]

Pannu v. lolab Corp.,

155 F.8d 1344 (Fed. Cir. 1998) 19

Price v. Symsek,

988 F.2d 1187 (Fed. Cir. 1993) 3

Pullman-Standard v. Swint,.

456 U.S. 273 (1982)... 15, 23, 24, 25

Putnam Res. v. Pateman,

958 F.2d 448 (1st Cir. 1992). oD

SSIH Equip. S.A. v. U.S. Int'l Trade Comm'n,

718 F.2d 365 (Fed. Cir. 1988)... 23

Trovan, Ltd. v. Sokymat SA,

299 F.3d 1292 (Fed. Cir. 2002) .. 24

United States v. Hasan,

609 F.3d 1121 (10th Cir. 2010).. 2d

W.L. Gore v. Garlock,

721 F.2d 1540 (Fed. Cir. 1983).................. te, £4

Z-4 Techs., Inc. v. Microsoft Corp..,

507 IF. Cir. Z007)..

3d 1340 (Fed

Statutes

28 U.S.C.

so U.5.C.

35 U.S.C.

Vili

§1254(1)

§102(f)

$116...

35 U.S.C. §2!

35 U.S.C. §2

35 U.S.C. §

35 U.S.C. §2

35 U.S.C. §:

Other Authorities

aneeeenene ee

..2,4, 14

.. passim

Oo)

soieken eee

vie. a

isunanon snes 17,18

Kristen Dietly, Note, Lightening the Load: Whether

the Burden of Proof for Overcoming a Patent’s

Presumption of Validity Should Be Lowered, 78

FORDHAM L. REV. 2615 (2010)

PETITION FOR WRIT OF CERTIORARI

The Petitioner, Vanderbilt University, respectfully

petitions for a writ of certiorari to review the ruling of

the United States Court of Appeals for the Federal

Circuit.

OPINIONS BELOW

The opinion of the Court of Appeals is published at

601 F.3d 1297 (App. at la-30a). A_ petition for

rehearing and petition for rehearing en banc was

denied without opinion on June 23, 2010. (App. at

86a).

The opinion of the United States District Court for

the District of Delaware is published at 594 F. Supp.

2d. 482 (App. at 3la-83a).

JURISDICTION

The United States Court of Appeals for the ederal

Circuit issued its opinion on April 7, 2010 (App. at la-

30a), and its order denying rehearing and rehearing en

banc was entered on June 23, 2010. (App. at 86a). The

jurisdiction of this Court is invoked under 28 U.S.C.

§1254(1).

RELEVANT STATUTORY PROVISIONS

35 U.S.C. §116. Inventors

When an invention 1s made by two or more

persons jointly, they shall apply for patent

jointly and each make the required oath, except

as otherwise provided in this title. Inventors

may apply for a patent jointly even though

(1) they did not physically work together or at

the same time, (2) each did not make the same

type or amount of contribution, or (3) each did

not make a contribution to the subject matter of

each claim of the patent.

If a joint inventor refuses to join in an

application for patent or cannot be found or

reached after diligent effort, the application

may be made by the other inventor on behalf of

himself and the omitted inventor. The Director,

on proof of the pertinent facts and after such

notice to the omitted inventor as he prescribes,

may grant a patent to the inventor making the

application, subject to the same rights which the

omitted inventor would have had if he had been

joined. The omitted inventor may subsequently

join in the application.

Whenever through error a person is named

in an application for patent as the inventor, or

through error an inventor is not named in an

application, and such error arose without any

deceptive intention on his part, the Director

may permit the application to be amended

accordingly, under such terms as he prescribes.

35 U.S.C. 8256. Correction of named

inventor

Whenever through error a person is named

In an issued patent as the inventor, or through

error an inventor is not named in an issued

patent and such error arose without any

deceptive intention on his part, the Director

may, on application of all of the parties and

assignees, with proof of facts and such other

requirements as may be .mposed, issue a

certificate correcting such error.

The error of omitting inventors or naming

persons who are not inventors shall not

invalidate the patent in which such error

occurred if it can be corrected as provided in this

section. The court before which such matter is

called in question may order correction of the

patent on notice and hearing of all parties

concerned and the Director shall issue a

certificate accordingly.

STATEMENT OF THE CASE

This petition seeks review of a decision of the

United States Court of Appeals for the Federal Circuit

(the “Court of Appeals”) to impose a clear and

convincing evidence burden of proof on a civil action

under 35 U.S.C. §256 where neither the statute nor its

legislative history indicate that Congress intended that

the burden of proof be higher than the preponderance

of evidence standard normally imposed upon civil

actions. This petition also seeks review of the Court of

Appeal’s decision not to remand the Petitioner’s 35

U.S.C. §256 claim to the District Court for

consideration of the evidence under the appropriate

legal standard for determining joint inventor status

under 35 U.S.C. §116, after the Court of Appeals

correctly held that the District Court had applied an

incorrect standard.

Factual Background. Petitioner Vanderbilt

University (“Vanderbilt”) alleges that three of its

faculty scientists made substantial contributions to the

conception of chemical compounds claimed in U.S.

Patents Nos. 5,859,006 and 6,140,329 (the “Patents”)

such that, under the standard established in 35 U.S.C.

§116, those scientists should have been named joint

inventors on those patents. The compounds claimed in

the Patents function as inhibitors of phosphodiesterase

V (“PDE V”), an enzyme found in smooth muscle tissue

that moderates the process through which such tissue

relaxes. In the case of vascular smooth muscle tissue

such relaxation results in dilation and increased blood

flow. (App. at 34a, |4). PDE V inhibitors have been

shown to be effective in treating erectile dysfunction

(“ED”) and the compounds claimed in the Patents

include the active ingredient in the prescription ED

medication Cialis®. (App. at 35a-36a, 77).

Vanderbilt Scientists, Jackie Corbin, PhD and

Sharron Francis, PhD, were pioneers in the study of

smooth muscle relaxation and are credited with having

been the first to identify the PDE V enzyme. (App. at

3a; 39a, 713). In November 1991 Drs. Corbin and

Francis, working with by Sekhar Konjeti, PhD,

developed a theory for designing more potent PDE V

inhibitors. Using that theory, they created a new PDE

V inhibitor by attaching an electron donating hydroxy

group

< and attaching the resulting 4-hydroxy

phenylthio

°-» to the 8 position on an existing PDE V inhibitor

known as IBMX

i 1S

oO” ~N N

I to create 8-(4-hydroxy phenylthio)-IBMX:

8 (4 OH PT) IBMNX

(App. at 52a-53a, 941). It is undisputed that, at the

time, this was a novel PDE V inhibitor and that

nothing in the published state of the art described a

PDE V inhibitor with the unique structure outlined

above in red.

In late December 1991, Dr. Corbin spoke with Dr.

Barry Ross, head of a group of scientists at Glaxo

working on the development of new drugs to treat

cardiovascular disease, about obtaining a research

grant from Glaxo to fund, among other things,

Vanderbilt’s work on designing new PDE V inhibitors.

(App. at 54a, 944). Asa result of the conversation Dr.

Ross asked Dr. Corbin to describe the work in a letter

and planned a trip from his home in England to

Nashville to hear more about Dr. Corbin’s work. (App.

at 57a, 949). Without describing the modifications, Dr.

Corbin’s January 3, 1992 letter explained how

Vanderbilt’s modifications to IBMX had increased by.

160 fold the compound’s potency as a PDE V inhibitor.

(App. at 55a-56a, 946). It was undisputed that sucha

dramatic increase in potency would have been

considered significant to scientists working in the field.

(App. at 80a-8la, 89).

During his visit to Nashville Dr. Ross asked Dr.

Corbin to provide more detail about the PDE V

inhibitor that he and his colleagues had developed. On

February 24, 1992, Dr. Corbin sent such detail to Dr.

Ross in the form of a formal research proposal. (App.

at 57a, 750). On April 8, 1992 Dr. Ross sent copies of

the 1992 Research Proposal to six Glaxo scientists,

including Dr. Richard Labaudiniere, a chemist at a

Glaxo research facility near Paris, France. (App. at

58a, 753). Fifteen days later, Glaxo’s PDE V team

tested, for the first time, compounds that embodied the

skeleton of the Vanderbilt compound, including

GR30040X:

GR 30040X

(App. at 58a-59a, 7954-56).

Dr. Labaudiniere directed one of the Glaxo chemists

under his supervision, Dr. Alain Daugan, to make

modifications to GR 30040X to improve its potency as a

PDE V inhibitor. (App. at 60a, 757). The undisputed

evidence at trial showed that the very first thing that

Dr. Daugan did to modify GR30040X was to

simultaneously replace of the pyridine ring

CA with a combination of a phenyl ring and an

electron-donating methoxy substituent: %, which

resulted in the synthesis of GF 173321X on September

23, 1992, shown here along side 8 — 4 hydroxy

phenylthio-IBMX:

.@)

ar) Me

| Ys

oFn a

O—H

8-(4-Hvdroxy phenvitbto)-IBMX GF 173321X

(App. at 74a-75a, 1179-80). As they did in the case of

the Vanderbilt 8-(4-hydroxy phenylthio)-IBMX

compound, these changes dramatically improved the

GR30040X’s potency in inhibiting PDIE5. Less than

two months later, Dr. Daugan made modifications to

the upper right portion of the compound, resulting in

the synthesis of the first of the compounds claimed in

the patents. (App. at 75a, 781).

Following its application for the Patents, Glaxo

assigned its rights in them to Respondent [COS

Corporation (“ICOS”). (App. at 33a-34a, 73). It was

undisputed at trial that the compounds claimed in the

patents incorporated the structural elements reflected

in the PDE V inhibitor developed by Vanderbilt and

communicated to Glaxo:

FIGURE 1

Bb ssential stewctu el elements found

In the TRVIN enalogs

H,CN } \ henry!) morwty

| 3” \

N \

oO N | 4 \

| if \

n° Hi \ / \

ff ol \

hvdioeen bond danar ute j

General Structure | Resonance elector ;

duces auiaaamas General Structure .

C -8 subsonited IDMX ansloes de. eloped by lonmua (1) frow US Patent Nos * 859.006 and

the Vandertill group 6140 4%

(App. at 72a, 176; 81a, 190). The sole named inventor

on the patent applications and the Patents is Dr.

Daugan. (App. at 36a, 49)

Lower Court Proceedings. Vanderbilt filed a

complaint requesting that the Court issue and order,

pursuant to 35 U.S.C. §256, directing the Director of

Patents at the United States Patent and Trademark

Office (“PTO”) to correct the certificates of the two

Patents by adding Drs. Corbin, Francis and Konjeti as

joint inventors of the compounds along with Dr.

Daugan. (App. at 32a). In its pretrial statement, at

trial before the District Court, and in its post trial

briefs Vanderbilt asserted that the burden of proof to

be applied to Vanderbilt’s claim under 35 U.S.C. § 256

should be a preponderance of evidence. (39a n. 8).

Vanderbilt further asserted that, even under a more

onerous clear and convincing burden, the evidence

demonstrated that the Vanderbilt scientists had made

a significant contribution to the invention of the

claimed compounds, such that the Patents should be

corrected to add the Vanderbilt scientists as joint

inventors with Dr. Daugan.

As the likely means by which the information

supplied by the Vanderbilt scientists to Glaxo could

have contributed to the discovery of the claimed

compounds, Vanderbilt demonstrated that a search on

Glaxo’s computerized compound database in April

1992 using the basic structure of Vanderbilt’s 8-(4-

hydroxy phenylthio)-IBMX compound would have led

to the identification of the GR30040X compound that

also contained that structure. (App. at 72a-74a, ]//76-

78). Vanderbilt also proved that the story of the

identification of GR30040X that Dr. Daugan, Glaxo

and ICOS had been telling to the scientific community

and to the District Court from the 1990’s through the

beginning of the trial was false. (App. at 61la-63a,

| 1160-64; 70a, 971-72). At trial ICOS proffered a new

story suggesting that GR30040X had been identified

through a search of the database using the carboline

A~ A,

A A

"AA

structure ““~~n

contained another compound, GR35273X

~ oO

ZA oo N~ ~

ean a )

7" N { GG

Mo (App. at 64a, 465). Vanderbilt

countered with evidence, including minutes of

meetings of the Glaxo PDE V team, which showed that

the Glaxo scientists did not consider the carboline

structure to be a significant component of GR35273X

until at least October 1992, many months after

GR30040X had been identified and a month after Dr.

Daugan made the modifications, consistent with the

Vanderbilt compound, to create GF173321X. A key

piece of the evidence introduced by Vanderbilt was an

English translation of minutes from an October 1992

meeting of the Glaxo scientists. (App. at 66a, n. 40).

The District Court, following precedent from the

Court of Appeals, applied a clear and convincing

evidence standard in evaluating the evidence. (App. at

38a-39a). The District Court erroneously failed to

consider the English translation of the October 1992

meeting minutes that had been admitted into

evidence (App. at 66a, n. 40) and, without considering

the fact that Glaxo and ICOS’ original story was

proven false, concluded that it was equally plausible

that GR30040X was identified through a search of the

Glaxo database using either the 8-(4-hydroxy

phenylthio)-IBMX compound provided by Vanderbilt to

Glaxo or the GR35273X compound. (App. at 81a-82a,

191).

Notwithstanding the District Court’s error with

respect to the October 1992 minutes, and the District.

Court’s consideration of the evidence against a clear

and convincing burden, the District Court found that.

Vanderbilt’s scientists contributed to the process

through which Dr. Daugan invented the compounds

claimed in the Patents. (App. at 80a, 487). ‘The

District Court also found that Glaxo made use of

Vanderbilt’s “disclosure that 8-(4-OH-PT)-IBMX was

“160-fold more potent that the parent IMBX and 6-fold

more potent than the best existing inhibitor,

zaprinast.” (App. at 80a, 788). “There was consensus

among the witnesses at trial that the 160-fold result

would have commanded attention.” (App. at 81a, 189).

Defendant’s position [that Glaxo made no

use of Vanderbilt’s disclosures} is also untenable

in view of the fact that, although they are (in

whole) different molecules having different

properties, 8-(4-OH-PT)-IMBX, GR380040x,

GF173321x, and the claimed compounds share a

common scaffold having a common shape (three-

dimensional configuration). It is the court’s

understanding that the shape of an inhibitor ts

directly related to its ability to bind to the

enzyme. Corbin communicated to Glaxo on

several occasions the importance of the spacial

relationships of the substituents he was

investigating: for example, Corbin’s April 1991

minuscript, discussing the 8-position

substituent (supra no. 29), and the 1992

Research Proposal, discussing the affinity of the

1,2 and 8-position modifications (supra nos. 51,

77).

further, there is a close proximity in time of

the relevant events which renders plausible

plaintiffs theory that Glaxo did take note of 8-

(4-OH-PT)-IMBX and _— incorporated — the

“Vanderbilt Structural Features” into the beta

carboline research it was conducting. F N51

(App. at 8la, (990, 91). Nonetheless, “compelled by

Federal Circuit precedent,” the District Court found

that the Vanderbilt scientists’ contributions were not

sufficient to qualify them as joint inventors of the

patented compounds. (App. at 80a, 788).

The precedent which compelled the District Court

to conclude that the Vanderbilt scientists did not

jointly invent the claimed compounds was the Court of

Appeal’s opinion in American Bioscience.

Indeed, on facts analogous to those at bar,!N19

the Federal Circuit in The Board of Education

of the Board of Trustees of Florida State

University v. American Bioscience, Inc. , 333 F.3d

1330 (Fed. Cir. 2003) (hereinafter, “Armmerican

Bioscience”), Geclined to add as_ inventors

scientists who contributed the “starting

materials” fora chemical compound. The Court

there held that conception of a chemical

compound requires “a conception of the specific

compounds being claimed, with all of their

component substituents.” Jd. at 1340. To put

the point another way, “l|hjaving in mind

specific portions of a claimed compound is not

the same as conceiving the compound with all of

its components.” /d.

(App. at 78a-79a, 784). As a result of some less than

clear statements in that opinion, the District Court.

read American Bioscience as establishing a rule that,

in order to be a joint inventor of a chemical compound

a person must conceive of the claimed compound in its

entirety.

Because there is no evidence that Corbin,

Krancis and Konjeti ever conceived the “specific

chemical structure of the compound” claimed,

Burroughs Wellcome, 40 F.3d at 1230, or “the

compound with all of its components,” American

Bioscience, 333 F.3d at 1340, or communicated

that compound to Glaxo,FN*® plaintiff has failed

to demonstrate, by clear and = convincing

evidence, that Corbin, Francis and Konjeti are

coinventors of the patents at issue.

(App. at 79a-80a, 186). Under the bright line rule that

the District Court divined from American Bioscience,

any contribution to the invention of a chemical

compound that did not rise to the level of conceiving

the entire compound is, by definition, “prosaic” and not

enough to merit joint inventor status. (App. at 80a,

187).

Vanderbilt appealed the District Court’s decision to

the Court of Appeals, and asserted that the District

Court had committed error by (1) imposing a clear and

convincing burden of proof rather than = a

preponderance of evidence standard; (2) failing to

consider key evidence such as the October 1992

minutes; and (3) applying an incorrect standard for

determining joint inventor status. The Court of

Appeals panel was unanimous in finding thav the

bright line rule that the District Court applied was not

consistent with 35 U.S.C. Section 116, which sets no

explicit lower limit on the quantum or quality of

inventive contribution required for a person to qualify

as a joint inventor. (App. at 19a, 22a-23a, 25a).

However, instead of remanding the case to the District

Court with directions that it review the evidence in

light of the proper standard, the majority of the Court

of Appeals panel, over the remaining judge’s dissent,

proceeded to apply the correct standard to some of the

factual findings stated in the District Court’s opinion

and, without comment on the District Court’s failure to

consider the October 1992 minutes, concluded that the

Vanderbilt failed to meet a clear and convincing

evidence burden with respect to that standard. (App.

at 23a).

As for Vanderbilt’s assertion regarding the proper

burden of proof, the Court of Appeals remarked:

We express no view on whether Vanderbilt

would prevail under a preponderance of the

evidence test. Vanderbilt is of course free to

seek en banc reconsideration of our settled law

on this issue.

(App. at 17a-18a, n. 3).

Vanderbilt filed a petition with the Court of

Appeals seeking panel rehearing and rehearing en

banc, both of which were denied by the Court of

Appeals. (App. at 86a).

REASONS FOR GRANTING THE PETITION

Neither the language of 35 U.S.C. §256 nor its

legislative history indicate that Congress intended that

the burden of proof in an action to correct the inventors

named on a patent be higher than the preponderance

of evidence standard normally imposed upon civil

actions. Notwithstanding that fact, and for reasons

that do not withstand even scant scrutiny, the Court of

Appeals has improperly imposed a clear and

convincing evidence standard upon parties, such as

Vanderbilt, who bring civil actions under the statute.

In addition, having found that the District Court

measured the evidence against an incorrect legal

standard for determining joint inventorship, the Court

of Appeal’s decision not to remand Vanderbilt’s claim

to the District Court for reconsideration of the evidence

in hight of the proper legal standard is in direct

contradiction of the controlling precedent of this

Court's decision in Pullman-Standard v. Swint, 456

U.S. 273 (1982). For either or both of these reasons,

Vanderbilt’s petition should be granted.

I THE COURT OF APPEALS SHOULD NOT

IMPOSE A CLEAR AND CONVINCING

EVIDENCE BURDEN ON A STATUTORY

CIVIL ACTION WHERE THERE IS NO

INDICATION IN THE STATUTE OR ITS

LEGISLATIVE HISTORY THAT CONGRESS

INTENDED A BURDEN OF PROOF HIGHER

THAN THE PREPONDERANCE OF

EVIDENCE STANDARD NORMALLY

IMPOSED UPON CIVIL ACTIONS.

35 U.S.C. §256 permits the correction of a patent

certificate so that it accurately reflects the identity of

the inventor or joint inventors. There is no language

in Section 256 to suggest that Congress intended that

the burden of proof imposed upon parties seeking to

correct the named inventors on a patent should not be

the normal preponderance of evidence standard that is

customarily applied to civil actions. Section 256 simply

states that “[tlhe court before which such matter 1:

called in question may order correction of the patent on

notice and hearing of all parties concerned and the

Director shall issue a certificate accordingly.” 35

U.S.C. §256. Likewise, there is nothing in the

legislative history of the statute that suggests that

Congress intended that the burden of proof be higher

than a preponderance of evidence. When Congress has

intended a higher burden, it has very capably

indicated such intent. See e.g., 35 U.S.C. §273(b)(4).!

35 U.S.C. §273 provides a defense to liability for infringement of a

method patent where the defendant can show that it had been using the

method for at Jeast one year prior to the filing of the patent. §273(b)(4

provides

While there is no single rule of statutory

interpretation that guides a court in ascertaining the

appropriate proof burden imposed on a statutory civil

action when both a statue and its legislative history

are silent, Alaska Dept. of Environmental Conservation

v. EPA, 540 U.S. 461, 494 n. 17 (2004), the default

presumption in civil litigation is that the movant bears

the burden under a preponderance of the evidence

standard. Harman & MacLean v. Huddleston, 459

U.S. 375, 390 (1983); Addington v. Texas, 441 U.S. 418,

’

423 (1979).

The Federal Circuit, which has exclusive appellate

jurisdiction at the Court of Appeals level over claims

under 35 U.S.C. §256, has departed from the default

rule and requires parties seeking to correct a patent

under that statute to prove that a correction is

necessary by clear and convincing evidence. Hess v

Advanced Cardiovascular Sys., Inc., 106 F.3d 976 (Fed

Cir. 1997), Hl: Lilly v. Aradigm Corp., 376 F.3d 1352

(Fed. Cir. 2004). The stated basis that the Court of

Appeals’ departure can be summarized as follows

(1) pursuant to 35 U.S.C. §282, an patent issued by the

PTO is presumed valid; (2) because a patent is

presumed valid, the inventors named on the patent

should be presumed correct; and (3) there is a risk that

Burden of proof.---A person asserting the defense under this

secuon shall have the burden of establishing the defense by clear

and convincing evidence

35 U.S.C. §273(b)(4)

* As Judge Lourie’s dissent in Eli Lilly reveals, the Court of Appeals is not

unanimous in its belicf that it ts logical to impose a clear and convincing

burden in cases under 35 U.S.C. §256. 376 F.3d at 1370

parties seeking to correct the inventors named on a

patent will “reconstruct” facts relating to their

contribution to the conception of the claimed invention.

See Hess v. Adv. Cardio. Sys., Inc., 106 F.3d 976, 980

(Fed. Cir. 1997). Such logic fails to justify a

heightened burden because (1) a Section 256 claim

does not challenge the validity of a patent; (2) there is

no factual basis for a presumption, in the context of a

Section 256 claim, that the inventors have been

correctly identified in a patent; and (3) there is no

inherently greater risk of factual reconstruction in the

context of a Section 256 claim than in any other civil

action.

35 U.S.C. §282 states that a patent, having

undergone examination and survived the prosecution

process, “shall be presumed valid.” That statute goes

on to state that invalidity of a patent is a defense to a

claim of infringement. Although Section 282 does not

express a Congressional intention that a defense of

invalidity be held to a heightened burden of proof,

because of the presumption of validity, the Court of

Appeals has held that, an alleged infringer asserting

such a defense must prove invalidity through clear and

convincing evidence. Z4 Technologies, Inc. v. Microsoft

Corp., 507 F.3d 1340, 1352 (Fed. Cir. 2007).8 Thus,

where an alleged infringer has asserted that a patent

is invalid under Section 282(2) because the plaintiffs

’ The application of the heightened clear and convincing evidence burden

to invalidity defenses under 35 U.S.C. §282 has faced increased criticism

by commentators arguing that preponderance of evidence is the more

appropriate standard in that context. See generally Kristen Dietly, Note,

Lightening the Load: Whether the Burden of Proof for Overcoming a

Patent's Presumption of Validity Should Be Lowered, 78 FORDHAM L

Rk&V. 2615 (2010)

appheant “did not himself invent the subject matter

sought to be patented” as required for patentability

under 35 U.S.C. §102(, the Court of Appeals has ruled

that the infringer was required to prove that assertion

though clear and convincing evidence. BJ Services Co.

Vv. Halliburton Energy Services, Inc. , 338 F.3d 1368,

1373 (Fed. Cir. 2003)

In contrast, an action under Section 256 cannot be

used to invalidate a patent. Section 256 is a “savings

provision” and provides only for remedial relief that

would protect a patent’s validity. Pannu v. Iolab

Corp., 155 F.3d 1344, 1350 (Fed. Cir. 1998). Section

256 can be invoked to correct a patent even where an

alleged infringer has proven, by clear and convincing

evidence, that the patent does not accurately identify

the inventors. /d., at 1350. Thus, the presumption of

a patent’s validity is irrelevant in the context of a

Section 256 claim.4

There is no factual basis for a presumption that,

simply because a patent has been issued, the inventors

thereon have been correctly identified. While patent

examiners consider whether an applicant’s patent

claims are obvious based upon, or anticipated by, prior

art, it is well known, and the parties in this case

stipulated, that the PTO typically undertakes no

action to verify that inventors have been correctly

* Amax Fly Ash Corp. v. United States, 514 F.2d 541 (Ct. Cl. 1975), upon

which the Court of Appeals relied in adopung the clear and convincing

evidence burden for Section 256 claims in Hess, involved an effort to raise

non-joinder of inventors as a basis for invalidating the plaintiff's patent,

and not an action under Section 256.

identified and did not undertake any such action in

connection with the Patents in this case.

According to the Court of Appeals “the temptation

for even honest witnesses to reconstruct, in a manner

favorable to their own position, what their state of

mind may have been years earlier, is simply too great

to permit. a lower standard” in Section 256 cases than

the clear and convincing standard. Hess, 106 F.3d at

980. See also Amax Fly Ash, 514 F.2d at 1050 (claim of

co-inventorship is viewed with skepticism). However,

all parties in htigation want to win, and while there

can be significant monetary and other ramifications

related to the outcome of a Section 256 claim, they are

not necessarily more significant than those related to

the outcomes of other types of patent claims to which

the preponderance of evidence standard is applied.

Indeed, there is no logical basis to conclude that

witnesses on either side of a Section 256 claim would

be more or tess tempted to reconstruct past events in a

manner favorable to his or her own position than a

witness, for example, in a patent infringement case.

Thus, there is no rational justification for applying the

higher clear and convincing standard to a_ co-

inventorship claim under Section 256, while the

assertion of the same facts in a priority action is

subject to the preponderance of evidence standard. See

Eli Lilly, 376 F.3d at 1370.

Moreover, any concern regarding the dependability

of testimony regarding past state of mind (which might

exist with respect to any type of civil action) is

uniquely and adequately addressed in the inventorship

context by the requirement that testimony of invention

be corroborated. Chen v. Bouchard, 347 F.3d 1299,

1309 (Fed. Cir. 2003) (purpose of corroboration

requirement is to prevent fraud, by providing

independent confirmation of the inventor's testimony);

Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1170

(Fed. Cir. 2006)(credibility concerns undergird the

corroboration requirement, the purpose of which is to

prevent fraud by providing additional safeguard

against deception by inventors who may be tempted to

mischaracterize past events through testimony). See

also Fina Owl and Chemical Co. v. Ewen, 123 F.3d

1466, 1474 (Fed. Cir. 1997).°

In short, the standard burden of proof in civil

litigation should be applied to claims under Section

296. As the Supreme Court observed in Addington. v.

Texas, 441 U.S. 418, 423-25 (1979), in the typical civil

case involving private parties and monetary disputes

in which society has minimal concern, the plaintiffs

burden is preponderance of evidence. The higher clear

and convincing evidence burden is reserved for “civil

cases involving allegations of fraud or some other

quasi-criminal wrongdoing by the defendant.”

The interests at stake in those cases are deemed

to be more substantial than mere loss of money

and some jurisdictions accordingly reduce the

risk to the defendant of having his reputation

tarnished erroneously by increasing the

plaintiffs burden of proof. Similarly, this Court

> The fact that the Vanderbilt scientists’ testimony regarding their

discovery of the novel PDES inhibitor structure reflected in 8-(4-OH-PT)-

IBMX was fully corroborated by contemporaneous documents has never

been disputed.

has used the “clear, unequivocal and

convincing” standard of proof to protect

particularly important individual interests in

various civil cases. See, e.g., Woodby v. INS,

supra, at 285 [87 S.Ct. at 487] (deportation);

Chaunt v. United States, 364 U.S. 350, 353 181

».Ct. 147, 149, 5 L.Ed.2d 120]

(1960)\(denaturalization); Schneiderman — v.

United States, 320 U.S. 118, 125, 159 163 S.Ct.

1333, 1336, 1353, 87 L.Ed. 1796]

(1943)(denaturalization).

Id. at 423-25. As the Supreme Court has more

recently observed, under the Patent Act a patent is

personal property, and there is no presumption that

the rights attendant thereto cannot be quantified in

terms of money. eBay, Inc. v. Mercexchange, LLC, 547

U.S. 388 (2006); 35 U.S.C. §261. Thus, whatever

interests may be implicated by a claim under Section

256, they are not the type of “important individual

interests” that warrant the imposition of a burden of

proof beyond preponderance of evidence.

For these reasons, Vanderbilt submits that the

burden of proof applied to civil actions under 35 U.S.C.

§256 should be preponderance of evidence and the

Court of Appeals decisions imposing a higher clear and

convincing evidence burden of proof, which the District

Court followed, were in error. It is well settled that

the application of the wrong burden of proof cannot be

harmless error. See Putnam Resources v. Pateman,

958 F.2d 448, 471 (1st Cir. 1992)(district court’s use of

improper burden of proof cannot be considered

harmless); Chen v. General Accounting Office, 821 .2d

2o3

732, 741 n. 13 (D.C. Cir. 1987)(same); Price v. Symsek,

988 F.2d 1187, 1194 (ed. Cir. 1993)(same). See also

SSTH Equipment S.A. v. U.S. Int'l Trade Comm’n, 718

l'.2d 365, 3838 (Fed. Cir. 1983)(“the degree of proof

below affects the appellate decision whether to affirm

or reverse .... ).

This Court should not sanction a lower court’s

legislation of a heightened burden of proof into a

statutory cause of action when there is no indication in

the statute or its legislative history that Congress

intended a burden beyond preponderance of evidence

and there is no logical basis for a heightened burden.

Vanderbilt’s petition, therefore, should be granted.

HW. THE DECISION OF THE COURT OF

APPEALS NOT TO REMAND THE CASE

CONTRADICTS THIS COUR'T’S DECISION IN

PULLMAN-STANDARD V. SWINT.

The Decision of the Court of Appeals is in direct

conflict with Pullman-Standard v. Swint, 456 U.S. 273

(1982). Where, as in this case, the District Court has

committed error in the interpretation and application

of the patent statute, and its factual findings “rest on

an erroneous view of the law,” those factual findings

may be set aside on that basis, regardless of whether

they are otherwise clearly erroneous. Pullman-

Standard, 456 U.S. at 287; W.L. Gore v. Garlock, 721

F.2d 1540, 1547 (led. Cir. 1983).

As the Supreme Court has noted, “[wlhen an

appellate court discerns that a district court has failed

to make a finding because of an erroneous view of the

law, the usual rule is that there should be a remand

for further proceedings to permit the trial court to

make the missing findings,” and “where findings are

infirm because of an erroneous view oj} the law, a

remand is the proper course unless the record permits

only one resolution of the factual issue.” Pullman

Standard, 456 U.S. at 291-92. See also W.L. Gore, '/21

F.2d at 1547 (where district court’s finding rests upon

erroneous view of law, appellate court should not

“engage in what would be an inappropriate reweighing

of facts”); Zmpax Labs., Inc. v. Aventis Pharm., Inc.,

468 F.3d 1366, 1383 (Fed. Cir. 2006); Trovan, Ltd. v.

Sokymat SA, 299 F.3d 1292, 1310 (Fed. Cir.

2002)(where district court did not properly construe

patent claims remand was required for resolution of

factual issues regarding whether alleged infringer was

a co-inventor); United States v. Hasan, 609 F.3d 1121,

1129 (10th Cir. 2010)(when the court of appeals notices

a legal error, it is not ordinarily entitled to weigh the

facts itself and reach a new conclusion; instead, it must

remand to the district court for it to make a new

determination under the correct law).

The Court of Appeals decision is in direct conflict

with this Court’s opinion in Pullman. Here the record

clearly permits more than one resolution of the

relevant factual issues. As Judge Dyk noted in his

concurring and dissenting opinion:

While the district court found that the

Vanderbilt scientists made some contribution, it

has not told us exactly what that contribution

was or why that contribution was not enough to

make the Vanderbilt scientists joint inventors

under the correct standard. If the Vanderbilt

scientists made contributions, as the district

court found, the fact that those contributions

may not have been “appropriated by Dr.

Labaudiniere for his substructure search,”

Majority Op. at 15 (App. at 18a) does not

foreclose the possibility that the Vanderbilt

scientists’ contribution was sufficient to make

them joint inventors.

Because the district court’s findings were

either contradictory or tainted by legal error, I

think we must vacate the judgment and remand

in order that the court may make factual

findings under the proper law.

(App. at 30a). Rather than attempt to reach its own

factual findings or to discern how the District Court

would have viewed the facts had it applied the

appropriate standard, the Court of Appeals should

have remanded the case to the District Court with

instructions that it reconsider all of the evidence in

light of the appropriate standard. Pullman requires

that the Court of Appeals’ decision be overturned and

that this case be remanded to the District Court for

factual findings that are not “tainted by legal error.”

This Court should not sanction an appellate court’s

usurpation of a trial court’s role in weighing evidence

against the appropriate legal standard for the claims

in suit. Vanderbilt’s petition, therefore, should be

granted.

CONCLUSION

For all of the forgoing reasons, the petition for a

writ of certiorari should be granted.

Respectfully submitted this 215' day of September,

2010,

Robert S. Brennen

Counsel of Record

Donald EK. English, Jr.

MILES & STOCKBRIDGE P.C.

LO Light Street

Baltimore, Maryland 21202

(410) 727-6464

rbrennen@miulesstockbridge.co

Kurt C. Rommel!

James T. Carmichael

MILES & STOCKBRIDGE P.C.

1751 Pinnacle Drive, Suite 500

McLean, Virginia 22102

(703) 903-9000

Counsel for Petitioner

APPENDIX

Appendix A:

Appendix B:

Appendix C:

Appendix D:

APPENDIX

TABLE OF CONTENTS

Opinion, United States Court of

Appeals for the Federal Circuit

(Revised April 9, 2010)........ la

Opinion, In the United States

District Court for the District of

Delaware

(January 27,2009) .......... 3la

Judgment in a Civil Case, In the

United States District Court for

the District of Delaware

(January 29, 2009) .......... 84a

Order denying rehearing, United

States Court of Appeals for the

Federal Circuit

(June ZS, BONO). esa s+ eave 86a

APPENDIX A

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT

‘Revised April 9, 2010

No. 2009-1258

[Filed April 7, 2010]

VANDERBILT UNIVERSITY,

Plaintiff-Appellant,

)

ICOS CORPORATION, )

)

Defendant-Appellee. )

)

Robert S. Brennen, Miles & Stockbridge P.C., of

Baltimore, Maryland, argued for plaintiff-appellant.

With him on the brief were Donald E. English, Jr.;

Kurt C. Rommel and James T. Carmichael, of McLean,

Virginia. Of counsel were Leona Marx and David

Williams, Il, Vanderbilt University, of Nashville,

‘Tennessee.

* . . .

Revised to correct name of attorney Robert S. Brennen.

Kevin M. Flowers, Marshall, Gerstein & Borun

LLP, of Chicago, Illinois, argued for

defendant-appellee. With him on the brief were

Thomas |. Ross and Matthew C. Nielsen. Of counsel on

the brief were Paul R. Cantrell, Donald L. Corneglio

and Dan _L. Wood, Eli Lilly and Company, of

Indianapolis, Indiana.

Appeal from the United States District Court for the

District of Delaware in case no. 05-CV-506,

Judge Sue L. Robinson.

Before MICHEL, Chief Judge, CLEVENGER and

DYK, Circuit Judges.

Opinion for the court filed by Circuit Judge

CLEVENGER. Opinion concurring in part and

dissenting in part filed by Circuit Judge DYK.

CLEVENGER, Circuit Judge.

This is an appeal from the United States District

Court for the District of Delaware in a patent action

that Vanderbilt University (“Vanderbilt”) brought

against ICOS Corporation (“ICOS”) on July 20, 2005.

Vanderbilt filed suit under 35 U.S.C. § 256 alleging

that Vanderbilt scientists Jackie D. Corbin (“Dr.

Corbin”), Sharron H. Francis (“Dr. Francis”), and

Sekhar R. Konjeti (“Dr. Konjeti”) (collectively the

“Vanderbilt Scientists”) should be added as _ joint

inventors on U.S. Patent Nos. 5,859,006 (“the ‘006

patent”) and 6,140,329 (“the ‘329 patent”). The district

court rendered its findings of fact and conclusions of

law in aJanuary 27, 2009 opinion. Vanderbilt Univ. v.

ICOS Corp., 594 F. Supp. 2d 482 (D. Del. 2009). The

district court entered fina] judgment on January 29,

2009, concluding that Vanderbilt failed to prove that

the Vanderbilt Scientists are joint inventors of the ‘006

and ‘329 patents. Vanderbilt appeals the district

court's final judgment. For the reasons stated below,

we affirm.

This case involves compounds and methods for

treating erectile dysfunction, including the compound

known as tadalafil, a PDES5 inhibitor and the active

ingredient in the drug Cialis’. PDES5 is. a

phosphodiesterase enzyme found in smooth muscle

cells that binds to and hydrolyzes or breaks down

cGMP, a cyclic nucleotide found in smooth muscle

tissues. In normal function, cGMP binds with and

activates a cGMP-dependent protein kinase which

results in relaxation and dilation of the smooth muscle

cell. PDE5 inhibitors bind to PDE5 and prevent it from

binding with and breaking down cGMP.

Drs. Corbin and Francis are employed by

Vanderbilt University and were among the first to

discover PDE5 in the late 1970s. Since that time, Drs.

Corbin and Francis have worked on both the

development of cGMP analogs and PDES5 related

research.

In December 1988, Dr. Corbin submitted a research

— “ss n\1 . .

proposal to Glaxo Inc. (“Glaxo”)’ requesting it sponsor

' Glaxo Inc., later renamed Glaxo Wellcome Inc., was a North

Carolina corporation that merged with SmithKline Beecham to

form Glaxo SmithKline in 2001. Glaxo Group Limited (“Glaxo

U.K.”) was a U.K.-based subsidiary of Glaxo. At all times relevant

to this litigation, Glaxo maintained a research facility in Les Ulis,

his research to develop cGMP analogs. The proposal

listed new cGMP analogs that Dr. Corbin hoped would

activate cGMP-dependent protein kinase.

In June 1989, Glaxo entered into an agreement

with Dr. Corbin through Glaxo’s “Cardiovascular

Discovery Grant” program to underwrite’ the

Vanderbilt Scientists’ research of cGMP analogs.

Under the agreement, the University retained

ownership of intellectual property, but Glaxo was

granted a license agreement to any discoveries. During

the three years of the program, Drs. Corbin, Francis,

and Konjeti submitted numerous presentations and

progress reports to Glaxo.

In November 1990, Dr. Corbin sent an abstract to

Glaxo U.K. disclosing his discovery that the potency of

cGMP analogs is enhanced by adding a pheny! ring at

the 8-position. Meanwhile, the Vanderbilt Scientists

continued to work on improving potency with new

cGMP analogs. In May 1991, however, Glaxo indicated

to Dr. Corbin its concern that cGMP analogs do not

work well as_ orally-administered drugs and

encouraged the Vanderbilt Scientists to shift their

future focus to PDE5D inhibitors.

Outside of the Glaxo program, the Vanderbilt

Scientists. continued to work on other research

interests. In November 1991, the Vanderbilt Scientists

applied the results of their CGMP analog research to

synthesize a new PDED5D inhibitor. The Vanderbilt

Scientists used a_ 3-isobutyl-l-methylxanthine

France (“Glaxo France”). The patents in suit list a Glaxo France

scientist as the sole inventor and are assigned to ICOS.

(“IBMX”") compound because it was a cheap and readily

available PDE5 inhibitor that is easily substituted at

the 8-position. Building upon their earlier research,

the Vanderbilt Scientists attached a phenyl ring to the

8-position of the compound and attached an

electron-donating hydroxyl group at the 4 position of

the phenyl ring. By applying the results of their cGMP

research to IBMX, the Vanderbilt Scientists created a

PDE5 inhibitor they thought was 160 times more

potent in inhibiting PDE5 than the original IBMX

molecule. Dr. Corbin drafted a letter to Vanderbilt’s

general counsel disclosing possible therapeutic uses for

the new IBMX analogs, including the treatment of

male impotence.

In December 1991, during discussions regarding a

new research agreement, Dr. Corbin mentioned

Vanderbilt’s work on PDE5 inhibitors to Dr. Barry

Ross, a scientist at Glaxo U.K. On January 3, 1992, Dr.

Corbin sent a research proposal to Glaxo U.K.

detailing the test results of the cGMP analogs

developed under the first research agreement. In the

proposal, Dr. Corbin also described the Vanderbilt

Scientists’ IBMX analog that was 160-fold more potent

as a PDE5 inhibitor than the original IBMX molecule.

Dr. Corbin explained the Vanderbilt Scientists’ overall

strategy that “the potencies of existing inhibitors. . .

could be enhanced by appending groups that would

allow the inhibitors to more closely resemble the entire

cyclic GMP molecule.” Dr. Corbin proposed that Glaxo

fund the Vanderbilt Scientists’ work on PDE5

inhibitors going forward. Dr. Corbin also noted in the

January letter that “the cG kinase has important

disease-related functions other than the induction of

vascular smooth muscle relaxation.” Male impotence

was listed as an area of interest, though Glaxo was not

researching male impotence at the time.

On February 3, 1992, Drs. Corbin and Francis met

with Dr. Ross regarding the January proposal. Later

that month, on February 24, Dr. Corbin sent a more

detailed research proposal to Dr. Ross which disclosed

the exact design of the Vanderbilt IBMX analog. The

detailed research proposal also identified a table of

IBMX and zaprinast’ analogs that Vanderbilt proposed

for further testing. Many of the listed compounds

contain what Vanderbilt now refers to as_ the

“Vanderbilt Structural Features” of Vanderbilt’s IBMX

analog.

On March 11 and 12, 1992, Glaxo France tested 26

compounds for PDE5 inhibition, including a compound

it designated GRO5273x.

On April 8, 1992, Dr. Ross forwarded copies of

Vanderbilt’s February 24, 1992 proposal to six Glaxo

scientists, including Dr. Richard Labaudiniere, the

head of chemistry and leader of the PDE5 project at

Glaxo France.

On April 23, 1992, Glaxo France tested 29

compounds for PDE5 inhibition, including a

beta-carboline compound designated GR30040x.

Vanderbilt claims all of the tested compounds make

some use of the Vanderbilt Structural Features with

11 of the 29 compounds containing nearly all of the

Vanderbilt Structural Features. Based on the PDE5

“ Zaprinast was the most powerful known PDE5 inhibitor at the

time of the research proposal.

inhibition test results, Dr. Labaudiniere identified

GR30040x as a lead compound for further research on

PDES inhibition. Dr. Labaudiniere assigned the

further GR30040x research to Dr. Alain Claude-Marie

Daugan, the named inventor on the patents at issue,

as a separate study. In the course of testing various

modifications to the GR30040x compound between

June 1992 and January 1994, Dr. Daugan discovered

tadalafil, the claimed compound at issue in this case.

In 1991, Glaxo assigned to ICOS the rights, title,

and interest in the compounds covered by the patents

at issue. Vanderbilt brought this suit under 35 U.S.C.

§ 256 against ICOS to correct inventorship of the ‘006

and ‘329 patents. Vanderbilt asserts that the

Vanderbilt Scientists should be added as_ joint

inventors. According to Vanderbilt, the GR30040x

compound could not have been identified by Dr.

Labaudiniere as the lead compound without his use of

the Vanderbilt Structural Features. Nor could tadalafil

have been identified by Dr. Daugan without his

rehance on Vanderbilt’s work. The district court held

a bench trial and found in favor of ICOS.

in its analysis, the district court noted that 35

U.S.C. § 116, the applicable section for joint

inventorship, sets “no explicit lower lmit on the

quantum or quality of inventive contribution required

for a person to qualify as a joint inventor.” Vanderbilt

Univ. v. ICOS Corp., 594 F. Supp. 2d 482, 504 (D. Del.

2009) (quoting Fina Oil & Chem. Co. v. Ewen, 123 F.3d

1466, 1473 (Fed. Cir. 1997)). The district court further

noted that “a person is a joint inventor ‘only if he

contributes to the conception of the claimed

invention.” Id. (quoting Hh Lilly & Co. v. Aradigm

Corp., 376 F.3d 1352, 1458-59 (red. Cir. 2004)). After

asummary ofthe law regarding conception of chemical

compounds, the = district court concluded — that

“conception of a chemical substance includes

knowledge of both the specific chemical structure of

the compound and an operative method of making it”

and “does not occur unless one has a mental picture of

the structure of the chemical.” Id. (quoting Burroughs

Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223, 1230

(Fed. Cir. 1994) and Amgen, Inc. v. Chugai Pharm.

Co., Ltd., 927 F.2d 1200, 1206 (Fed. Cir. 1991)). The

district court determined that the Vanderbilt

Scientists could not be co-inventors because they never

“conceived the specific chemical structure of the

compound claimed or the compound with all of its

components.” Id. at 505 (citations omitted).

To guide its analysis, the district court reviewed

our decision in American BioScience and concluded the

‘ase contained similar facts and thus controlled its

decision. Id. at 504-05. The district court recognized,

that in American BioScience we declined to add

inventors who provided the “starting materials” for a

chemical compound. See Bd. Of Educ. ex rel. Bd. of

Trustees of Fla. State Univ. v. Am. BioScience Inc.,

333 F.3d 1330 (Fed. Cir. 2003) (“American

BioScience”). The district court found that “[t}he

‘Vanderbilt Structural Features’ constitute no more

than a ‘specific portion|] of a claimed compound’ in the

language of American BioScience.” Vanderbilt Univ.,

594 F. Supp. 2d at 505.

The district court concluded that “[b]ecause there

is no evidence that [the Vanderbilt Scientists] ever

conceived the ‘specific chemical structure of the

compound’ claimed, Burroughs Wellcome, 40 F.3d at

1230, or ‘the compound with all of its components,’

American BioScience, 333 F.3d at 1340, or

communicated that compound to Glaxo, plaintiff has

failed to demonstrate by clear and convincing evidence,

that Corbin, Francis and Konjeti are coinventors of the

patents at issue.” Id. The district court noted that

“even if the court were to find that plaintiffs disclosure

of [the Vanderbilt Structural Features] led to the

identification of GR30040x and the subsequent

discovery of tadalafil, American BioScience precludes

the result plaintiffseeks: namely, that the contribution

of a molecular scaffold in the context of one molecule

.. renders the disclosing party or parties inventors of

a different family of molecules containing the same

scaffold.” Id. at 506-07.

Even after reaching the conclusion that its decision

was bound by American BioScience, the district court

provided a detailed analysis of the remaining facts of

the case. First, the court noted that “[t]his is not to say

that Corbin, Francis, and Konjeti did not make

contributions to Daugan’s inventive process; only that,

under the applicable law, these contributions fall more

into the category of ‘prosaic’ contributions because they

did not conceive the invention as claimed.” Id. at 505.

After again reviewing the conflicting stories of the

parties, the district court alternatively noted that “the

court views plaintiffs theory ... and defendant’s story

.. equally plausible with respect to the identification

of GR30040x.” Id. at 506. Also, in the absence of any

evidence of collaboration between the Vanderbilt

Scientists and Dr. Daugan, the district court rejected

Vanderbilt’s claim to have contributed to Dr. Daugan’s

identification of tadalafil. Id. at 505-06.

10a

iT]

We begin by reviewing our case law on joint

; i . carers

inventorship. The statutory requirements for joint

inventorship are found in 35 U.S.C. § 116 which states,

in pertinent part:

When an invention is made by two or more

persons jointly, they shall apply for patent

jointly and each make the required oath, except

as otherwise provided in this title. Inventors

may apply for a patent jointly even though (1)

they did not physically work together or at the

same time, (2) each did not make the same type

or amount of contribution, or (3) each did not

make a contribution to the subject matter of

every claim of the patent.

35 U.S.C. § 116 (1988).

Section 116 was amended, in relevant part, in 1984

to clarify the law of joint inventorship by codifying the

principles set forth in Monsanto Co. v. Kamp, 269 F.

Supp. 818 (D.D.C. 1967). See Kimberly-Clark Corp. v.

Proctor & Gamble Distrib. Co., Inc., 973 F.2d 911, 916

(Fed. Cir. 1992). The court in Monsanto stated:

A joint invention is the product of collaboration

of the inventive endeavors of two or more

persons working toward the same end and

producing an invention by their aggregate

efforts. To constitute a joint invention, it is

necessary that each of the inventors work on

the same subject matter and make some

contribution to the inventive thought and to the

final result. Each needs to perform but a part of

lla

the task if an invention emerges from all of the

steps taken together. It is not necessary that

the entire invention concept should occur to

each of the joint inventors, or that the two

should physically work on the project together.

One may take a step at one time, the other an

approach at different times.

Monsanto, 269 F. Supp. at 824.

In Kimberly-Clark, we applied section 116 to a

situation where Proctor & Gamble wished to attribute

inventor status to one of its employees who did not

collaborate with the named inventor. 973 F.2d at

912-13. While both employees worked on the same

subject matter, the court noted that the named

inventor “worked alone and was completely unaware

of earlier work done by other [] employees.” Id. at 913.

The court reviewed the amendments and Monsanto

and stated that:

lor persons to be joint inventors under Section

116, there must be some element of joint

behavior, such as collaboration or working

under common direction, one inventor seeing a

relevant report and building upon it or hearing

another’s suggestions at a meeting. Here there

was nothing of that nature. Individuals cannot

be joint inventors if they are completely

ignorant of what each other has done until

years after their individual efforts. They cannot

be totally independent of each other and be joint

inventors.

Kimberly-Clark, 973 F.2d at 917.

12a

A primary focus of section 116 has thus always

been on collaboration and joint behavior. A person

must contribute to the conception of the claimed

invention to qualify as a joint inventor. Hh Lilly & Co.

v. Aradigm Corp., 376 F.3d 1352, 1359 (Fed. Cir.

2004). Yet, each contributor need not have their own

contemporaneous picture of the final claimed invention

in order to qualify as joint inventors. See Fina Oil &

Chem. Co. v. Ewen, 123 F.3d 1466, 1473 (Fed. Cir.

1997) (“One need not alone conceive of the entire

invention, for this would obviate the concept of joint

invention.”). Rather, “the qualitative contribution of

each collaborator is the key — each inventor must

contribute to the joint arrival at a definite and

permanent idea of the invention as it will be used in

practice.” Burroughs Wellcome Co. v. Barr Labs. Inc.,

40 ¥.3d 1223, 1229 (Fed. Cir. 1994). The interplay

between conception and collaboration requires that

each co-inventor engage with the other co-inventors to

contribute to a joint conception.

Inventorship is a question of law that we review

without deference. Ethicon, Inc. v. U.S. Surgical Corp.,

135 F.3d 1456, 1460 (Fed. Cir. 1998). We review the

underlying findings of fact for clear error. See Hess v.

Advanced Cardiovascular Sys., Inc., 106 F.3d 976, 980

(Fed. Cir. 1997).

Vanderbilt raises two arguments on appeal. First,

Vanderbilt argues that its disclosure of the Vanderbilt

Structural Features led to Glaxo’ France’s

identification of the GR30040x molecule incorporating

the same molecular scaffold. In this regard, the gist of

Vanderbilt’s case is that Dr. Labaudiniere could only

l3a

have identified GR380049%x by using the Vanderbilt

Structural Features. Second, Vanderbilt alleges that

the key modification to GR30040x that yielded

tadalafil was the addition of an electron-donating

substituent on the phenyl ring based upon the work of

the Vanderbilt Scientists.

There is no dispute raised between the parties

regarding the district court’s finding that Dr.

Labaudiniere at Glaxo France identified GR380040x as

a lead compound for research regarding PDE5

inhibition. Thus, as all relevant contact between the

Vanderbilt Scientists and Glaxo occurred at Glaxo

U.K., Vanderbilt attempts to piece together sufficient

facts to demonstrate that the Vanderbilt Structural

Features must have been used by Dr. Labaudiniere to

identify GR30040x. As Vanderbilt’s argument is based

largely upon criticizing ICOS’s evidence regarding how

GR30040x was recognized, we first review Glaxo’s

version of the story.

ICOS contends that Dr. Labaudiniere

independently discovered the compounds to be tested

for PDES5 inhibition through his knowledge of

beta-carbolines and their vasorelaxation effect. This

theory can be found in a paper received by the Journal

of Medicinal Chemistry on February 5, 2003, entitled

“The Discovery of Tadalafil: A Novel and Highly

Selective PUES Inhibitor.” According to Glaxo, Dr.

Labaudiniere became aware of the vasorelaxation

effect of beta-carbolines from his review of two

references: a 1983 article in the European Journal of

Pharmacology (“the Koe article”) and a May 1992

article in the Journal of Pharmacology and

Experimental Therapeutics (“the Elgoyhen article”).

Glaxo claims that Dr. Labaudiniere identified two

l4a

beta-carboline compounds, $-CEE and GR35273x, in

March 1992 as potential PDE-5 inhibitors. Dr.

Labaudiniere then searched an internal database in

April 1992 with the beta-carboline core structure of

these two molecules and his search yielded GR30040x.

Glaxo’s internal “PDE V Inhibitors Project Annual

Report for the Year Ending 30/4/93” confirms this

story.

Vanderbilt takes issue with Glaxo’s story because

Glaxo’s internal testing records indicate’ that

GR30040x was first tested by Glaxo on April 23, 1992.

The Elgoyhen article was not published until May 8,

1992. As the district court found, GR30040x could not

have been identified based upon the Elgoyhen

reference.

At trial, ICOS backed away from the Elgoyhen

story and instead argued that Dr. Labaudiniere took

GR35273x from another Glaxo program and tested it

on March 11 and 12, 1992 for PDE5 inhibition.

According to ICOS, Dr. Labaudiniere undertook

substructure searches using the tetrahydro

beta-carboline scaffold of GR35273x, based upon the

“impressive” PDE5 inhibition results and _ his

knowledge from the Koe article, and_ identified

GR30040x, among other compounds. ICOS points to

the large number of tetrahydro beta-carbolines tested

between March and July 1992 to support its theory.

ICOS also points to Glaxo documents to corroborate

various details of its story. For example, the minutes

of a Glaxo Cardiovascular Research Management

Committee meeting in April 1992 describe GR35273x

as a compound used in a different study. In the June

1992 minutes, the same committee noted that

l5a

GR35273x displayed a high PDE5 inhibition activity

and noted that Glaxo was starting a program testing

GR35273x analogs. At the same meeting, GR30040x

was identified as a new PIES inhibitor

ICOS also points to testimony of Dr. Labaudiniere

and Dr. Daugan to corroborate its theory on the

identification of GR30040x. Dr. Labaudiniere testified

that he did not have any knowledge about the

Vanderbilt Scientists’ research until June 1993, he did

not consider IBMX as a starting point for his work on

PDE5 inhibitors, and he was not aware of anyone at

Glaxo France using data relating to IBMX analogs or

trying to develop PDE5 inhibitors that would resemble

cGMP. Dr. Daugan confirmed his recollection matches

that of Dr. Labaudiniere. In sum, ICOS argues that

Vanderbilt's case fails for lack of evidence of any joint

collaboration on the invention since neither of the

Glaxo France scientists had any knowledge of the work

of the Vanderbilt Scientists when they did their work

relating to the discovery of tadalafil.

Vanderbilt argues a different view of the same

facts. First, Vanderbilt points out that GR30040x is

never identified in any Glaxo documents as a

GR35273x analog. Vanderbilt also argues that a

GR35273x substructure search would not yield

GR30040x because no documents demonstrate that

Glaxo identified the beta-carboline structure in

GR35273x as significant until October 1992. Finally,

Vanderbilt argues that Glaxo lacks credibility as it had

previously claimed GR30040x was identified from a

B-CEE search until that was proven false. In sum,

Vanderbilt attacks Glaxo’s story based upon missing

documentary evidence.

l6a

Vanderbilt instead proposes that Dr. Labaudiniere

reviewed the February 1992 research proposal and

conducted a substructure search based upon the

Vanderbilt IBMX analog. Vanderbilt points out that in

April, just weeks after receiving the February

proposal, Glaxo France tested 29 compounds for PDE5

inhibition. Vanderbilt points out a number of

structural similarities between the tested compounds

and its February research proposal.

Vanderbilt’s second argument is that after the

GR30040x project was assigned to Dr. Daugan, he

added to tadalafil an additional element of the

Vanderbilt Structural Features by replacing the

pyridine ring in GR30040x with a combination of a

phenyl ring and an electron-donating methoxy

substituent. Vanderbilt argues that this modification

directly uses the results of the Vanderbilt Scientists’

research. ICOS responds that the modifications were

all part of a standard trial and error procedure that

would be tried with any molecules of interest.

The only evidence of record regarding Glaxo’s

modifications to GR30040x is the testimony of Dr.

Daugan and Dr. Labaudieniere. Dr. Daugan testified

that “[t]he first thing [he] did in this series was explore

the replacement of the pyridinyl[] moiety with other

heterocyclic or aromatic moieties.” Dr. Labaudiniere

testified that there are a_ standard group of

substitutions or additions that would be tried with any

molecules of interest. Dr. Labaudiniere characterizes

the modifications leading to tadalafil as “obvious” and

conducted in a “trial-and-error” fashion. There is no

testimony or documentary evidence demonstrating a

link between the Vanderbilt Scientists and Dr. Daugan

prior to the identification of tadalafil. Indeed,

lva

Vanderbilt admitted in the district court that it had no

direct evidence to support its view of the facts; instead

Vanderbilt argued that it “need not prove specifically

how that occurred, but simply how it logically could

have occurred.”

Vanderbilt’s challenge to the stated inventorship of

the ‘006 and ‘329 patents turns on competing claims to

inventorship of GR30040x and to tadalafil. As

explained above, Vanderbilt admits that no direct

evidence supports its claims to joint inventorship.

Nonetheless, Vanderbilt argues that Dr. Labaudiniere

could not have identified GR30040x as a lead

compound independently; nor could Dr. Daugan have

identified tadalafil on his own. ICOS counters

Vanderbilt's arguments with direct evidence

supporting Dr. Labaudiniere’s claim to_ sole

identification of GR30040x and with similar direct

evidence pointing to Dr. Daugan’s independent

discovery of tadalafil

To succeed on its claim to joint inventorship,

Vanderbilt must prevail by clear and convincing

evidence. Our precedent has long required proof of

misjoinder or nonjoinder of co-inventors by clear and

convincing evidence.” See Eli Lilly & Co. v. Aradigm

‘Vanderbilt recognizes that the clear and convincing evidence test

for correction of inventorship is settled law which binds the court

It suggests that the law should be changed to a lower standard of

proof, namely preponderance of the evidence, and that under the

lower test it should prevail in this case. We express no view on

whether Vanderbilt would prevail under a preponderance of the

l&a

Corp.,376 F.3d 1352, 1364 (Fed. Cir. 2004); Ethicon v.

U.S. Surgical Corp., 135 F.3d 1456, 1460-61 (Fed. Cir.

1998); Hess v. Advanced Cardiovascular Sys., Inc., 106

F.3d 976, 980 (Fed. Cir. 1997). The district court

correctly concluded that Vanderbilt failed to meet its

burden.

We find no clear error in the district court's factual]

findings underpinning its determination regarding

Glaxo’s identification of GR30040x. The district court

noted that “there is a close proximity in time of the

relevant events which renders plausible plaintiff's

theory that Glaxo did take note of [the Vanderbilt

IBMX compound] and incorporated the ‘Vanderbilt

Structural Features’ into the beta-carboline research

it was conducting.” Vanderbilt Univ. v. ICOS Corp.,

594 F. Supp. 2d 482, 506 (D. Del. 2009). However, after

a thorough review of all of the evidence, the district

court concluded “the court views plaintiffs theory

(which is devoid of evidence regarding the alleged

substructure searches based on |the Vanderbilt IBMX

compound}) and defendant’s story (which is devoid of

the aforementioned foundation) equally plausible with

respect to the identification of GR30040x.” Id. We

agree that Vanderbilt fails to present clear and

convincing evidence to support its argument that the

work of the Vanderbilt Scientists was appropriated by

Dr. Labaudiniere for his substructure search.

As for Vanderbilt’s argument that Dr. Daugan

made use of the Vanderbilt Scientists’ research for the

modifications to GR30040x, the district court noted

evidence test. Vanderbilt is of course free to seek en bance

reconsideration of our settled law on this issue.

19a

that “plaintiff admitted that Corbin, Francis and

Konjeti never had any direct communication with

Daugan regarding this subject matter.” Id. at 505 n.50.

The district court also noted “a lack of evidence”

supporting Vanderbilt’s request for an inference that

Dr. Labaudiniere communicated the Vanderbilt

Structural Features to Dr. Daugan. Id. There is

nothing in the record to suggest that these factual

findings are erroneous. Thus, Vanderbilt also fails to

present clear and convincing evidence to support its

argument that the modifications to GR30040x by Dr.

Daugan made use of the Vanderbilt Scientists’

research.

Vanderbilt makes much of what it perceives to be

an error of jaw committed by the district court. We

agree that the district court opinion contains some

erroneous statements regarding the law of joint

inventorship and a misunderstanding of the relevance

of American BioScience to the facts of this case. These

errors, however, do not affect the outcome of this

appeal and are therefore harmless in context. When

tested by the correct law, the facts of the case still

require affirmance.

The district court understood our decision in

American BioScience to require that each co-inventor

have an independent conception of the final compound

for a chemical invention. The district court ruled that

because the Vanderbilt Structural Features constitute

no more than a portion of a claimed compound, the

Vanderbilt Scientists cannot, as a matter of law, be

joint inventors. Vanderbilt Univ., 594 F. Supp. 2d at

505. The district court hinged this portion of its

20a

opinion on the following language from American

Bioscience:

Having in mind specific portions of a claimed

compound is not the same as conceiving the

compound with all of its components. One must

have a conception of the specific compounds

being claimed, with all of their component

substituents ....

333 F.3d at 1340. Yet, when this language from

American BioScience is reviewed in context, the

district court’s error is clear.

The portion of the opinion quoted by the district

court phrased the question under review as “whether

the district court erred in determining that the FSU

scientists were true inventors of the claimed

compounds.” Id. (emphasis added). In American

BioScience the court was faced with choosing between

two competing groups of inventors.

Prior to the invention of the compounds at issue in

American BioScience, Dr. Tao, a scientist at Florida

State University (“FSU”), left FSU to join a group of

scientists at American BioScience that were working

on similar subject matter. Id. at 1333-35. Shortly after

Dr. Tao joined American BioScience, the company filed

a patent application that led to the patent in suit,

which claimed three taxol analog compounds. The

patent named Dr. Tao and three American BioScience

scientists as joint inventors. In the district court, FSU

claimed that the patent named the wrong inventors.

FSU asserted that three of its scientists, along with

Dr. Tao, were the correct team of joint inventors. The

district court reviewed the evidence on behalf of both

Z2la

competing teams of joint inventors, and concluded that

the SU team was the true group of joint inventors.

Accordingly, the district court ordered that the three

American BioScience scientists be removed from the

patent and the patent be corrected to add the three

FSU scientists as inventors. Bd. of Educ. v. Am.

BioScience, Inc., No. 4:99cev131/RV, 2001 WL

34104924, at *11(N.D. Fla. 2001).

American BioScience appealed to this court,

arguing clear error in the fact findings made by the

district court to support its correction of inventorship.

Because the record provided no evidence of conception

by any of the FSU scientists, acting individually or

together, this court found clear error in awarding

inventorship to the FSU joint inventor team. Properly

understood, American BioScience correctly states the

law governing joint inventorship. Absent conception

within an inventorship team, there can be no

invention.

This court began its inquiry with the statement

that “liJnvention requires conception, and ‘conception

does not occur unless one has a mental picture of the

structure of the chemical . . . or whatever

characteristics sufficiently distinguish it. It is not

sufficient to define it solely by its principal biological

property.”” American BioScience, 333 F.3d at 1340

(quoting Amgen Inc. v. Chugai Pharm. Co., 927 F.2d

1200, 1206 (Fed. Cir. 1991)). This court held that the

FSU group could not have been the true inventors

unless the group had a complete mental picture of the

structure of the chemical compounds at issue, and

continued its analysis with the language relied upon

by the district court. See id. at 1340 (“One must have

a conception of the specific compounds being claimed,

22a

with all of their component substituents, and the

record does not support a finding that [anyone in the

FSU group] conceived the three claimed compounds

kg}

While it is true that the court used the term “one”

in reference to conception, it is apparent from context

that the court was referring to “the inventor” or, in the

case of joint inventors, “the group of inventors.” Thus,

in American BioScience, the court found that the FSU

inventors were not part of any group or collaboration

that together envisioned the final claimed compounds.

This is because “|w]hile Holton may have invented

many of the compounds synthesized in his laboratory

... there is nonetheless no evidence of conception by

Holton or anyone else at FSU of analogs having the

|required combination of molecules].” Id. at 1341. The

court’s finding in American BioScience was premised

on the fact that the FSU and American BioScience

scientists were not working together, but rather

competing for the patent rights in the compounds at

issue. There was no evidence of conception within the

FSU group, and this court found sufficient evidence of

conception within the American BioScience group.

Vanderbilt is correct that the district court erred in

reading American BioScience to find that each

co-inventor must have an independent mental picture

of the complete compound claimed. Such an

interpretation is clearly wrong under our established

precedent. Instead, a group of co-inventors must

collaborate and work together to collectively have a

definite and permanent idea of the complete invention.

Similarly, the district court’s statement that “the

contribution of a molecular scaffold in the context of

one molecule” could never rise to the level of joint

28a

inventorship for “a different family of molecules

containing the same scaffold” is in error. Vanderbilt

Univ., 594 F. Supp. 2d at 506-07. “The determination

of whether a person is a joint inventor is fact specific,

and no bright-line standard will suffice in every case.”

Fina Oil & Chem. Co. v. Ewen, 123 F.3d 1466, 1473

(Fed. Cir. 1997). Our case law was not intended to

create such a bright line rule as was used by the

district court.

As previously stated, the district court, however,

did not rest its opinion solely on this interpretation of

our case law. The district court correctly noted that

conception requires identification of the specific

chemical structure of the compound. The parties agree

that Dr. Daugan was the first to conceive of tadalafil.

After a careful review of the evidence, the district

court concluded that the parties’ respective stories

about whether the Vanderbilt Scientists contributed to

the identification of GR30040x were “equally

plausible” and that Vanderbilt failed to produce any

evidence of joint invention of tadalafil. For Vanderbilt

to succeed in its inventorship claim, it must carry its

burden of proof of demonstrating that the Vanderbilt

Scientists contributed to the claimed invention with

clear and convincing evidence. See Hess v. Advanced

Cardiovascular Sys., Inc., 106 F.3d 976, 980 (Fed. Cir.

1997). The district court’s findings demonstrate that

under the correct legal test, Vanderbilt did not carry

its burden. Thus, any erroneous interpretations of our

case law were harmless error.

24a

COSTS

INO cost

AFFIRMED

DYK, Circuit Judge, concurring in part and dissenting

in part.

There is no question that the district court applied

the wrong standard for joint inventorship. The

majority agrees, and I agree. However, I respectfully

dissent from the majority’s conclusion that the district

court’s legal error was harmless, because in my view,

the findings are either contradictory or infected by the

court’s legal error. I would vacate the judgment and

remand, requiring the district court to make findings

of fact in light of the correct law.

Vanderbilt University (“Vanderbilt”) argues that its

scientists—Drs. Jackie D. Corbin, Sharron H. Francis,

and Sekhar R. Konjeti (“the Vanderbilt

scientists”)—should be added as joint inventors to the

patents in suit under two theories: (1) Dr. Richard

Labaudiniere (“Labaudiniere”) at Glaxo, Inc. (“Glaxo”)

used the Vanderbilt scientists’ disclosure of

8-(4-hydroxy phenylthio)-IBMX to identify the

compound GR30040x, which was in turn used by Dr.

Alain Daugan (“Daugan”), the sole inventor listed on

the patents in suit, and (2) Daugan used the

Vanderbilt scientists’ disclosure of 8-(4-hydroxy

phenylthio)-IBMX to modify GR30040x and create the

patented compounds. ICOS Corporation (“ICOS”)'

responds that the Vanderbilt scientists’ disclosure

played no role in Glaxo’s identification of GR30040x er

‘In 1991, Glixo and ICOS entered into a collaboration agreement

wherein all rights, title, and interest in the compounds ultimately

covered by the patents in suit were assigned to ICOS.

26a

the patented compounds. I agree with the majority

that the district court’s findings with respect to the

second theory are not clearly erroneous. The court

found that Daugan did not himself directly utilize the

Vanderbilt scientists’ contributions; this finding was

supported by Daugan’s testimony that he was not

aware of the contributions and Labaudiniere’s

testimony that he did not forward the Vanderbilt

scientists’ work to Daugan.

However, the findings with respect to the first

theory were either tainted by the district court’s legal

error or are contradictory on their face. The district

court found that the Vanderbilt scientists did in fact

make contributions to Glaxo’s work, a point the

majority ignores. After incorrectly explaining that the

Vanderbilt scientists could not be joint inventors

because there was no evidence that they had ever

conceived the complete patented compound, the

district court went on to state:

This is not to say that Corbin, Francis and

Konjeti did not make contributions to Daugan’s

inventive process; only that, under the

applicable law, these contributions fall more

into the category of “prosaic” contributions

because they did not conceive the invention as

claimed.

Vanderbilt Univ. v. ICOS Corp., 594 F. Supp. 2d 482,

505 (D. Del. 2009) (quoting Eh Lilly & Co. v. Aradigm

Corp., 376 F.3d 1352, 1358-59 (Fed. Cir. 2004))

(emphases added). The district court also found that

ICOS’s position that Glaxo made no use of the

Vanderbilt scientists’ disclosures was “untenable.” Id.

at 505—06. It further stated that ICOS “loses

Zila

credibility in the court’s view for failing to

acknowledge that Glaxo made any use of plaintiff's

disclosure.” Id. at 506. The court even cited a number

of factors supporting its finding that Glaxo relied on

the Vanderbilt scientists’ work in Glaxo’s research: the

disclosed potency of 8-(4-hydroxy phenylthio)-IBMX,

the common structure of the compounds, and the short

time between the Vanderbilt disclosure and Glaxo’s

identification of GR30040x. Id. at 505—06.

At the same time, the district court found that

ICOS’s theory as to how Labaudiniere identified

GR30040x was unsupported. Prior to trial, ICOS

asserted that Labaudiniere identified GR30040x by

following up on research reported in two journal

articles. ld. at 496. But after it was shown that one of

those articles was not published until after GR30040x

had been tested, ICOS offered a different story at trial.

ICOS claimed that Labaudiniere arrived at GR30040x

by performing substructure searches based on the

tetrahydro beta-carboline fragment of GR35273, a

compound discovered in a separate Glaxo program. See

id. at 497-98. However, the district court noted that

“nowhere in its papers did [ICOS] articulate why

Labaudiniere selected tetrahydro beta-carbolines

(more specifically, the tetrahydro beta-carboline

fragment of GR35273) for his substructure searches.”

Id. at 506.

Thus the district court found that the Vanderbilt

scientists did make a contribution to the identification

of GR30040x. The district court then went on to find

that “[Vanderbilt]’s theory (which is devoid of evidence

regarding the alleged substructure searches based on

8-(4-OH-PT)-IMBX |[sic]) and [[COS]’s story (which is

devoid of the aforementioned foundation) [are] equally

28a

plausible with respect to the identification of

GR30040x.” Id. at 506 (emphasis added). As a footnote

to this finding, the district court added: “Notably, even

ifGR380040x were the invention, the balance would not

so tip in favor of plaintiff such as to constitute clear

and convincing evidence.” Id. at 506 n.53.

There are two possible ways to interpret the district

court’s findings, either of which requires a remand.

The first is that the district court’s findings are

directly contradictory. The court could not have

properly found that the Vanderbilt scientists made a

contribution to the identification of GR30040x if it

were “equally plausible” that they did not make a

contribution. In this situation, we must send the case

back to the district court so that it can reconsider its

findings. Both this circuit and other circuits have

uniformly found that judgments based on

contradictory findings cannot stand. See, e.g., Essex

Electro Eng’rs, Inc. v. Danzig, 224 F.3d 1288, 1295

(Fed. Cir. 2000); Mattson v. Dep’t of Treasury, 86 F.3d

211, 215 (Fed. Cir. 1996); Lyles v. United States, 759

F.2d 941, 944 (D.C. Cir. 1985); Grano v. Dep’t of Dev.

of City of Columbus, 637 F.2d 1073, 1081-82 (6th Cir.

1980); Legate v. Maloney, 334 F.2d 704, 708 (1st Cir.

1964).

The alternative is that the district court found that

Vanderbilt did not establish by clear and convincing

evidence that the Vanderbilt scientists’ contributions

were sufficient to make them joint inventors. The

problem with this interpretation of the finding is that

it is obviously tainted by the district court’s view that

in order to be joint inventors, the Vanderbilt scientists

29a

must have “conceived the ‘specific chemical structure

of the compound’ claimed or ‘the compound with all of

its components,’ or communicated that compound to

Glaxo.” Vanderbilt, 594 F. Supp. 2d at 505 (citations

omitted). In particular, the district court

misinterpreted our decision in American Bioscience

when it stated that the Vanderbilt scientists could not

be joint inventors “even if the court were to find that

[their] disclosure of 8-(4-OH-PT)-IMBX [sic] led to the

identification of GR30040x and the subsequent

discovery of [the patented compounds]” because “the

contribution of a molecular scaffold in the context of

one molecule . . . [could not] render||] the disclosing

party or parties [joint] inventors of a different family

of molecules containing the same scaffold.” Id. at

506—07; see Bd. of Educ. ex rel. Bd. of Trustees of Fla.

State Univ. v. Am. BioScience, Inc., 333 F.3d 1330

(Fed. Cir. 2003). The majority correctly rejected this

legal error. See Majority Op. at 19.

An alleged joint inventor does not have to conceive

of the entire claimed invention, as the district court

mistakenly required. He merely must contribute to the

conception of the claimed invention. Eli Lilly, 376 F.3d

at 1359. There is “no explicit lower limit on the

quantum or quality of inventive contribution required

for a person to qualify as a joint inventor.” Fina Oil &

Chem. Co. v. Ewen, 123 F.3d 1466, 1473 (Fed. Cir.

1997). The law does not require that the joint

inventors physically work together or at the same

time, or each make the same level of contribution. 35

U.S.C. § 116; see also Kimberly-Clark Corp. v. Procter

& Gamble Distrib. Co., 973 F.2d 911, 917 (Fed. Cir.

1992) (providing “one inventor seeing a relevant report

and building upon it” as an example of joint inventive

effort). A joint inventor need only “make a contribution

30a

to the conception of the claimed invention that is not

insignificant in quality, when that contribution is

measured against the dimension of the full invention.”

Fina Oil, 123 F.3d at 1473. While the district court

found that the Vanderbilt scientists made some

contribution, it has not told us exactly what that

contribution was or why that contribution was not

enough to make the Vanderbilt scientists joint

inventors under the correct standard. If the Vanderbilt

scientists made contributions, as the district court

found, the fact that those contributions may not have

been “appropriated by Dr. Labaudiniere for his

substructure search,” Majority Op. at 15, does not

foreclose the possibility that the Vanderbilt scientists’

contribution was sufficient to make them joint

inventors.

Because the district court’s findings were either

contradictory or tainted by legal error, I think we must

vacate the judgment of the district court and remand

in order that the court may make factual findings

under the proper law. | dissent from the majority’s

decision to affirm what I view as an untenable district

court decision.

APPENDIX B

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF DELAWARE

Civ. No. 05-506-SLR

[Filed January 27, 2009]

VANDERBILT UNIVERSITY,

Plaintiff,

ICOS CORPORATION.

Defendant.

Vincent A. Bifferato, Jr., Esquire, lan Connor

Bifferato, Esquire, and Raj Srovatsan, Esquire of

sifferato Gentilotti LLC, Wilmington, Delaware

Counsel for Plaintiff. Of Counsel: Kurt C. Rommel,

Esquire of Miles & Stockbridge P.C., McLean, Virginia;

Robert S. Brennen, Esquire and Donald E. English,

Jr., Esquire of Miles & Stockbridge P.C., Baltimore,

Maryland.

tichard K. Hermann, Esquire and Mary B. Matterer,

Esquire of Morris James LLP, Wilmington, Delaware

Counsel! for Defendant. Of Counsel: Kevin M.

Flowers, Esquire, Thomas I. Ross, Esquire, and

")*),

SPAT

Matthew C. Nielsen, Esquire of Marshall, Gerstein &

Z,orun LLP, Chicago, Illinois

OPINION

Dated: January 27, 2009

Wilmington, Delaware

/s/ Sue L. Robinson

ROBINSON, District Judge

I. INTRODUCTION

Plaintiff Vanderbilt University (“plaintiff or

“Vanderbilt”) brought the present action pursuant to

35 U.S.C. § 256 against defendant ICOS Corporation

(“defendant” or “ICOS”) on July 20, 2005, requesting

that the court direct the United States Patent and

Trademark Office (“PTO”) to correct U.S. Patent Nos.

5,859,006 (“the ‘006 patent”) and 6,140,329 (“the ‘329

patent”) by adding three Vanderbilt professors as

inventors. (D.I. 1) A bench trial was held between

January 7, 2008 and January 15, 2008 on the issues of

inventorship of the ‘006 and ‘329 patents. Post-trial

briefing has been completed. (D.J. 153, 150, 154) The

court has jurisdiction pursuant to 28 U.S.C. §§ 1351

and 1338. Having considered the documentary

evidence and testimony, the court makes the following

findings of fact and conclusions of law pursuant to I*ed.

R. Civ. P. 52(a).

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II. FINDINGS OF FACT AND CONCLUSIONS OF

LAW'

A. The Parties

1. Vanderbilt is a Tennessee not-for-profit

corporation with its principal place of business in

Nashville, Tennessee. (D.I. 130, ex. 1 at 7 1)

Vanderbilt brought this action pursuant to 35 U.S.C.

§ 256, requesting that the court add Jackie D. Corbin,

Ph.D., Sharron H. Francis, Ph.D., and Sekhar R.

Konjeti, Ph.D. as inventors on the ‘006 and ‘329

patents. (D.I. 1) All three scientists are employed as

professors at Vanderbilt and, consistent with their

terms of employment, have assigned all rights that

they may have in the ‘006 or ‘329 patents to

Vanderbilt. (PTX-6; PTX-7; PTX-8)

2. ICOQS is a Delaware corporation with its

principal place of business in Bothell, Washington.”

(id. at J 2) ICOS is the owner by assignment of the

‘006 and ‘329 patents (together, the “patents at issue”).

3. Glaxo Wellcome Inc. is a North Carolina

corporation (hereinafter, “Glaxo”).’ Glaxo Group

' The court is appreciative of ICOS’ counsel’s submission of DVDs

containing the parties’ post-trial briefs and exhibits in searchable,

hyperlinked format.

* ICOS was acquired by Eli Lilly and Company on January 29,

2007; it is now a wholly-owned subsidiary of that company. (D.I.

130, ex. 1 at { 3)

3 In 2001, Glaxo merged with SmithKline Beecham to form Glaxo

SmithKline.

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Limited is Glaxo’s English subsidiary (hereinafter,

“Glaxo U.K.”). In 1991, Glaxo* and Glaxo U.K. entered

into a collaboration with ICOS, assigning to ICOS the

rights, title, and interest in the compounds covered by

the patents at issue. (PTX-406) At all times relevant to

the present litigation, Glaxo maintained a research

facility in Les Ulis, France (hereinafter, “Glaxo

France”).

B. The Technology at Issue

4. Cyclic guanosine monophosphate (“cGMP”) is a

chemical messenger in the body that activates cGMP

kinase,’ resulting in the relaxation of smooth muscle

tissue. The relaxation of vascular smooth muscles lead

to vasodilation® and increased blood flow. (103:5-23)

Phosphodiesterase-5 (“PDE5”) is an enzyme that

breaks down cGMP. (Tr. 103:4-5) PDE5 has two

different binding sites: one for binding cGMP to

regulate it, and another for binding cGMP to break it

down. (D.I. 140 at 115:20-116:24) Phosphodiesterase

(or “PDE”) inhibitors prevent the degradation of

cGMP, thereby enhancing and/or prolonging smooth

muscle relaxation.

5. The ‘006 patent claims at issue (claims 1-8, 10,

12 and 13) are directed to chemical compounds and

* At that time, Glaxo Wellcome’s predecessor, Glaxo, Inc.

° Also called protein kinase G or PKG. Generally, kinases are

enzymes that phosphorylate particular target molecules. Protein

kinases act on and modify the activity of proteins.

° Generally, the widening of blood vessels, resulting from

relaxation of smooth muscle cells within the vessel walls.

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methods for making those compounds. The compounds

are tetracyclic derivatives of the following general

structure:

A compound of formula (1)

The ‘006 patent provides that such compounds are

“potent and selective inhibitors of cyclic guanosine

3',5'-monophosphate specific phosphodiesterase (eGMP

specific PDE).” (006 patent, col. 1, Il. 8-12)

6. The ‘006 patent teaches that PDE5 inhibition

caused by the claimed compounds results in elevated

cGMP levels, resulting in, amongst other benefits,

improved vasodilation. (‘006 patent, col. 5, ll. 15-35)

Such compounds are of interest “for the treatment of

a variety of conditions where inhibition of [PDE5] is

thought to be beneficial,” for example, the treatment of

cardiovascular disorders. (‘006 patent, col. 1, Il. 12-15;

col. 5, Il. 9-14)

7. The ‘329 patent cleims at issue (1, 2, 3, 5-12, and

15-21) are directed to compositions and methods of

treating impotence, also called erectile dysfunction

(“ED”), in a male animal involving the administration

of at least one of the compounds claimed in the ‘006

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patent. One such compound is “tadalafil,”’ the active

ingredient in the prescription ED drug Cialis”.

Tadalafil has the following structural formula:

C. Nature of the Dispute

8. Plaintiff asserts that Corbin, Francis and Konjeti

conceived of a compound, 8-(4-hydroxy phenylthio)-

IMBX (also referred to as 8-(4-OH-PT)-IMBX), which

was communicated to Glaxo in 1992 pursuant to a

research agreement. According to plaintiff, the

disclosure of 8-(4-OH-PT)-IMBX led to Glaxo’s

development of two molecules incorporating the same

molecular scaffold and, ultimately, the general

chemical structure of formula 1 of the ‘006 and ‘329

patents.

9. Glaxo scientist Dr. Alain Daugan, who began

work on Glaxo’s PDE inhibitor project in June 1992, is

the sole named inventor on the ‘006 and ‘329 patents.

Defendant asserts that Daughan independently

* Tadalafil has the formula C,,H,,N,0, and IUPAC name (6R-

trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro

-2-methyl-pyrazino [1',2':1,6] pyrido{3,4-bJindole-1,4-dione.

ofa

conceived the claimed compounds by conducting a

comprehensive medicinal chemistry study between

June 1992 and January 1994.

D. Legal Framework

10. 35 U.S.C. § 116 provides that “|w]hen an

invention is made by two or more persons jointly, they

shall apply for a patent jointly and each make the

required oath, except as otherwise provided in this

title. Inventors may apply for a patent jointly even

though (1) they did not physically work together or at

the same time, (2) each did not make the same type or

amount of contribution, or (3) each did not make a

contribution to the subject matter of every claim of the

patent.”

All that is required of a joint inventor is that he

or she (1) contribute in some significant manner

to the conception or reduction to practice of the

invention, (2) make a contribution to the

claimed invention that is not insignificant in

quality, when that contribution is measured

against the dimension of the full iavention, and

(3) do more than merely explain to the real

inventors well-known concepts and/or the

current state of the art.

Pannu v. lolab Corp., 155 F.3d 1344, 1351 (Fed. Cir.

1998). Section 116 “sets no explicit lower limit on the

quantum or quality of inventive contribution required

for a person to qualify as a joint inventor. Rather, a

joint invention is simply the product of a collaboration

between two or more persons working together to solve

the problem addressed.” Fina Oil and Chem. Co. v.

Ewen, 123 F.3d 1466, 1473 (Fed. Cir. 1997) (citii.g

38a

Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d

1223, 1227 (Fed. Cir. 1994)).

11. “A patent is invalid if more or fewer than the

true inventors are named.” Gemstar-TV Guide Intern.,

Inc. v. Intl Trade Com’n, 383 F.3d 1352, 1381 (Fed.

Cir. 2004) (citing Jamesbury Corp. v. United States,

518 F.2d 1384, 1395 (Ct. Cl. 1975)); 35 U.S.C. § 102(f)

(“A person shall be entitled to a patent unless... he

did not himself invent the subject matter sought to be

patented|.]”) Because patents are presumed valid, 35

U.S.C. § 282, there is a presumption that the named

inventors on a patent are the true inventors. Gemstar,

383 F.3d at 1381 (citation omitted). This presumption

may be overcome by demonstrating, by clear and

convincing evidence, that the alleged omitted inventor

“contributeld] in some significant manner to the

conception of the invention” claimed. Jd. (quoting Fina

Oil & Chem. Co. v. Ewen, 123 F.3d 1466, 1473 (Fed.

Cir. 1997)).

12. 35 U.S.C. § 256 provides that an error in

naming persons who are not inventors or in omitting

inventors will not invalidate a patent where a

correction is requested (and approved by) the PTO

Director, or where “[t}he court before which such

matter is called in question [orders] correction of the

patent on notice or hearing of all parties concerned|.|”

Plaintiffat bar does not seek to invalidate the ‘006 and

‘329 patents, but seeks an order directing the Director

of the PTO to correct the named inventorship. (D.I. 153

at 50) Regardless of the relief requested, Corbin,

Francis, and Konjeti must’ establish’ their

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co-inventorship by facts supported by clear and

convincing evidence.” See Gemstar, 383 F.3d at 1382.

E. Inventorship Evidence

The court turns now to the findings of fact upon

which its ultimate conclusion on inventorship will be

based.

1. Pre-collaboration

13. Corbin and Francis have been proiessors of

molecular physiology at Vanderbilt University Schoo]

of Medicine since the 1970s. Their research focuses on

the molecular aspects of smooth muscle relaxation.

Francis specifically focuses on cGMP. Corbin and

Francis identified PDE5 in the late-1970s. (D.1. 140 at

115:20-116:24)

14. Prior to their collaboration with Glaxo, Corbin

and Francis tested several dozen cGMP analogs.

(PTX-35 at VM601; D.I. 140 at 133:9-10) They

discovered that there were two forms of cGMP kinase,

type la and If. (D.1. 140 at 133:17-19)

* Despite plaintiff's invitation to apply a lesser standard in view

of the fact that the PTO does not verify named inventors, the

court declines to apply a preponderance of the evidence standard

absent compelling Federal Circuit authority.

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2. Plaintiffs cGMP analog work & the

communication of 8-(4-OH-PT)-IMBX to

Glaxo

15. On December 16, 1988, Corbin completed an

application for a “Glaxo Cardiovascular Discovery

Grant.” (PTX-32) Along with this application, Corbin

and Francis submitted an abstract of their research

proposal and the research proposal itself (hereinafter,

“the 1988 Research Proposal”). (PTX-35)

16. The objective of the 1988 Research Proposal was

described as “develop[ing] cGMP analogs|’], or

combinations of analogs, that are potent and specific,

and that exhibit an appropriate pattern of reversibility

or persistence, in causing relaxation of vascular

smooth muscle[.]” (PTX-35, ex. A, p. 10 at VM599) New

cGMP analogs would be tested for their activation “of

smooth muscle type Ia and If isozymes|'’} of cGMP

kinase,” which isozymes have two specific cGMP

binding sites (“site 1 and 2”). Ud.) In other words, the

team sought to identify compounds that would activate

cGMP kinase, just like cGMP would activate cGMP

kinase to achieve smooth muscle relaxation, therefore

mimicking an increase in cGMP."' The proposal

” A compound that is similar in structure to cGMP

'. Generally, enzyme variants having different amino acid

sequences but which catalyze the same chemical reaction (2.e.,

have the same function).

' In this regard, the “focus” would be on four analog groups: “(a)

analogs that are selective for cGMP-binding site 1-of cGMP

kinase; (b) analogs that are selective for site 2; (c) analogs that

bind with high affinity to both sites; and (d) analogs that are

4la

provided that combinations of cGMP analogs and

specific cGMP PDE inhibitors would be tested for

synergistic effects. Ud. at VM599) Also included was a

list of the new cGMP analogs that had _ been

synthesized by Corbin and Francis: 8-pCL-pheny]

S-cGMP, a compound with an_= eight-position

substitution, as well as several other 8-substituted

compounds (e.g., compound GI118611A). (Ud. at

VM601; D.I1. 143 at 651:23-652:11)

17. Corbin was selected for a Glaxo Cardiovascular

Discovery Grant. Following a visit from Glaxo

representatives, plaintiff and Glaxo executed a “Glaxo

Cardiovascular Discovery Grants Research

Agreement” (hereinafter, “the 1989 Research

Agreement”) dated July 1, 1989. (PTX-35) The 1988

Kesearch Proposal (and abstract of that agreement)

became appendices to the 1989 Research Agreement.

18. The 1989 Research Agreement provided that

the project would be funded for a three-year period,

and contemplated renewal by mutual agreement of all

of the parties. (Ud. at 2-3) Any inventions made by a

participant in the project “and conceived or reduced to

practice during the course of and under the project

shall be the property of the University subject to the

rights agreed herein to be granted to Glaxo under a

license agreement to be entered into between the

parties.” (Ud. at 3-4) Glaxo retained the right to delay

publication and dissemination of the results of

plaintiffs work relating to the Agreement for up to

persistent in causing relaxation of artery strips.” (PTX-35, ex. A,

p. 10 at VM600)

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three months if Glaxo believed the publication would

jeopardize its patent rights. (/d. at 12)

19. On November 1, 1989, Corbin presented his

zroup’s work to a group of senior Glaxo scientists in

North Carolina: Dr. Crist Frangakis, Joel Shaffer, Jeff

Wiseman, and Dr. Thomas Rimele. (PTX-37)

20. In January 1990, Konjeti joined the Vanderbilt

lab as a postdoctoral fellow to collaborate with Corbin

and Francis on cGMP analogs under the 1989

Research Agreement. (647:2-8) Konjeti studied Corbin

and Francis’s work on cGMP and PDES5 upon his

arrival, as well as the research proposal, to familiarize

himself with their work. (647:23-648:5)

21. From March 22 to 24, 1990, by the invitation of

Dr. Don Kirksey, Director of Glaxo’s “Discovery

Program,” Corbin attended a “Cardiovascular

Discovery Conference” in Tucson, Arizona. (D.1. 140 at

134:19-135:4; PTX-36) During the conference, Corbin

had a lunch meeting with several scientists: Dr.

Joseph Beavo (from the University of Washington

(“UW”)) and Kirksey, Shaffer, Rimele and Wiseman

(all from Glaxo). (PTX-42) The parties discussed a

potential collaboration between plaintiff and UW to

determine the DNA sequence for and ultimately clone

PDE5.” (Id.)

22. Aside from doing work under the 1989 Research

Agreement, Corbin and Francis continued their work

on PDE5 during this period, funded by the National

'’ Cloning PDE5 would avoid the process of purifying PDE5 from

rat and cow lung for testing purposes. (!0.I. 140 at 139:24-140:24)

43a

Institutes of Health. (D.I. 140 at 141:7-143:5) An

article received for publication in the Journal of

Biological Chemistry on April 11, 1990 describes

Corbin and Francis’s purification of PDE5 from cow

lung.’’ (PTX-43) This work illustrated that zaprinast

was a PDED inhibitor. (D.1. 140 at 141:24-142:2)

According to Corbin, these results got the team

thinking that “the studies of cyclic GMP analogs on

lcGMP kinase] that we had already done might apply

to PDES.” (/d. at 142:7-14)

23. Following the 1990 Cardiovascular Discovery

Conference, Corbin, Francis and Konjeti submitted a

progress report to Glaxo on work done under the 1989

Research Agreement, entitled “Cardiovascular

Discovery Grant 1989-1990 Annual Report”

(hereinafter, “the 1990 Progress Report”). (PTX-44)

The 1990 Progress Report listed newly synthesized

cGMP analogs that were tested over the past year for

activation of cGMP kinase (both types Ifalpha] and

I[beta]), including: 8-napthylthio-cGMP, 8-o-Br-PT

-cGMP, and 8-p-OH-PT-cGMP. (/d. at VC-78) The 1990

Progress Report stated that “[i]t should be noted that

'’ This PDE5 work was also published in 1990 as a book chapter

entitled “Cyclic Nucleotide Phosphodiesterases: Structure,

Regulation and Drug Action.” (PTX-420; D.I. 143 at 779:7-14)

Also named on both publications is Melissa K. Thomas, a

graduate student at Vanderbilt University

'* -1,4-Dihydro-5-(2-propoxypheny])-7H-1,2,3-triazolo[4,5-d]

pyrimidine-7-one. A compound originally developed as an

anti-allergy treatment

' Defendant does not contest plaintiffs representation that the

1990 Progress Report was presented following the Cardiovascular

Discovery Conference in 1990

44a

the most potent smooth muscle _ relaxants,

8-Br-PET-cGMP and 8-pOH-PT-cGMP, are ~20 times

more potent than the best cGMP analog

(8-pCL-PT-cGMP) tested prior to this study.” (Ud. at

VC-79)

24. On November 28, 1990, Corbin sent Kirksey at

Glaxo U.K."° a copy of an abstract he sought to be

published at a Federation of American Societies for

¢xperimental Biology (“FASEB”) conference scheduled

in 1991 (hereinafter, the “FASEB abstract”). (PTX-47)

The results contained in the FASEB abstract included

the discovery that the potency of the cGMP analogs

with certain functional groups attached at the

8-position was enhanced by the attachment of

electron-donating groups to the phenyl! ring. (/d.)

(“Analogs modified with a derivatized phenyl-

activating group at the 8-position were 100-1000 fold

more potent in activating [CGMP kinase type Ia] than

[CGMP kinase type If]). Electron donating

substituents such as OH, NH2 and OCH3 on the

phenyl ring enhanced the potencies of these analogs in

activating [type Ia].”)) Corbin testified that Glaxo

required him to withdraw the FASEB abstract.

(150:11-12)

25. On March 18, 1991, Corbin made a presentation

at the “Glaxo Discovery Conference” in North Carolina

on his team’s progress to date. (P'TX-53) In attendance

were Kirksey (Glaxo), Beavo (UW), two Glaxo

' On October 23, 1990, Glaxo informed Corbin that the

administration of Glaxo’s cardiovascular program was being

transferred from North Carolina to Glaxo Group Research

(“GGR”) in the United Kingdom. (PTX-45)

45a

scientists from the United Kingdom (Barry Moss, Mike

Drew), and several others. Ud.; D.I. 140 at 151:7-25)

26. Also on March 18, 1991, Rimele authored a

“Cardiovascular Status Report” (hereinafter, the

“Glaxo CSR”) detailing the history and results of

Glaxo’s research in the area of smooth muscle

relaxation. (PTX-51) The Glaxo CSR states that the

first examples of cGMP analogs were submitted in

May 1990. Ud. at GLAX15564) Testing on these

analogs began in June 1990. (/d.) Among the list of

cGMP analogs was G1118611A, Glaxo’s designation for

8-(4-chloro-phenylthio)-cGMP, a compound previously

listed by plaintiff in the research proposal portion of

the 1989 Research Agreement. (/d. & GLAX15570; D.L.

143 at 651:22-652:10) In addition to GI118611A, the

Glaxo CSR lists four additional cGMP analogs that

had been included in either the 1989 Research

Agreement or the 1990 Progress Report: (1) Gl

120446A, or l-napthylthio cGMP (D1. 143 at

652:12-653:12; PTX-51 at GLAX15571; PTX-35 at VM

602"’); (2) GI 118815A, or napthylthio cGMP; (3) GI

119889A, or 8-octobromo cGMP (DJ. 143° at

653:13-654:1;: PTX-51 at GLAX15570: PTX-40 at

VK347""); and (4) GI 1205474, a hydroxythio cGMP”

The research proposal of the Agreement notes that “[t]he more

bulky l-napthyl-S-cGMP (analog 14) will be made by using

] napthylenethiol as Starting material.”

Konjetis lab notebook lists 8-napthylthio cGMP and

8-or tobromo cGMP as compound: synthesized as of February 13

1990. (PTX-40 at VK-347; D.I. 143 at 649:12-650:6)

- Because the pres ISs© nomenclature o! thi: compound dor not

appear to be of record, the court cannot match up GI 120547A

46a

(D.I. 143 at 654:2-654:22; PTX-5] at GLAC15621).”

Zaprinast and a compound SC-44238 were listed as

cGMP PDE inhibitors, and IMBX, caffeine, and

theophyline were listed as nonselective inhibitor:

(PTX-51 at GLAX15632)

27. The Glaxo CSR described the progress on cGMP

analogs, discussed at a May 4, 1990 mecting, as

follows

The important interactions of the protein with

cGMP were presented along with the location of

a novel lipophilic binding pocket off of the eight

position of the guanine base. This modeling will

serve as the basis to design novel cGMP analog:

to synthesize.

Ud. at GLAX15594: see also id. at GLAX15596 (““Bused

upon the location of a novel lipophilic binding pocket

off the eight position of the guanine base, compounds

with bulky groups off the &-position are being

synthesized.”))

28. The Glaxo CSR described future work regarding

PDES5 as: (1) continuling to] develop an SAR ol

with the 1990 Propvre Report as per Konjeti’s testimony

Defendant, however, did not contest this point in its answering

brief

” Glaxo patent coun el conducted a literature search in April

1991, and concluded that several of these compounds were not

previously described. (PIT'X-57) It is unclear from the record

exactly which compounds were deemed novel as of that date

47a

zaprinast”’; (2) synthesizling] compounds that vary the

distance of a particular zaprinast; (3) synthesiz[ing] a

substrate for an affinity column for PDES:

(4) developling] syntheses of zaprinast-cGMP hybrids;

and (5) validatfing] the cGMP PDE enzyme assay.

(PTX-35 at GLAX15597)

29. In April 1991, Corbin and his group sent a

minuscript for Glaxo’s approval for publication,

entitled “Relaxation of Pig Coronary Arteries by New

and Potent cGMP Analogs that Selectively Activate

Type Ia Compared to Type If cGMP-Dependent

Protein Kinase.””’ (PTX-56) In the article, Corbin et al.

hypothesized that the potency of 8-position substituted

cGMP analogs was due to the “spacial tolerance of

large substituents at C-8, preference of this binding

site for the syn[**] conformation of cyclic nucleotides

and the electron-withdrawing/donating properties of

*! A weak PDE inhibitor known at the time.

*? This paper was eventually published in 1992. (D.I. 140 at

163:5-8)

“ cGMP has two segments which can rotate around a specific

point of the molecule, resulting in two 3-D configurations. When

cGMP is in the “syn” position, the guanine moiety and the ribose

cyclic phosphate moiety are pointed in the same direction. In the

“anti” position, the two moieties are turned away from each other.

° o

— HY N

i, IL» ioe

> As 0

HN HN n "

o ¥

oe re)

Fr On \_Lo

° Pp

. “»

Pe lied o” “S

ee *%

SvbD position Anti position

48a

the substituent.” Ud. at VC-146) “It was thus

concluded that a bulky halogen substituent with low

electron withdrawing power favors the activation of

the cGMP kinases.” (/d.) Corbin testified that analogs

with large bulky groups at the 8-position are fixed in

the syn position; they cannot rotate to the anti position

due to the substituent. (D.I. 140 at 163:9-165:1)

30. On May 29, 1991, Dr. M. W. Elwes of Glaxo’s

External Scientific Affairs Division, Glaxo U.K., sent

Corbin a letter stating the foilowing:

{Glaxo has] now had time to examine the

projects in [ ] light of our new arrangements for

supervision of the cardiovascular therapeutic

area within the Glaxo research organization. As

you will be aware responsibility for this

therapeutic area now rests with Glaxo Greup

research and our CVS Research Management

Committee (RMC) is not lead by Dr. Barry

Ross. ... We consider your work to be very close

to our own project interests and so we would

hke to develop as close a collaboration with you

as geography will allow for the remaining period

of the grant. I would ask you, therefore, to send

your reports in the future to Dr. Fiona Roberts,

our Academic Liason Manager, at this {U.K.]

address. ...

(PTX-59A)

31. Corbin testified that he and _ Glaxo

representatives engaged in informal discussions

during that time regarding the continuation of

plaintiffs grant. (D.I. 140 at 171:8-172:20) During

these discussions, Glaxo indicated a_ potential

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bioavailability issue insofar as cGMP breaks down in

the stomach and intestines, never reaching its

destination tissue. (/Jd.) According to Corbin, Glaxo

also indicated that future work should focus more on

PDE5 than the original grant did. (/d.)

32. Corbin responded to Elwes’ letter on July 24,

1991, in which he noted that he was pleased with

Glaxo’s interest in plaintiffs work, and that it “seems

[from previous informal discussions with Glaxo

representatives] that any future relationship with

Glaxo, following the award termination, would be an

open-ended proposition.” (P'TX-71) Corbin asked to be

informed “if there is anything [he] could do now to

improve the chances for such a continuation ... We

feel that this particular project is going quite well, and

we wish to carry on with it if possible.” Ud.)

33. Glaxo meeting minutes for the “PDE Project”

dated June 3, 1991 state that Glaxo’s goal at that time

was “[tlo discover a potent specific inhibitor of

cGMP-specific (‘type V’) [PDE] for the treatment of

hypertension, angina pectoris, etc.” (PTX-62) Some

specific “molecules already obtained in the U.S., with

some biological results,” were “azapurines” and

“imidazoles.” (Id.) Action items included “search|ing]

for available molecules.” (U/d.) “The compound that

seems to be the most interesting at this point is

AH19041xx (azapurine family ... ).” Ud.) The

following “[o]ther molecules to be studied (various

vasodilators and PDE inhibitors” were listed:

** Generally, imidazole is a organic compound with the formula

HC,H,N,. Purine is a heterocycle consisting of a pyrimidine ring

fused to an imidazole ring. Azopurines are purine analogs.

50a

hydralazine, dihydralazine, eudralazine, minoxidil,

pinacidil, diazoxide, flosequinan, nicotinamide ethers,

nitraquazone, imidazolidinones, rolipram analogs, and

cicletanine. (/d.)

34. From June 17-20, 1991, Dr. Jorge Kirilovsky, a

scientist with Glaxo France, traveied to North

Carolina for meetings with Rimele, Domanico, and

other Glaxo scientists regarding PDE V.” (PTX-58;

PTX-58A) Glaxo sent compounds listed in the meeting

minutes of June 3, 1991 to Glaxo France. (/d.; DI. 142

at 474:20-475:3, 478:12-19) The American scientists

proposed to test “AH19041X-type imidazoles fairly

soon” to determine any effects on the central nervous

system. (PTX-58A at GLAX15734; D.I. 142 at 477:3-8)

Glaxo was in discussions with ICOS at this time,

which was to clone and express about 30 enzymes

which would be used to test different types of

compounds developed by Glaxo. “ICOS’s prierity would

be type IV, followed by types V and II] .” (PTX-58A at

GLAXI15735-36)

35. Dr. Paul Grondin was hired by Glaxo in June

1991 by George Kirilovsky to carry out experiments for

the PDE V project at Glaxo France; he was the first

person assigned to do so. (D.I. 142 at 473:7-15, 474:1-4)

36. Minutes ofa Glaxo France PDE Project meeting

on July 9, 1991 reflect that

*° “Individuals who have been involved in the PDE V program in

the past;” in addition, chemists David Uchling and Paul Feldman.

(PTX-58A) Scientists Steve Simpson and Verghese were also listed

in the memorandum discussing the trip. (/d.)

5la

lal ist of model compounds already

characterized as PDE inhibitors has been drawn

up on the basis of published work and the GI

results. These compounds will be analyzed

using the various tests currently being set up at

Les Ulis: enzymology, isolated artery, isolated

heart, whole animal.

The “proposed list of model compounds” for a “type V

inhibitor” consisted of AH 91041XX, GI 122529X, and

zaprinast. (PTX-69) “The second step will be to

determine the lead compounds, drawing from either

the PDE inhibitors presented in published work, the

known vasodilators, or model compound analogs

(above list).” Ud.)

37. The Glaxo July 1991 minutes state that a

ChemBase computer file was set up to include all of

the compounds tested and the results obtained.

“Compounds of interest” GI 122529X and AH 19041XX

were to be compared to zaprinast. (/d.) Neither

compound was available in sufficient amounts at that

time, and needed to be synthesized for the study. Ud.)

Glaxo France’s “|gloal for the end of the year {1991]”

was “[o]perational enzymology and pharmacology tests

with in-house results on compounds chosen as

references.” (/d.)

38. Minutes of a Glaxo PDE Project meeting of

August 27, 1991 reflect that Glaxo was, as of that date,

“beginning [] in vivo testing of zaprinast and

rolipram.” (PTX-58A at GLAX15759) Dr. Bernard

Dumaitre was planning to synthesize AH19041X as a

reference compound, which was accomplished in

September 1991. (PTX-58A; PTX-75) Compound

G1122529X would not be available for six weeks, and

o2a

G1121730 was to be tested in its stead. (PTX-58A at

GLAX15759) Finally, Glaxo noted an “action” item of

“l{i]mmediate synthesis of rolipram and denbuflyn” by

Dumaitre and another scientist. (/d.)

39. A PDE Project meeting was held at Glaxo

France on October 9, 1991. (JTX-7; PTX-77) At that

time, Glaxo”” was working to complete an assay to

measure PDE5S inhibition. (D.1. 142 at 423:25-484:11)

Following completion of the assay, Glaxo’s obiective

was to “develop a_ specific tool of the zaprinast

{asapurinone) type with 10 times greater activity.”

Ud.; PTX-77) Glaxo expected that in the near future,

ICOS would possess a “type V [PDE] (human lung)...

for screening.” (PTX-77)

49. Also in October 1991, Corbin wrote Roberts at

Glaxo requesting permission to provide plaintiffs

“close coliaborators” with the cGMP analogs “for basic

research purposes.” (PTX-81) Corbin indicated that

Glaxo had approved, as of that date, “the publication

of the syntheses and properties of the compounds.”

(J TX-43) Corbin testified that his request for a blanket

approval to provide compounds to third parties was

denied by Glaxo. (D.1. 140 at 175:4-6)

41. In November 1991, Corbin, Francis and Konjeti

synthesized a new PDE5 inhibitor. (PTX-88 at

VK-1737, 1757-62) IMBX was chosen as a parent

compound for the new PDE5 inhibitor because it was

known to work, it was cheap and readily available, and

26 . > ; :

Glaxo considered the PDE Project to be an international

collaboration between Glaxo and Glaxo France. (PTX-77 (“The

PDE project is international|.]”))

58a

was easily substituted at the 8-position. (1).1. 140 at

185:4-17; D.I. 143 at 663:12-16, 786:2-21) A phenyl

ring was attached to the 8-position of IMBX, and an

electron-donating hydroxy group at the 4 position of

that phenyl ring. The result was 8-(4-hydroxy

phenylthio)-IMBX (or 8-(4-OH-PT)-IMBX), a potent

PDE5B inhibitor.

N _

7 H / N

O—H

42. Also in November 1991, Corbin drafted a letter

to plaintiffs General Counsel, Jackie Schrago, with

respect to Corbin’s request for plaintiff to sponsor the

compounds Corbin was developing. (PTX-89; D.I. 140

at 176:17-177:3) Corbin communicated to Schrago

possible therapeutic uses for the new analogs,

including the treatment of male impoteice. (PTX-89)

The treatment of ED with cGMP analogs had not been

published in the literature as of this time. (D.I. 143 at

784:1-9, 796:8-25; D.J. 145 at 1139:9-17)

43. In December 1991, Dr. Richard Labaudiniere

was hired by Glaxo France as the head of chemistry.

(D.I. 141 at 392:10-393:23) Labaudiniere assumed

leadership of the PDE5 project. Ud.) As head of

chemistry, Labaudiniere was involved in all projects of

that department and was responsible for discussing

the best approaches for chemists’ work, including

suggesting modifications to compounds. Additionally,

Labaudiniere was involved in management and

54a

discussed methods of drug development with the head

of biology. Ud.)

44. Also in December 1991, Corbin spoke with Ross

at’ Glaxo U.K. about the possibility of extending

plaintiffs collaboration with Glaxo. (D.I. 143° at

668:19-23, 784:20-785:10; PTX-41) On Janua.” 3,

1992, Corbin sent Ross a “general outline of a propcsal

for a> extension of the Corbin/Glaxo corroboration

(hereinafter, the “January 1992 general proposal”).

(JTX-41) “The major change [of this proposal] is that

it emphasize[d] a combined protein kinase/[PDE]

approach|.]” Ud.) Corbin testified that the “major

change” referenced was a focus on PDE5 inhibitors, at.

the encouragement of Glaxo scientists. (D.I. 140 at

178:17-179:23) Corbin theorized that “cyclic GMP

analogs might apply to PDES5 as they applied to PKG”

and, therefore, “|wle could in practical terms even use

the same analogs that we already synthesized for PKG

to test on PDE5.” Ud.)

45. The January 1992 general proposal contained

three sections: cGMP analogs; “liJnhibitors of a

lcGMP]-binding [PDE]”; and “other projects to

consider.” (J'‘TX-41) Regarding cGMP analogs, Corbin

stated the following:

We will expand on our most significant finding

that analogs modified at the 1,2- and 8-positions

of the guanine moiety of cyclic GMP are the

most potent relaxants. We originally proposed

to synthesize such analogs because = 1,2-

modified analogs bind to one_ cyclic

GMP-binding site of the cG kinase and 8&-

modified analogs bind to the other site. As

predicted, when these two structural elements

dda

were combined, the resulting compounds were

even more efficacious because they bound well

to both binding sites. We now believe that the

high potencies of these analogs are due not only

to the high kinase affinity of 1,2- and

8-modifications, but also to a strong [PDE]

resistance due mainly to the 8-modifications.

This latter property also contributes to the

long-lasting analog effect observed in the intact

tissue (and presumably in the intact

organism)... .

(JTX-41 at VC-225-26) Corbin testified that the

“persistence” of the analogs, or failure to break down,

was believed to be the result of resistence to PDE in

the tissue. (D.I. 140 at 180:2-15)

46. With respect to PDE inhibitors, the January

1992 proposal stated the following:

We will design [PDE] inhibitors based on the

theory that the potencies of existing inhibitors,

such as 3-isobutyl-l-methylxanthine (IMBX)

and zaprinast, could be enhanced by appending

groups that would allow the inhibitors to more

closely resemble the entire cyclic GMP molecule.

The existing inhibitors resemble only the

guanine component. Our preliminary results

indicate that this strategy works. We have

synthesized one compound that is about

160-fold more potent than the parent

IMBX, and 6-fold more potent than the best

existing inhibitor, zaprinast....This section

overlaps neither with our NIH grant... nor

with our ICOS/Glaxo collaboration described

56a

above. However, each of these projects should

benefit from the others.

(JTX-41 at VC-226-27) (emphasis added) Corbin and

Francis testified that they believed that compounds

having both the guanine component and an appendage

to make contact with the (exposed) ribose phosphate

portion would be more potent. (DI. 140 at

181:21-183:12; D.1. 143 at 790:3-792:9) Notably, Corbin

and Francis did not have the genetic sequence of PDE5

at the time and did know the structure of the catalytic

site; their theory was based upon observations of

cGMP binding on PKG.” (791:23-794:11)

47. Finally, under the “other projects” heading of

the January 1992 general proposal, Corbin noted that

“the cG kinase has important disease-related functions

other than the induction of vascular smooth muscle

relaxation.” (JTX-41 at VC-227) “Corpus cavernosum

relaxation (male impotence)” was listed as an

application of interest. (Jd.) Corbin suggested Glaxo

support plaintiffs research for three years starting in

July 1992. Ud.)

27 That is, as explained in the FASEB abstract, hydrophobic

groups of atoms, such as a phenyl ring, with additional

electron-donating groups appeared to bind well to binding sites on

PKG in the vicinity of the ribose phosphate moiety of cGMP.

(PTX-47; D.I. 140 at 149:15-150:12) Francis acknowledged at trial

that scientists at the time did not believe that PKG and PDES

catalytic sites were related. She testified, however, that the team

believed a relationship was “plausible” because a new PKG was

developed in the lab that was identical in amino acid sequence but

differed dramatically in affinity for cGMP, illustrating chemical

preferences. (D.I. 143 at 793:4-794:11)

ova

48. Glaxo was not researching male impotence in

early 1992. (D.1. 141 at 407:12-24)

49. Ross flew from England for a presentation of

the January 1992 general proposal on February 3,

1992. (JTX-42; D.1. 140 at 187:14-22; D.I. 142 at

583:10-19) On February 11, 1992, Glaxo France

purchased a quantity of IMBX. (PTX-115)

50. On February 24, 1992, Corbin mailed Ross a

final proposal including “|mjore detail of the

experimental design” with “increased emphasis on use

of the newly synthesized compounds to study basic

mechanisms of the protein kinase and [PDE]”

(hereinafter, the “1992 Research Proposal”).*°

(PTX-117; PTX-118) Like the January proposal, ,the

1992 Research Proposal specifically identified

8-(4-OH-PT)-IMBX as a new compound “that is about

160-fold more potent than the parent IMBX, and 6-fold

more potent than the best existing inhibitor,

zaprinast.” (PTX-117 at 3) Other IMBX and zaprinast

analogs were also listed. (/d. at 4; PTX-424) All but one

had 8-position substitutions, (D.I. 143 at 672:3-6)

51. In addition, the 1992 Research Proposal stated

that Corbin’s team “now believeld] that the high

potencies of these analogs in intact tissues are not only

due to the high kinase affinity of the 1,2- and

8-modifications, but also to a strong PDE resistance

and antagonism due mainly to the 8-modifications.”

(PTX-117 at VC250) “|Slome cGMP analogs are not

only PDE-resistent, but they also act like

*® Corbin testified that he, Francis, and Konjeti jointly prepared

the February 1992 proposal. (D.1. 140 at 190:22-24)

methylxanthine inhibitors of the enzyme by binding

tightly to its catalytic site.” (/d.)

52. On March 11 and 12, 1992, Glaxo tested 26

compounds for PDE5 inhibition, including a compound

designated GR35273x, discussed in further detail

infra. (DTX-IG at GLAX13202)

53. On April 8, 1992, Ross sent copes of the 1992

ltesearch Proposal to six Glaxo scientists, including

Dr. Francois Hyafil, head of the Glaxo France lab, and

Labaudiniere. (PTX-121; D.I. 130, ex. l at J 21) In his

cover, Ross stated that Corbin’s work on cGMP analogs

and “probling] the mechanism and role of smooth

muscle protein kinases and [PDEs]” was “a substantial

collaboration and the only one of the original US CV

discovery grants that remains.” (PTX-121) Further,

Ross stated that

Corbin is collaborating with the ICOS/Glaxo

strategic alliance in the area of type V [PDE]

enzyme mechanisms and_ function. This

proposal is distinct from that collaboration and

is primarily directed towards the cGMP

simulated kinases. As a_e spinoff some

compounds have demonstrated type V PDE

inhibitory activity. Results eminating from this

collaboration may provide the foundation for a

future in-house discovery programme directed

towards hypertension and congestive heart

failure.

Ud.)

54. On April 23, 1992, Glaxo tested the PDE5

inhibitory capacities of 29 compounds. (PTX-425)

59a

Among these were zaprinast, and a_ molecule

designated GR30040x, discussed in detail infra.

(PTX-140) There is no evidence of record

demonstrating the date GR30040x was identified by

Glaxo for the purpose of this testing

55. Plaintiff asserts 11 of these 29 compounds

contain what it calls the “Vanderbilt Structural

features,” or “a 6-member ring fused to a 5-member

ring, with some substitution at the &-position.” (D.]

153 at 27)

3. The identification of GR30040x

preceded the discovery of tadalafil

56. This case pivots around GR30040x, a

beta-carboline*” compound having the following

four-ring scaffold structure

(D.1. 150 at 11)

“ Beta-carbolines are compounds comprising the following general

(three-ringed) structure

HOa

57. There is nodispute that Labaudiniere identified

GR30040x as a “lead” compound for research regarding

PDES5 inhibition. Following its identification, Daugan

conducted research on GR30040x. Through the course

of this research, Daugan discovered tadalafil

58. Plaintiff asserts that Labaudiniere used the

“Vanderbilt Structural Features” for two purposes

First, plaintiff claims that the disclosure of

8-(4-OH-PT)-IMBX led to the discovery of the lead

compound GR30040x. Second, plaintiff asserts that it:

disclosure of &-(4-OH-PT)-IMBX contributed to the

course of the modifications to GR30040x performed by

Daugan.”’ The court addresses the facts relevant to

each assertion in turn

59. Plaintiff asserts that the “only logical source for

the identification of GR30040x and the inclusion of the

Vanderbilt Structural Features in the patented

compounds” was the 1992 Research Proposal. (D.1. 154

at 12) To give context to plaintiffs claim, and in view

of the presumption that Daugan invented the

compositions and methods claimed in the patents at

issue, the court first addresses Gliaxo’s evidence

regarding how GR30O040x was identified as the lead

compound for Daugan’s research

The compounds of formula 1] of the patents at issue are beta

carboline/piperazinedione compounds; GR30040x and GF'17332 1)

are beta-carboline hydantoin compounds, and are not part of th

claimed invention

' The parties debate the sequence of modifications to GR30040»x

I {

performed by Dauvyan, as it relates to this argument

Ola

a. Glaxo’s evidence” regarding — the

identification of GR30040x

i. Elgoyhen

60. In its pretrial disclosure, Glaxo asserted that

Labaudiniere became aware in early 1992 of literature

suggesting that beta-carbolines could alter cGMP

levels, which caused him to use the “basic

beta-carboline structure” ofthe prior art compounds to

conduct a substructure search. (IDE. 130, pt. 4 at 3)

When these compounds were tested, some were found

to be fairly potent PDE5 inhibitors. Labaudiniere then

asked Daugan to pursue the modification of these “lead

compounds,” including GR380040x. (/d_)

61. This theory is reflected in a paper received by

the Journal of Medicinal Chemistry on February 5,

2003, entitled “The Discovery of Tadalafil: A Novel and

Highly Selective PDEDS Inhibitor[.]” (hereinafter, the

“Padalafil Paper”). (JTX-29) As reflected in’ the

Tadalafil Paper, “f$-carbolines had been previously

found to increase basal level of CGMP in rat cerebellum

. land] were also reported to inhibit crude rate aortic

cyclic nucleotide [PDE] activity.” Two references are

cited: (1) a 1983 article in the Furopean Journal of

Pharmacology by B. Koe et al. entitled “Contrasting

Kiffects of Ethyl $-Carboline-3-Carboxylate and

Diazepam on Cerebellar Cyclic GMP Content and

Antagonism of Both Effects by Ro 15-1788, A Specific

Benzodiazepine Receptor Blocker” (hereinafter, “Koe”);

and (2) a May 1992 article in the Journal of

Pharmacology and Experimental Therapeutics by B.

Elgoyhen et al. entitled “Relaxant Effects of f-

Carbolines on Rat Aortic Rings” (hereinafter,

“Elgoyhen”). (JTX-29 at ICOS737 & n. 10 & n.11) The

62a

Tadahfil Paper proceeds to state that “[t}he Bb carboine

scaffold was: then used as a basis for substructure

searching in our internal database to find novel type 5

IPD] inhibitors (chart 1)." 7d. at 1COS737)

62. Of record is a Glaxo document entitled “PDE V

Inhibitors Project Annual Report for the Year lending

30/4/93” (hereinafter, the “1992-98 Annual Report”).

(DTX-P) The 1992-92 Annual Report reflects that Koe

and/or Elyoyhen led Labaudiniere to beta-carbolines

generally, while substructure searches on the

tetrahydro beta-carboline portion of GR35273" led to

the identification of GR380040x in particular:

4.7. a- GR80040 analogues

It is a new series of compounds we began to

study last year starting from literature data on

B-carboline and benzodiazepine’ derivatives

having some- vasorelaxant effect on

precontracted rat aortic rings. These compounds

displayed in our hand some PDE V inhibition

activities. Substructure searches from $-CCE[”"|

and GR35273 on tetrahydro-f-carboline

analogues in GLAX led to the idenfification of

GR380040, a specific PDE Vo inhibitor, with

activities similar to zaprinast (see figure 11).

Studies have been performed to improve

potency.

” A beta-carboline compound. (D.[. 143 at 891:22-892:9)

“ B-CCE or BCCE, chemical name ethyl beta-carboline-3

carboxylate (or beta-carboline-3-carboxylic acid ester), Is a

benzodiazepine antagonist and a member of the beta-carboline

chemical family.

Ud. at GILAX00037)

63. Glaxo’s internal testing record indicates that

GR80040x was subjected to ai 10 micromolar

: J4 “1 «ype ‘ ane

concentration test™ on April 28, 1992, scoring an 86 for

Inhibition. (PTX-140) GR380040x was then tested to

: bh 2 ‘ ‘ '

determine an IC...” value on April 24, 1992, which

revealed a value of 0.2 micromolar. Ud.) Tests on

GRS0040x using PDEI1, or a type 1 PDE inhibitor,

were performed on May 12 (10 micromolar

concentration test) and June 38, 1992 (IC, 2.0

micromolar, a poor result). 7d.) Additional IC... tests

were performed on GR30040x (PDE5) on June 9 and

10, 1992 IC... = 0.6 and 0.15 micromolar, respectively)

(Id.) A IC, test was performed on BCCI on July 38,

1992, revealing a IC,,. value of O.8 micromolar

(P'TX-170; D.L. 146 at 1215:18-1216:2)

64. Raiferty conceded that any searches conducted

by Glaxo based on Elgoyhen or SCCE would have had

to have occurred after Elyoyhen was published on May

8 1992. (DTX-RJ; DI. 146 at 1256:2-23) In short,

GRS0O040x was not identified following Labaudiniere’s

reading of Elgoyhen.

* Plaintiff represents that this test measures inhibition using a

set concentration of the compound, usually 10 micromolar, on a

scale from 0-10%, with 100% representing complete inhibition

(D.1. 153 at 29)

" 1C,, is a measure of the biochemical function of a compound,

indicating the quantity of the drup required to inhibit a biological

process (or component of a process, te., an enzyme, cell, cell

receptor or microorganism) by half. See ven. www.wikipedia

orge/wikV/lC50

04:1

ii. Substructure searches

65. Glaxo distanced itself from Klgoyhen at trial,

asserting that GR80O040x was identified through a

substructure search of GR3&d52738, a) beta-carboline

compound having the following structure.

66. Raflerty opined at trial that Labaudiniere

identified GR35273, a compound ofinterest taken from

Glaxo’s “APOB100"" program, “another internal

discovery program in Glaxo,” in an effort to identify

new leads for the PDIE5 > program. (1D.1. 146. at

1202:5-18) GR352738 was tested on March Ll and 12,

1992, and was identified as an “impressive” PDIH5

inhibitor. Vd.; DTX-IG at GLAX13202) According to

Rafferty, Labaudimere then undertook substructure

searches based on the tetrahydro beta-carboline

Glaxo argues in its papers that “in May 1992, the Elgoyhen

publication reinforced Dr. Labaudiniere’s interest in

beta-carbolines as potential PDE-5 inhibitors by showing that

they could relax blood vessels.” (D.1. 150 at 8) (emphasis added)

“ APOB-100 is one of the two main isoforms of apolipoprotein B,

the primary apolipoprotein of low-density lipoproteins (“LDL”,

commonly referred to as “bad cholesterol”). See gen

www.wikipedia.org/wiki/apolilipoprotein B

ODa

fragment” of GR35273, leading to the identification of

(7 R30040x (among other compounds), which was tested

on April 238, 1992. (D.1 M46 at 1202:5-18,

1204:15-1206:14) Rafferty explained that, among the

compounds tested by Glaxo between March and July

1992, there are “a rather disproportionate number of

tetrahydro beta -carbolines, which suggests [|] asearch

was conducted .. . and that Dr. Labaudiniere was

exploring possibilities that turned up from. that

search.” Ud. at. 1299:1-5)

a. Documentary evidence

67. Minutes of a meeting held by Glaxo’s

Cardiovascular Research Management Committee on

April 9, 1992 describe GR385273 as ai compound

synthesized by Prof. Campbell of Bath University that

“selectively down-modulates apoB-100 production.”

(JTX-22 at GLAX25738) Notes from that same

commiuttee’s meeting on June 11, 1992 reflect that

3A orp .

* Tetrahydro beta-carboline has the following structure

” This mention of GR35273 occurred in the section entitled

“Status Reports” and subtitled “6.1 Atheropgenic and

Thrombogenic Risk Factors.” (J'TX-22 at GLAX25738) Aside from

an appendix containing its structure, the document does not

appear to mention GR35273 elsewhere. (/d.)

66a

GR3852738x, a compound coming from— our

APOB100 screen{,| displayed a high PDE V

inhibition activity (IC50=30nm). A closed

analogue AH2O905xx displayed a similar

activity (IC50—50nm). ‘These compounds can be

considered as conformationally constrained

analogues of zaprinast, which are not patented

as PDE V inhibitors. We are starting now a

chemical programme on GR35273x analogues

(JITX-24 at GLAX10365) Minutes from Glaxo’s PDI

Project meeting of June 28, 1992 (hereinafter, the

“June 23, 1992 minutes”) also lst GR352738x as an

. : . . . 40

analog of zaprinast, having the following structure

rer ™ ad

a ae NA

CKO

* Plaintiff points to JTX-15 at GLAX16277-80, an untranslated

version of minutes from an October 1992 Glaxo France strategy

meeting, in support for the proposition that the PDE Project team

“debated and concluded [in October 1992] that GR35273x was

more appropriately considered a carboline than a zaprinast

analog.” (D.1. 154 at 10) No English translation appears to have

been admitted and the court is not in the position to judge this

statement. The court does note, however, that GR35273x appears

to contain the beta-carboline core (three-ringed) structure.

67a

(J'TX-13 at’ GILAX16000) At this same meeting,

GR380040x was characterized as a “new” PDES5

inhibitor.” dd. at GLAX15986)

68. Also of record are the untranslated minutes of

a PDE Meeting held at Glaxo France on September 9,

1992. (DTX-AQ) Among these minutes appears a “{

carbolines” chart, handwritten by Labaudiniere. (/d. at

GLAX16099) GR380040 is structurally depicted among

several compounds related to BCCE” (including a

compound designated as GR142799); structure-activity

relationships between the various compounds are

noted. Ud.; D.I. 144 at 894:17-22)

69. Glaxo’s “PDE V Inhibitors Project Annual

Report for the Year Ending 80/4/03” (hereinafter, the

“1992-93 Annual Report”), issued April 30, 1993,

discusses results of zaprinast analogues as well as “[a]

new series of PDE V inhibitors .. . based on [al]

tetrahydro-f$-carboline structure,” the best of which

was identified as GFI185990. (DTX-P, abstract)

Additionally, the 1992-93 Annual Report states as

follows:

“Plaintiff does not point to an English translation of JTX-13. It

is clear ,from the transcript that GR30040x was characterized as

a “new” PDE5 inhibitor, though little else from this document is

readily discernable. (1.1. 146 at 1250:1-15)

42m ° ~ ° . . °

rhe precise nature of the relationship (analogs, derivatives, etc.)

is unclear.

“The 1992-93 Annual Report is in memorandum format,

addressed from Labaudiniere to Drs. Baxter, Finch, and Johnson

of Glaxo France, with distribution to Glaxo’s central files, 30 other

employees (presumably scientists), and a department titled

“Science Information, Les Ulis.” (DTX-P)

OS8a

4. 7. §$-Carboline Series

4. 7. a- GR30040 analogues

It is a new series of compounds we began

to study last year starting from literature

data on $-carboline and benzodiazepine

derivatives having some vasorelaxant

effect. on precontracted rat aortic rings.

These compounds displayed in our hand

some PDE V_ooinhibition activities

Substructure searches from $-CCE and

GR385273 on tetrahydro-f-carboline

analogues in GLAX led to the

identification of GR380040, a specific PDE

V inhibitor, with activities similar to

zaprinast (see figure 11). Studies have

been performed to improve votency.

(DTX-P at 9) Figure 11, as referenced above, is

’

reproduced below. Compound CC123002 is BCCE.

69a

PDE V INHIBITORS

Heta-Carboline Derivatives

Z De CO a >

rt -. oD

S nef ~™ wu | ~e

CC123002 7 GRISI3 i \

I1C.=800 nM “ 1C,.-30 nM “ 7

ECY>>10uM EC y= 7 uM .

GR142799 (;R30040

IC,,=650nM IC. =200 nM

EC,.=S-10uM

70. A 2003 Glaxo document also contains the same

illustration (hereinafter, the “Beta-Carboline

Derivatives Chart”) On February 24, 2008,

Labaudiniere sent a report entitled “Progress in the

Chemistry and Biology of PDE V Inhibitors” to Dr.

Steve Stimpson at Glaxo.** (DTX-SU) This report

identified three compounds, inciuding $SCCE, for

“evaluation as PDE V inhibitors.”” (Ud. at

GILAX16454) The Beta-Carboline Derivatives Chart

was provided. Ud. at GLAX16455)

** “Enclosed are the acetates of the last ICOS [meeting] for the

overview presentation and the cellular biology working session

where all the data relevant for PDE V inhibition were presented.”

(DTX-SU)

® Several tetrahydro-beta-carboline PDE5 inhibitors (GF 169502;

GF171885; GF 173322; GF 173321) were also identified. (DTX-SU

at GLAX16456)

70a

b. Testimony

71. Labaudiniere testified that the term “search” in

the Beta-Carboline Derivatives Chart indicates that

GR142799 and GR30040x were identified through a

substructure search. (D.I. 141 at 441:7-25)

Labaudiniere testified that he used Glaxo’s ChemBase

system to “identify analogues with the beta-carboline

core structure.” Ud. at 436:23-437:3. 437:21-25)

Daugan corroborated this testimony. (D.I. 144 at

891:12-892:24)

72. Elgoyhen published prior to the June 1992

testing of BCCE. There was some debate at trial

regarding whether a substructure search of BCCE

would yield the compounds tested by Glaxo on April

23, 1992, including GR30040x (as indicated by the

Beta Carboline Derivatives Chart). Rafferty testified

that substructure searches based on the BCCE

scaffold, removing the ethylcarboxylate ester from the

six-membered notrogen-containing ring (and leaving

open the possibility for either single or double bonds on

that ring), would have retrieved GR148799 asa result.

(D.1. 146 at 1271:21-1272:25; DTX-TC) Plaintiff

emphasizes that a substructure search based on the

complete BCCE molecule, without modification, would

not have returned any of the compounds tested on

April 23, 1992. (D.I. 153 at 38, n. 31; D.I. 146 at

1274:3-11)

b. Plaintiffs challenges to Glaxo’s

inventorship theory based on GR35273x

rye)

73. Plaintiff challenges Glaxo’s position that

GR30040x was gleaned from substructure searches on

GR35273x (rather than from substructure searches

Tla

based on the Vanderbilt Structural Features contained

in 8-(4-OH-PT)-IMBX) in several additional ways.

First, plaintiff points out that the documents do not

seem to connect GR380040x and GR385273x. (D.1. 153 at

39) GR380040x is not described as a GR35273x analog

in the foregoing meeting notes and minutes. Analogs

of GR380040x were listed in the June 23, 1992 minutes,

but GR385273x was not among them. (/d. at

GLAX15995-96) GR30040x was characterized as a

“new” PDES inhibitor. (/d. at GLAX15986)

74. Plaintiffalso argues that, while Glaxo’s internal

1992-93 Annual Keport specifically ties the

identification of GR380040x to a substructure search on

GR352"3, Glaxo held out to the scientific community

in the Tadalafil Paper that GR30040x was identified

through substructure searching using “the (}-carboline

scaffold” based upon the disclosures of Koe and/or

Elgoyhen. (JTX-29 at I1COS737)

75. Finally, plaintiff argues, without testimonial

support, that a substructure search based on “the

structural elements the Glaxo. scientists found

important in GR35273x would have identified only one

compound among the April 23rd compounds other than

GR35273x itself.” (D.1. 153 at 39, n.33; D.1. 154 at 10*°)

“ The exhibits cited by plaintiff do not support this

representation.

V2a

c. Plaintiff's theory that its disclosure

of 8-(4-OH-PT)-IMBX led to the

identification of GR30040x

76. Plaintiff asserts that 8-(4-OH-PT)-IMBX and

the claimed compounds share a common scaffold. The

portion of the compound of formula 1 corresponding to

the asserted “Vanderbilt Structural Features” is

circled below.

FIGURE 1

Essential structural elements Loum’

ta the TRAIN analogs

ly dropen boud dance sie ~*~ ,

General S - Keiouaoce elect

neral Structure | Revouagce General Structns

GonoT mMsotwenst

C8 sub tiated LAMX agalogs dey ehryped b Fe vie {ly fiom US Parwet 6 wal

the V aude: but gray pa

(D.I. 153 at 35)

77. As noted previously, the 1992 Research

Proposal disclosed that some of the eGMP analogs

plaintiff had created were not only PDE resistant, but

acted like inhibitors of the enzyme by binding tightly

to its catalytic site. (PTX-117 at VC250) Plaintiff

asserts that the 1992 Research Proposal would have

communicated to a chemist that the 8-position

modification of the cGMP analogs prevented the cGMP

from being degraded; attaching a “biomimetic’ of the

ribose phosphate moiety, consisting of groups like

4-hydroxy phenylthio, to the 8-position of existing

inhibitors, that biomimetic would bind in the same

ray,

region of the catalytic site as the ribose phosphate

group that it is mimicking, and the result would be

increased inhibition.” (D.1. 153 at 23, citing D.1. 145 at

963:22-969:3)

78. Plaintiff asserts that Labaudiniere, upon

receiving a copy of plaintiff's 1992 Research Proposal,

conducted a substructure search based upon the

Vanderbilt Structural Features contained in

8-(4-OH-PT)-IMBX. Plaintiff admits that no direct

evidence supports its theory that such a search

occurred.*’ Plaintiff relies on the _ following

circumstantial evidence in order to demonstrate the

likeliness of its hypothesis: (1) the 1992 Research

Proposal contained impressive and stand-out results

for 8-(4-OH-PT)-IMBX; (2) these results came from a

respected source; (3) a substructure search based on

the Vanderbilt Structural Features could have been

performed with ease in only a few minutes; (4) On

April 23, 1992, a few weeks after Labaudiniere

received the 1992 Research Proposal, Glaxo tested 29

compounds for PDE5 inhibition including zaprinast;

(5) none of these 29 compounds had originally been

developed and registered in Glaxo France; and (6) each

compound had a skeleton including a “6-membered

ring fused to a 5-membered ring”; (7) 26 of the 29

compounds tested had “some substitution at the

8-position,” as did the IMBX analogues identified by

plaintiff in the 1992 Research Proposal; and (8) 11 of

the 29 compounds contained both “a 6-member ring

fused to a 5-member ring, with some substitution at

(D.1. 154 at 4 (“Vanderbilt need not prove specifically how that

occurred, but simply how it logically could have occurred.”))

fda

the 8-position” (i.e., th -called “Vanderbilt

Structural Features’). (D.1. 153 at 26-28)

79. Upon Glaxo's identification of GRS0040x,

plaintiff asserts that Daugan incorporated into that

compound “the only element of the Vanderbilt

Structural Features and design that was lacking in

GR30040x,” electron-donating substituent on the

phenyl ring. (D.I. 153 at 31) The result was

GF173321x, having the following structure (a:

compared to 8-(4-OH-PT)-IMBX)

‘)

} , N

S ar Cn

f T

2 Se ( I +

O N° fy V/; N jj

2 /

§-(4-Hvydroxyv phenvithio)-IBNLN GF 171321

([d.) According to plaintiff, Daugan and Labaudiniere

“completely absorbed the Vanderbilt design and

Vanderbilt Structural Features with the synthesis of

GF173321 x.”” Ud. at 34)

On or about November 23, 1992, another Glaxo chemist

synthesized a zaprinast analog, GF178534x, incorporating the

alleged “Vanderbilt Structural Features,” which plaintiff asserts

is “Iflurther evidence of Dr. Labaudiniere’s role in directing the

modifications made to GR30040x[.)” (D.J. 153 at 32)

To be clear, plaintiff does not assert in this litigation that

Labaudiniere should be named as a co-inventor on either the ‘O06

or 329 patents

15a

4. Modifications to GR30040x

80. According to plaintiff, the methoxy substituent,

or the “electron-donating substituent on the pheny]

ring, was “the only element of the Vanderbilt

Structural Features and design that was lacking in

CGR30040x.” ().1. 153 at 31) Plaintiff asserts that the

first modification made by Daugan to GR30040x wa

to replace the pyridine ring with a combination of a

phenyl ring and an eclectron-donating methoxy

substituent. (DT. 153 at 30) Plaintiffasserts that these

changes occurred simultancously, “compelfling] the

conclusion that Dr. Labaudiniere directed Dr. Daugan

to make them as a direct result of Dr. Labaudiniere’:

knowledge of the Vanderbilt) design from the 1992

ltesearch Proposal.” (D.1. 154 at 14) In support for it:

assertion that both modifications occurred together,

plaintiff cites to Daugan’s testimony. (D.1. 1538 at 30

Daugan, however, stated only that “|t]he first thing

[ne] did in this series was explore the replacement of

the pyridiny}| | moiety with other heterocyclc.§ or

aromatic moieties.” (896:2-4)

81. Plaintiff asserts that Daugan next continued t

make “obvious” modifications to GI173321x, “the

Vanderbilt Structural Features persistling]

throughout,” including “the replacement of the

D-member hydantoin ring with a §6-member

piperazinedione ring,” and eventually synthesized th

first compound with all of the features of formula 1 of

the ‘006 patent. (D.T. 158 at 34) In support, plaintiff

relies upon the testimony of Labaudiniere. (/d.)

Labaudiniere stated that modifying the phenyl ring at

(5 would have been an obvious location to modify the

GR80040x molecule. (D1. 141 at 424:11:425:18)

Labaudiniere also testified that there are a “standard

76a

yroup of substitutions or additions” that would be tried

with any molecules of interest, in a “trial-and-error”

fashion. (Ud. at 426:2-17) Hle stated that the

“n-substitution on the hydantion ring,” as discussed in

the Tadalifil Paper, was an “obvious place to make a

modification.” Ud. at 426:18-24) Because the hydantion

series of molecules had poor oral pharmokinctics,

meaning that they were generally ineffective oral

drugs, further modifications to the hydantion were

made leading eventually to the 6-member

piperazinedione ring. Labaudiniere characterized the

6-member piperazinedione ring as “a possibility among

others.” Ud. at 427:6-428:24) There was no specific

motivation to move from a 6-member ring from the

5-membered ring, only to find an orally active

compound. (/d.)

I’, Discussion

82. As noted previously, 35 U.S.C. § 116 sets “no

explicit lower limit on the quantum or quality of

inventive contribution required for a person to qualify

as a joint inventor.” Fiza Oil, 128 F.8d at 1473.

Federal Circuit jurisprudence makes clear, however,

that a person 1s a joint inventor “only if he contributes

to the conception of the claimed invention.” felt Lilly &

Co. v. Aradigm Corp., 376 F.3d 1352, 1358-59 (Fed.

Cir. 2006) (collecting cases). “The line between actual

contributions to conception and the remaining, more

prosaic contributions to the inventive process that do

not render the contributor a co-inventor is sometimes

a difficult one to draw.” Id. at 1359.

83. The Federal Circuit has provided clear guidance

in the context of claims to chemical compcunds.

“Conception of a chemical substance includes

T7Ta

knowledge of both the specifie chemical structure

of the compound and an operative method of making

it,” unless “a method of making a compound with

conventional techniques is a matter of routine

knowledge among those skilled tn the art, [in which

case] a compound has been deemed to have been

conceived when it was described.” Burroughs Wellcome

Co. v. Barr Labs., Inc., 40 F.3d 1223, 1230 (Fed. Cir.

1994) (emphasis added); Oka v. Youssefyeh, 849 F.2d

981, 583 (led. Cir. 1988). That is, “|clonception does

not occur unless one has a mental picture of the

structure of the chemical, or is able to define it by its

method of preparation, its physical or chemical

properties, or whatever characteristics sufficiently

distinguish it. It is not sufficient to define it solely by

its biological activity|.|” Amgen, Inc. vo. Chugat Pharm

Co., Ltd., 927 F.2d 1200, 1206 (Fed. Cir. 1991)

Loa

84. Indeed, on facts analogous to those at bar,” the

Federal Circuitin The Board of Education of the Board

of Trustees of Florida State University v. American

Bioserence, Inc., 333 F.3d 13830 (Fed. Cir. 2003)

(hereinafter, “American Bioscience”), declined to add as

inventors scientists who contributed the “starting

materials” for a chemical compound. The Court there

held that conception ofa chemical compound requires

“a conception of the specific compounds being claimed,

with all of their component substituents.” /d. at 1340

fo put the point another way, “(|hlaving in mind

Be , ] >

The patent at issue » American Broscrence clarumed thre

compounds which are analogs of docetaxel, an anticancer druy

(similar to the natural compound paclitaxel) having two distinct

)

substituents: (1) a 10-hydroxy group; and (2) atertbutoxyearbonyl

group attached to its 3’ mtrogen atom. 333 F.3d at 1332-33

Scientists at Florida State University (“FSU”), including Robert

Holton (“Holton”) and Chunhn Tao (“Tao”), made paclitaxe!)

analogs, including “PNIP,” a promising anticancer compound

havinga 10-acetoxy group substituent. /d. at 1334. Following an

industry conference at which Holton spoke regarding the

synthesis of paclitaxel, scientists at VivoRx Pharmaceuticals,

predect ssor to Amenean 10S6 mence, lnc - hare d ‘lao and a signed

him the task of creating docetaxel analogs using, 10-deacety!]

baccatin, a compound sirmilar to that (baccatin ITT) used at FSU to

synthesize paclitaxel but having a 1O-hydroxy group. Tao made

several compounds and a patent application was filed. Issuing

were claims to three docetaxel analoys having the 10-hydroxy

group. Because there was “no evidence of record that the idea of

making [paclitaxel] analogs having a both a 10-hydroxy pvroup

(i.e., [\docetaxels]) and a nitro functional group came from anyone

other than [ABI’s inventors],” or any “evidence of conception by

Holton or anyone else at FSU of analogs having the combination

of a 10 hydroxy group, a = nitrophenyl group, ands an

N-alkoxy-carboyl (z.e., tertbutoxycarbonyl, isopropoxycarbony}, o1

isubutoxycarbonyl) substituent,” FSU ’s arguments fell short of

meeting the clear and convincing standard of proof required to

prove inventorship. 7d. at 1339, 1341

19a

specific portions of a claimed compound is not the

same as conceiving the compound with all of its

components.” [d

85. The same result is compelled in the case at bar

The “Vanderbilt Structural Features” constitute no

more than a “specific portion|] of a claimed compound”

in the language of American Bioscience. The record is

devoid of evidence that Corbin, Francis, and/or Konjeti

communicated to Glaxo a compound of the general

structure of formula 1 of the patents at issue. Plaintiff

concedes that, prior to January 21, 1994 (the priority

date for Glaxo’s U.K. application), its scientists were

not aware of the existence of (or structure of) any of

the claimed compounds. (D'TX-RG at Response Nos

13-22) There is no indication that Corbin, Francis, and

Konjeti were working with beta carboline

86. Because there 1s no evidence that Corbin

Francis and Konjeti ever conceived the “specifi

chemical structure of the compound” claimed,

Burroughs Wellcome, 40 F.3d at 1230, or “the

compound with all of its components,” American

Bioscience, 333 F.8d at 1340. or communicated that

compound to Glaxo, plaintiff ha failed te

Defendant points out that plamntiff admitted that Corbin,

Krancis and Konjeti never had any direct communication with

Daugan regarding this subject matter. (DTX- RG at Response Nos

23-26) Plaintiff seeks an inference’ that Labaudiniere

communicated the “Vanderbilt Structural Features” to Daugan,

and directed Daugan to incorporate them tnto his research

Notwithstanding the lack of evidence in this regard, even had

Corbin, Francis or Konjeti communicated 8-(4-O11-PT)-IMBX to

Daqgan directly, plaintiff could not demonstrate on this record

SOa

demonstrate, by clear and convincing evidence, that

Corbin, Francis and Konjeti are coinventors of the

patents at issue

87. This is not to say that Corbin, Francis and

Konjeti did not make contributions to Daugan’s

inventive process; only that, under the applicable law,

these contributions fall more into the category of

“prosaic” contributions because they did not conceive

the invention as claimed. Hi: Lilly, 376 F.3d at

1358-59

88. Notwithstanding the result compelled by

federal Circuit precedent in this case, the court notes

that it finds defendant's htigation position troubling

Defendant submits that Glaxo made no_ use. of

plaintiffs disclosure that 8-(4-OH-PT)-IMBX was

“160-fold more potent that the parent IMBX and 6-fold

more potent than the best existing inhibitor,

Zzaprinast” a position that this court deems

untenable. (D.1. 150 at 3 (“[Plaintiff] did not provide

any direct (or even circumstantial) evidence that

the four “Structural leatures” played any role in Dr

Daugan’s conceptions.) (emphasis in original))

89. By the spring of 1992, of the twenty oryinal

Glaxo Cardiovascular Discovery grants, only one

remained — and plaintiff was its recipient. (PTX-121)

It is difficult to imagine that Glaxo maintained this

particular relationship for no particular” benefit

Defendant loses credibility in the court’s view for

failing to acknowledge that Glaxo made any use of

that Corbin, Francis or Konjeti ever conceived a compound within

the family of claimed compounds

Sla

plaintiffs disclosure. There was a consensus among

the witnesses at trial that the 160-fold result would

have commanded attention. (D.I. 145 at 1067:9-20

(acknowledging result was “interesting”); D.I. 146 at

1233:1-4 (acknowledging that result was “significant,”

despite denying that a single test result would have

been “particularly useful”) (R

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