`_JAN 3 1 1~95
`
`PAT.&T.M. OFFICE
`BOAilrJ OF PATENT APPEALS
`AND INTERFERH!Ci::S
`
`Paper No. 119
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE BOARD OF PATENT APPEALS
`AND INTERFERENCES
`
`SOMPONG WATTANASIN
`
`Junior Party, 1
`
`v.
`
`YOSHIHIRO FUJIKAWA, MIKIO SUZUKI, HIROSHI IWASAKI,
`MITSUAKI SAKASHITA and MASAKI KITAHARA
`
`Senior Party. 2
`
`Patent Interference No. 102,648
`
`Before CALVERT, Vice Chief Administrative Patent Judge, and
`SOFOCLEOUS and DOWNEY, Administrative Patent Judges.
`
`SOFOCLEOUS, Administrative Patent Judge.
`
`FINAL DECISION
`
`The subject matter of this interference relates to a
`
`method of inhibiting cholesterol biosynthesis using novel
`
`mevalonolactones. These compounds inhibit the enzyme, B-hydroxy-
`
`B-methyl-glutaryl-CoA reductase (HMG-CoA), which controls a key
`
`step in the biosynthesis of cholesterol, by catalyzing the
`
`conversion of the substrate HMG-CoA to mevalonate, an
`
`Application 07/498,301 filed March 23, 1990. Accorded the
`benefit of u.s. Application 07/318,773 filed March 3, 1989, now
`abandoned. Assignor to Sandoz Pharmaceuticals Corporation.
`
`2 Application 07/233,752 filed August 19, 1988. Accorded the
`benefit of Japan Applications 207224 filed August 20, .1987,
`193606 filed August 3, 1988 and 15585 filed January 26, 1988.
`Assignors to Nissan Chemical Industries Ltd.
`
`NCI Exhibit 2020
`Page 1 of 27
`
`
`
`Interference No. 102,648
`
`intermediate of cholesterol. The count of this interference is
`
`as follows:
`
`Count 3
`
`A method of inhibiting cholesterol biosynthesis in a
`patient in need of said treatment comprising administering a
`cholesterol synthesis inhibiting amount of a compound of the
`formula:
`
`wherein
`
`hydrogen,
`cl-6 alkyl,
`cl-6 cycloalkyl,
`ukoxy,
`c1
`_
`3
`n-butoxy,.
`i-butoxy,
`sec-butoxy,
`
`(wherein R7 and Ra
`hydrogen or c1_3 alkyl),
`
`are
`
`independently
`
`-2-
`
`NCI Exhibit 2020
`Page 2 of 27
`
`
`
`Interference No. 102,648
`
`. '
`
`trifluoromethyl,
`trifluoromethoxy,
`difluoromethoxy,
`fluoro,
`chloro,
`b.:olf.O,
`phenyl,
`phenoxy,
`benzyloxy,
`hydroxy,
`hydroxymethyl,
`-O(CH2 )aOR19 (wherein R19 is hydrogen or
`c1_3alkyl and a is 1, 2 or 3),
`or when
`located at
`the ortho
`R3 and
`·R4
`other,
`together
`-CH,.CH-CH=CH-;
`
`to each
`position
`optionally fo~
`
`hydrogen,
`c1_6 alkyl,
`c2_3 alkenyl,
`c3_6 cycloalkyl,
`phenyl substituted by R9 (wherein R9 is hydro-
`fluoro, chloro, bromo
`gen, cl-4alkyl, cl-3alkoxy,
`or trifluoromethyl),
`(wherein m
`phenyl-(CHzlm-
`-(CHz)nCH(CH3)-phenyl
`or
`(wherein n is 0, lor 2).
`
`2 or
`is 1,
`3),
`phenyl-(CHz)nCH(CH3 )-
`
`Y is
`
`-CH2 -,
`-CH2CH 2 -,
`-CH=CH-,
`-CH2-CH=CH-, or
`-CH,.CH-CH2-;
`
`-3-
`
`. ·.-· '' ~ .
`
`NCI Exhibit 2020
`Page 3 of 27
`
`
`
`Interference No. 102,648
`
`z is
`
`Q is
`
`or
`
`-CH(OH)-.
`-C(O)-, or
`13
`.
`-C(OR
`)2-,
`
`is hydroc;sen or
`
`w is
`
`-C(Rll) (OH).;.
`
`(where Rll
`alkyl),
`
`is hydrogen
`
`or c1_3
`
`two Rll are independently primary or secondary c1_
`the
`6
`alkyl; or two R13 together form -(CH2 J2- or -(CH2 J3-;
`physiologically hydrolyzable alkyl or· M (wherein M
`is NH4, sodiWII, potassium, l/2 calcium o.r a hydrate
`of
`lower alkylamine,
`di-lower alkylamine
`or
`tri-lower alkylamine); and
`
`R17 and R18 are inde:pendently I:ydrogen or c1_3 alkyl;
`as defined in combination with pharmaceutically
`acceptable carrier.
`
`NCI Exhibit 2020
`Page 4 of 27
`
`
`
`Interference No. 102,648
`
`Wattanasin's claims 8 and 9 and Fujikawa et al.'s
`
`(Fujikawa's) claims 35, 37 and 38 correspond to the count. No
`
`question of interference-in-fact or separate patentability of
`
`claims under 37 CFR 1.633(b) and (c)(4) has been raised.
`
`This interference was initially declared with three
`
`parties on two counts. Count 1 was directed to compounds per se;
`
`count 2, to a method of administering the compounds to inhibit
`
`cholesterol biosynthesis. The intermediate party, Picard et al.,
`
`U.S. Patent No. 4,761,419, filed a request for adverse judgment
`
`and judgment was entered against it. During the motion period,
`
`Fujikawa filed, inter alia, a preliminary motion (Paper No. 15)
`
`to add two proposed counts to this interference, which motion was
`
`denied by the administrative patent judge (APJ). As a result of
`
`the APJ's Decision on Preliminary Motions, method count 3 was
`
`substituted for count 2 and Interference No. 102,975 was declared
`
`on a count directed to compounds per se. Times for taking
`
`testimony were set. Wattanasin presented testimony in order to
`
`establish priority of invention within the meaning of 35 U.S.C.
`
`102(g). Fujikawa took cross-examination and presented rebuttal
`
`testimony. Both parties filed briefs and appeared, through
`
`counsel, at final hearing.
`
`The briefs raise the following issues:
`
`-5-
`
`NCI Exhibit 2020
`Page 5 of 27
`
`
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`Interference No. 102,648
`
`. '
`
`1. Whether the Fujikawa preliminary motion {Paper No. 15) to add
`
`two proposed counts to this interference should have been
`
`granted?
`
`2. Whether Wattanasin has established priority of invention
`
`prior to August 20, 1987, Fujikawa's effective filing date?
`
`FUJIKAWA'S PRELIMINARY MOTION TO ADD COUNTS
`
`After having reviewed the arguments of the parties, we
`
`hold that the party Fujikawa has not sustained its burden to show
`
`that the interfering subject matter should have been redefined by
`
`adding two proposed counts to this proceeding.
`
`As the moving party, Fujikawa has the burden of proof
`
`on the motion. Kubota v. Shibuya, 999 F.2d 517, 27 USPQ2d 1418
`
`(Fed.Cir. 1993). The motion proposed that two counts be added to
`
`this interference and that Wattanasin present claims 11 and 12 in
`
`his application to correspond to the proposed counts. As the
`
`moving party, Fujikawa had the burden to •..
`
`show the patentability of any proposed claims to the
`opponent and apply the terms of the claims to the
`disclosure of the opponent's application.
`§ 1.637(c)(1)(iii).
`
`The APJ denied the motion on the ground the Wattanasin application
`does not contain a written description with the meaning of 35 u.s.c.
`
`112, first paragraph, for proposed claims 11 and 12.
`
`In qccordance
`
`with 37 CFR 1.655(a), the APJ's decision on a preliminary motion
`
`constitutes an interlocutory order which is presumed to have been
`
`-6-
`
`NCI Exhibit 2020
`Page 6 of 27
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`
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`Interference No. 102,648
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`correct and the burden of showing error or abuse of discretion is
`
`upon the party attacking the order. Gustavsson v. Valenti, 25 USPQ2d
`
`1401 (BPAI 1991) and Suh v. Hoefle, 23 USPQ2d 1321 (BPAI 1991).
`
`Having reviewed the Wattanasin disclosure, we agree with
`
`the APJ that the disclosure does not contain a written description
`
`for proposed claims 11 and 12.
`
`·proposed claims 11 and 12 are as follows:
`
`11. The compound of claim 1, wherein R1 and R2 are
`
`hydrogen, R. is
`
`X is -CH=CH-, R is
`
`cyclopropyl, Q is
`
`-ca(cid:173)
`l
`oa
`
`~ is H, R8 is an alkyl of
`
`1-3 carbon atoms and M is sodium.
`
`12. A method of inhibiting cholesterol biosynthesis in
`a patient in need of said treatment comprising
`administering a cholesterol biosynthesis inhibiting amount
`of the compound of Claim 11 in combination with a
`pharmaceutically acceptable carrier.
`
`The compounds embraced by proposed claims 11 and 12 are as follows:
`z
`
`wherein R0 is 4-flurophenyl, and
`R is cyclopropyl
`
`-7-
`
`NCI Exhibit 2020
`Page 7 of 27
`
`
`
`Interference No. 102,648
`
`The Wattanasin application has the following pertinent
`
`disclosure:
`
`This invention relates to compounds of the formula
`
`(A)
`
`wherein each of R and R0 is, independently C1_6alkyl
`(primary, secondary or tertiary) , C3_7cycloalkyl or ring A
`
`each of R11 ~' R3 , ~ and R5 is, independently hydrogen,
`C14alkyl, C14alkoxy, trifluoromethyl, fl uoro, chloro,
`phenoxy, benzyloxy or hydroxy; with the provisos that not
`more than one of R1 and ~ is trifluoromethyl, not more than
`one of R1 and ~ is phenoxy, not more than one of R1 and R2
`is benzyloxy, not more than one of R1 and R2 is hydroxy, not
`more than one of R3-R5 is the trifluoromethyl, not more than
`one of R3-R5 is phenoxy, not more than one of R3-R5 is
`benzyloxy and not more than one of R3-R5 is hydroxy; [page
`1, lines 1 to 14]
`
`* * * *
`Preferred compounds of this invention are the
`following.
`
`R1 and R2 are preferably hydrogen;
`one of R and Ra is preferably C- 1_6alkyl, more preferably
`isopropyl or methyl, and ~he other is preferably Ring A,
`more preferably phenyl, 4-fluorophenyl or 3,5-
`
`-8-
`
`NCI Exhibit 2020
`Page 8 of 27
`
`
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`Interference No. 102,648
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`dimethylphenyl; more preferably R is the alkyl group and R0
`is Ring A; [page 4, lines 26 to 34]
`
`It is clear from the foregoing that the application does
`
`not describe in ipsis verbis the compounds of proposed claims 11 and
`
`12 where R is cyclopropyl. This, however, is not necessary in order
`
`to comply with the description requirement of 35 USC 112, first
`
`paragraph, In re Lukach, 442 F.2d 967, 169 USPQ 796 {CCPA 1971); all
`
`that is required is that the application reasonably convey to persons
`
`skilled in the art that, as of the filing date thereof, the inventor
`
`had possession of the subject matter later claimed by him.
`
`In re
`
`Edwards, 558 F.2d 1349, 196 USPQ 465 (CCPA 1978) and In re Driscoll,
`
`562 F.2d 1245, 195 USPQ 434 (CCPA 1977). The question of whether an
`
`application contains a sufficient written description within the
`meaning of 35 u.s.c. 112, first paragraph, for a compound which is
`
`not specifically disclosed but which is among those suggested by
`
`general language in the application must be decided on its own facts.
`
`In re Driscoll, supra and Prutton v. Fuller, 230 F.2d 459, 109 USPQ
`
`59 {CCPA 1956).
`
`In our view, the Wattanasin application would not
`
`reasonably lead one of ordinary skill to the compounds of claims 11
`
`and 12 where R is cyclopropyl, i.e., the application does. not
`
`reasonably convey to those skilled in the art that ~attanasin
`
`invented the compounds. Cf. Flynn v. Eardley, 479 F.2d 1393, 178
`
`USPQ 288 {CCPA 1973) i Fields v. Conover, 443 F.2d 1386, 170 USPQ 276
`
`-9-
`
`NCI Exhibit 2020
`Page 9 of 27
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`
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`Interference No. 102,648
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`(CCPA 1971);
`
`Irikura v. Petersen, 18 USPQ2d 1362 (BPAI 1991); and
`
`Heymes v. Takaya, 6 USPQ2d 1448 at 1452 (BPAI 1988).
`
`The Wattanasin application does not disclose any compound
`
`where R is C3_7 cycloalkyl, much less cyclopropyl. Rather,
`
`cyclopropyl is merely one moiety embraced by C3_7 cycloalkyl which is
`
`among a myriad of possibilities for either R or R0 disclosed in the
`
`application on page 1, lines 1 to 5. Further, the application at
`
`page 4, lines 26 to 34, lists its preferred compounds. None of the
`
`listed preferred compounds includes cyclopropyl or even C3_7
`
`cycloalkyl in the R position. Nor does the application have any
`
`examples directed to cycloalkyl compounds. Nor are there either any
`
`blazemarks or any motivation to guide one skilled in the art to
`
`select the cyclopropyl compounds of proposed claims 11 and 12 from
`
`Wattanasin's broad generic disclosure. Admittedly, one skilled in
`
`the art might fortuitously select a cyclopropyl compound within the
`
`scope of claims 11 and 12 out of the myriad of possibilities. This,
`
`however, is not sufficient to provide a written description of the
`
`small subgenus of claims 11 and 12. The selection of all the
`
`substituents of the genus must necessarily happen. Flynn v. Eardley,
`
`supra; In re Rushig, 379 F.2d 990, 154 USPQ 118 (CCPA 1967); and
`
`staehelin v. Secher, 24 USPQ2d 1513 (BPAI 1992). As noted by the
`
`Court in Rushig, 154 USPQ 122,
`
`Specific claims to single compounds require
`reasonably specific supporting disclosure and while
`
`-10-
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`NCI Exhibit 2020
`Page 10 of 27
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`
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`Interference No. 102,648
`
`we agree with the appellants, as the board did, that
`naming is not essential, something more than the
`disclosure of a class of 1000, or 100, or even 48,
`compounds is required. Surely, given time, a chemist
`could name (especially with the aid of a computer)
`all of the half million compounds within the scope of
`the broadest claim, which claim is supported by the
`broad disclosure. This does not constitute support
`for each compound individually when separately
`claimed.
`
`We consider the Court's statement concerning claims to specific
`
`compounds is equally applicable to the situation here where proposed
`
`claims 11 and 12 are directed to a small subgenus of cyclopropyl
`
`compounds within the scope of Wattanasin's broad generic disclosure.
`
`For the foregoing reasons, we hold that the party Fujikawa
`
`has not sustained its burden to show that the interfering subject
`
`matter should have redefined by adding the two proposed counts to
`
`this proceeding.
`
`WATTANASIN'S CASE FOR PRIORITY
`
`Fujikawa is the senior party, having been accorded under
`the provisions of 35 u.s.c. 119 the benefit of its earliest filed
`
`Japan application Serial No. 207224, filed August 20, 1987. For its
`
`case for priority of invention, the junior party Wattanasin relies
`
`upon actual reduction to practice prior to Fujikawa's effective
`
`filing date or upon prior conception coupled with diligence starting
`
`just prior ~o Fujikawa's effective filing date up to actual reduction
`
`to practice.
`
`-11-
`
`NCI Exhibit 2020
`Page 11 of 27
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`
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`Interference No. 102,648
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`Burden of Proof
`
`Wattanasin, as the junior party, whose application is
`
`copending with the senior party's application, has the burden of
`
`proving priority of invention by a preponderance of the evidence.
`
`Holmwood v. Sugavanam, 948 F.2d 1236, 20 USPQ2d 1712 (Fed.Cir. 1991)
`
`and Morgan v. Hirsch, 728 F.2d 1449, 221 USPQ 193 (Fed.Cir. 1984).
`
`Fujikawa's argument that the party Wattanasin must prove
`
`its case for priority by clear and convincing evidence is not well
`
`taken. This argument is based on the fact that this interference was
`
`initially declared with the party Picard, whose patent issued prior
`
`to the filing date of Wattanasin's involved application.
`
`If the
`
`party Picard were involved in this interference, we would have agreed
`
`with Fujikawa that Wattanasin, whose application was filed after the
`
`issuance of Picard's patent, would have had the burden of proof by
`
`clear and convincing evidence with respect to Picard. See Price v.
`
`Symsek, 988 F.2d 1187, 26 USPQ2d 1031 (Fed.Cir. 1993). Since Picard
`
`is no longer involved in this proceeding, having filed, through
`
`counsel, a request for adverse judgment, the burden of proof upon
`
`Wattanasin vis-a-vis Fujikawa is the preponderance of the evidence,
`
`inasmuch as both Wattanasin's and Fujikawa's applications are
`
`copending.
`
`Count Interpretation
`
`The count is directed to a "method of inhibiting
`
`cholesterol biosynthesis in a patient in need of said treatment." on
`
`-12-
`
`:·_,_
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`NCI Exhibit 2020
`Page 12 of 27
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`
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`Interference No. 102,648
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`page 54 of its main brief, the party Fujikawa urges that we should
`
`construe the count as being directed to a method for "treating human
`
`patients," because there is
`
`no known value in reducing cholesterol, or
`controlling blood cholesterol levels, in animals
`other than humans. Main brief at page 32.
`
`In support of its position, the party Fujikawa points to page 35 of
`
`the Wattanasin application which specifically identifies humans as
`
`the target patients and gives dosage values only for humans.
`
`We note that the term "patient" in the count is neither
`
`present in the parties' claims corresponding to the count nor defined
`
`in the parties' applications. The count of this interference is a
`
`"phantom" count which is not patentable under 35 U.S.C. 112, first
`
`paragraph, to either party. A count of an interference is merely the
`
`vehicle for determining priority of invention. It is settled
`
`interference practice that a count must be given its broadest
`
`reasonable interpretation possible, DeGeorge v. Bernier, 768 F.2d
`
`1318, 226 USPQ 758 (Fed.Cir. 1985), and it is an established
`
`principle of interference practice that the count must be
`
`sufficiently broad as to encompass the broadest corresponding
`
`patentable claim of each party. Manual of Patent Examining
`
`Procedure, § 2309.02 (Fifth Edition).
`
`Based on our review of the parties' claims corresponding to
`
`the count in light of their application disclosures, we necessarily
`
`-13-
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`NCI Exhibit 2020
`Page 13 of 27
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`
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`Interference No. 102,648
`
`conclude that the term "patient" as used in the context of the count
`
`includes the testing of mammals.
`
`Wattanasin's claim 8 is directed to a method of inhibiting
`
`cholesterol biosynthesis comprising administering a compound to a
`
`mammal in need of such treatment. The Wattanasin application, page
`
`35, lines 1 to 19, teaches that the compounds of his invention are
`
`useful for lowering blood cholesterol level in "animals, g_,_g_._,
`
`mammals, especially larger primates," with humans being listed as an
`
`example of larger primates. Further the application at page 34
`
`contains examples directed to the in vivo testing of male Wistar
`
`Royal Hart rats.
`
`Fujikawa's claims 35, 37 and 38 are directed to a method
`
`for treating hyperlipidemia, hyperlipoproteinemia, or atherosclerosis
`
`which comprises administering an effective amount of the compound.
`
`The claims are open-ended in that they do not limit the
`
`administration of compound to any particular group; rather, the
`
`compound may be administered to either a human, mammal or other
`
`animal. The Fujikawa application at page 26, lines 5 to 13, teaches:
`
`The compounds of the present invention exhibit
`high inhibitory activities against the choleste~ol
`biosynthesis wherein HMG-CoA reductase acts as a rate
`limiting enzyme, as shown by the test results given
`hereinafter, and thus are capable of suppressing or
`reducing the amount of cholesterol in blood as
`lipoprotein.
`
`The Fujikawa application contains examples directed to the in vivo
`
`testing of male Sprague-Dawley rats.
`
`-14-
`
`:,..:.,
`
`NCI Exhibit 2020
`Page 14 of 27
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`Interference No. 102,648
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`Since the claims of Wattanasin are directed to the
`
`treatment of mammals and the claims of Fujikawa embrace the treatment
`
`of any animal, including humans and mammals, and since both
`
`applications contain examples directed to the in vivo testing of
`
`rats, we necessarily conclude that in the context of this
`
`interference, the term "patient" as used in the count embraces the
`
`treatment of mammals, and, in particular, rats, the species
`
`exemplified by both parties' applications.
`
`The Wattanasin Record
`
`Wattanasin presented a record consisting of the testimony
`
`of 16 witnesses together with 51 associated exhibits. The testimony
`
`will be referred to by WR followed by its page number; each exhibit,
`
`by WX followed by its identifier. The record shows that Sandoz
`
`Pharmaceuticals Corporation, the assignee of the involved Wattanasin
`
`application, has been involved since 1979 in a research program to
`
`discover compounds having HMG-CoA reductase inhibiting activity.
`
`In
`
`1979, Dr. Kathawala, a Ph.D., was the section head of a research team
`
`responsible for the research. This team was expanded over time to
`
`five laboratory units, each headed by a Ph.D.
`
`In 1982, Dr.
`
`Wattanasin, the named inventor, joined the project, worked under Dr.
`
`Kathawala and was later appointed as head of one of the five
`
`laboratory units. WR 136.
`
`-15-
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`NCI Exhibit 2020
`Page 15 of 27
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`Interference No. 102,648
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`The First Phase Activity
`
`I
`
`The record shows that during the period from May 31, 1984
`
`to May 17, 1985, Dr. Wattanasin synthesized three compounds (63-366,
`
`63-548 and 63-549) falling within the scope of the count. Employees
`
`reporting to Dr. Barcza, a Ph.D chemist and director of the Sandoz
`
`Department of Physical Organic Chemistry, performed the spectra,
`
`microanalyses and thin layer chromatography (TLC) on the various
`
`intermediates and the final compounds. Samples of the final
`
`compounds were sent to the Drug Room of Sandoz and their receipt was
`
`recorded in the computer database. Dr. Damon, a Ph.D. chemist, who
`
`was in charge of the Drug Room, had samples of the compounds
`
`forwarded to Dr. Scallen for testing. WR 22 to 24, 27 to 44, 48 to
`
`54, 172 to 185 and 196; WX A-1, A-2, B-1, B-2, C-1 to 3, D-1, D-2, G-
`
`1, G-2, H-1 and I-1.
`
`Dr. Scallen, a professor of biochemistry and medical doctor
`
`at the School of Medicine, University of New Mexico, received the
`
`compounds and had them tested in an established protocol using rat
`
`liver microsomes to determine whether they were competitive
`
`inhibitors of HMG-CoA reductase, the rate limiting enzyme in
`
`cholesterol biosynthesis. On or before December 13, 1984, Dr.
`
`scallen had an in vitro biological assay of compound 63-366 performed
`
`in his laboratory under his supervision. The results indicated HMG(cid:173)
`
`CoA reductase activity and Dr. Scallen reported the results to Dr.
`
`-16-
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`NCI Exhibit 2020
`Page 16 of 27
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`Interference No. 102,648
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`Damon of Sandoz. Likewise, on or before June 13, 1985, Dr. Scallen
`
`had in vitro biological assays of compounds, 63-548 and 63-549,
`
`performed in his laboratory under his supervision. The results
`
`indicated HMG-CoA reductase activity and were reported to Dr. Damon
`
`of Sandoz. WR 187 to 191; WX E-1 and E-2.
`
`Upon receiving the results, Dr. Damon calculated the IC50
`
`for each compound. The IC50 value is the concentration of the test
`
`substance in the assay system to produce a 50% inhibition of HMG-CoA
`
`reductase. The smaller the IC50 value, the more active the compound
`
`was in the assay. Dr. Damon would send Dr. Wattanasin within three
`
`or four days of receiving the test results a report with the assay
`
`data (including the IC50 ) and the structure of the compound. The
`
`report (WX E-5), stamp-dated December 20, 1984, indicated that
`
`compound 63-366 had an IC50 of 1.58 }.Lmoles
`
`(J.LM); the reports {WX E-5),
`
`stamp-dated June 28, 1985, indicated that compounds 63-548 and 63-549
`
`each had, respectively, an IC50 of 3. 775 J.LM and 7. 3100 J.LM. He
`
`compared these values to the IC50 value of compactin, a known HMG-CoA
`
`inhibitor for administration to patients to·inhibit cholesterol
`
`biosynthesis. Compactin has an IC50 value of 1.011 J.LM. WR 196 to 201
`
`and 483; WX E-1 and E-5.
`
`Concerning these test results, Dr. Damon testified that
`
`based on his knowledge and experience,
`
`it was my judgment on or prior to December 31, 1984,
`that there was a high probability that Wattanasin
`
`.-17-
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`NCI Exhibit 2020
`Page 17 of 27
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`Interference No. 102,648
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`compound 63-366 would be active when administered in
`vivo to a patient to inhibit cholesterol
`biosynthesis, i.e. for the treatment of
`hypercholesteremia or atherosclerosis. WR 201.
`
`He testified that he had the same opinion for the other tested
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`compounds.
`
`Dr. Wattanasin testified that no other experimental work
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`was done on his invention after May 17, 1985, because of a manpower
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`shortage in his lab. WR 106 to 110. Ms. Patel was hired in January
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`1987.
`
`In March of 1987, Dr. Wattanasin submitted an Invention
`
`Disclosure (A-3), dated March 16, 1987, to the Sandoz Patent and
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`Trademark Department. WR 24 and 25; WX A-3.
`
`II
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`We hold that during the first phase of activity the
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`Wattanasin record does not establish actual reduction to practice.
`
`It is well settled that a reduction to practice must
`
`include every limitation of the count. NewKirk v. Lulejian, 825 F.2d
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`1581, 3 USPQ2d 1793 (Fed.Cir. 1987); Land v. Regan, 342 F.2d 92, 144
`
`USPQ 661 (CCPA 1965) and Schoenwald v. Waltersdorf, 226 USPQ 446
`
`(Bd.Pat.Int. 1984).
`
`The compounds, 63-366, 63-548 and 63-549, which were made
`
`and tested during the first phase, were not administered to a mammal,
`
`a necessary step in the performance of the method of the count.
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`Consequently, Wattanasin did not reduce to practice the invention of
`
`count 1 during the first phase activity. At best, this work would
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`NCI Exhibit 2020
`Page 18 of 27
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`Interference No. 102,648
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`establish conception of the invention of the count by at least June
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`13, 1985.
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`The Second Phase Activity
`
`I
`
`Pages 31 to 44 of the Wattanasin main brief with references
`
`to the testimony and exhibits set forth a detailed explanation of
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`Wattanasin's renewed activity.
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`Essentially from early March 1987 into September 1987, Ms.
`
`Patel synthesized four compounds, 64-933, 64-934/NA, 64-935 and 64-
`
`936/NA, within the scope of the count and forwarded the compounds to
`
`the Sandoz Drug Room. By July 28, 1987, she synthesized compound 64-
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`933; by July 29, 1987, compound 64-934/NA; by August 20, 1987,
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`compound 64-935; and by August 25, 1987, compound 64-936/NA. During
`
`the synthesis, purification and characterization of the compounds,
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`Dr. Wattanasin went to a meeting in New Orleans for over a week and
`
`when he returned, he found out that the next scheduled shipment out
`
`of the Sandoz drug room to Dr. Scallen would be on October 2, 1987,
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`even though the compounds were made before October 2. He wanted all
`
`the compounds shipped together for testing so that he could get a
`
`better comparison of their potency in the same study. The compounds
`
`were shipped on October 2, 1987 overnight to Dr. Scallen. Dr.
`
`Scallen received the compounds, tested them in an established
`
`protocol using rat liver microsomes to their biological activity in
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`-19-
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`NCI Exhibit 2020
`Page 19 of 27
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`Interference No. 102,648
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`vitro and reported the raw results to Dr. Damon on or before October
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`20, 1987.
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`Dr. Damon calculated the IC50 for each compound and compared
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`each value with compactin which has an IC50 of 1. 011 MM. Compound 64-
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`933 had an IC50 of 2.3700 MMi compound 64-934/NA, an IC50 of 2.6100 MM;
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`compound 64-935, an IC50 of 0.4130 MMi and compound 64-936/NA, an IC50
`
`of 0.5300 MM. WR 183 to 195; WX E-1 to E-5, H-1 and I-1.
`
`Dr. Engstrom of the Sandoz Lipid Metabolism Department
`
`commenced the in vivo testing of compound 64-936 on or before October
`
`22, 1987 and the testing of compounds 64-933 and 64-935 on October
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`29, 1987. The testing was completed on or prior to December 9, 1987.
`
`The compounds were administered to male Wistar Royal Hart rats in
`
`accordance with the protocol described at WR 204. Mr. Slaughter, Dr.
`
`Engstrom's lab assistant, entered the raw data into a computer
`
`program which converted the data to nano Curies (nCi) of sterol per
`
`100 ml. of serum at 4 hours after injection of 14C-acetate.
`
`Thereafter Dr. Engstrom entered this data into a computer program
`
`which calculated the ED50 values for the compounds. The ED50 value3
`for compound 64-,933 is >1; for compound 64-935, o. 49; and for
`
`compound 64-936, >1. Dr. Wattanasin testified that the data on WX K-
`
`1 indicates that the compounds would have activity as a HMG-CoA
`
`3 The ED50 values for compounds 64-933 and 64-935 were.
`inadvertently switched as explained in Dr. Engstrom's
`supplemental declaration at WR 207 and 208.
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`NCI Exhibit 2020
`Page 20 of 27
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`Interference No. 102,648
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`reductase inhibitor when administered to a patient. Compactin has an
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`ED50 of 3.5. WR 56, 203 to 212 and 485; WX K-1 and Q.
`
`Contemporaneous with these second phase activities, the
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`Sandoz Patent committee met on April 29, 1987 and considered the
`
`wattanasin invention disclosure (A-3). According to the testimony of
`
`Linda Rothwell and Joanne M. Giesser, the committee deferred a
`
`decision for three months on whether to file an application because
`
`of the ongoing work. Again at its meeting on July 29, 1987, the
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`committee deferred its decision for another three months. As a
`
`result of the october 28, 1987 and November 25, 1987 meetings, the
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`committee's decision was deferred to January, there being no
`
`committee meeting during the month of December. At the January 27,
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`1988 meeting, the committee decided that an application should be
`
`filed on the Wattanasin disclosure. The disclosure, which had been
`
`assigned to Mr. Weinfeldt, was reassigned to Ms. Giesser, a junior
`
`patent attorney in the Sandoz Patent Department. The application was
`
`filed on March 3, 1989. WR 213 to 215 and 319 to 323; WX M-1 to M-5
`
`and P-1 to 3.
`
`II
`
`We hold that the wattanasin record establishes prior
`
`conception coupled with due diligence from just prior to August 20,
`
`1987, Fujikawa's effective filing date, up to December 9, 1987, the
`
`date of the in vivo testing of compound 64-935.
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`:· . ..:..
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`NCI Exhibit 2020
`Page 21 of 27
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`Interference No. 102,648
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`Prior conception is established by June 13, 1985, when the
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`work performed during the first phase of the interference was
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`completed. Thus the Wattanasin record establishes prior conception.
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`With respect to diligence, Wattanasin has the burden to
`
`establish diligence just prior to August 20, 1987, up to the date of
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`in vivo testing on December 9, 1987. As noted by Wattanasin in his
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`reply brief at page 24, "it does not appear that Fujikawa contest
`
`diligence as to this period." We agree. Nowhere in its brief has
`
`the party Fujikawa shown where Wattanasin was not reasonably diligent
`
`during this period. Accordingly, we hold that the Wattanasin record
`
`establishes reasonable diligence during the critical period in
`
`question.
`
`III
`
`We hold that the Wattanasin record establishes actual
`
`reduction to practice by December 9, 1987, the date compound 64-935
`
`was successfully tested in vivo in rats and found to have an ED50
`
`value of 0.49 ~M.
`
`Before we discuss the Wattanasin record, we must consider
`
`Fujikawa's motion (Paper No. 109) to suppress, which was filed at the
`
`same time as Fujikawa's brief.
`
`In the motion, Fujikawa requests that
`
`we not consider Dr. Engstrom's testimony at WR 204 to 208 because the
`
`testimony relies upon a computer-generated summary to obtain the ED50
`values. We agree with Wattanasin's opposition (Paper No. 113) that
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`NCI Exhibit 2020
`Page 22 of 27
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`Interference No. 102,648
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`the ED50 value for compound 64-935 should not be invalidated because
`of a purported lack of foundation for the underlying computer
`
`programs used to calculate the value from the raw data. As pointed
`
`out by Wattanasin, Dr. Holmlund, Fujikawa's rebuttal witness, had "no
`
`quarrel with the techniques for determining statistical activity."
`
`Likewise, we do not consider that Wattanasin had to have placed in
`
`evidence the computer programs used to calculate the value from the
`
`experimental data. It is enough to have placed into evidence the
`
`experimental data, which showed that the compound had significant
`
`activity. Accordingly, the motion to suppress is denied.
`
`As we noted above, a reduction to practice must include
`
`every limitation of the count. Newkirk v. Luleiian, suprai Land v.
`
`Regan, suprai and Schoenwald v. Waltersdorf, supra. The Wattanasin
`
`record shows that by December 9, 1987 compound 64-935 was
`
`administered to a rat. The compound exhibited significant activity
`
`at levels of 1 and 0.1 milligrams per kilogram and its ED50 value was
`
`calculated to be 0.49 MM, an activity greater than compactin. Dr.
`
`Wattanasin testified that this activity showed that the compound
`
`would be active as a HMG-CoA reductase inhibitor when administered to
`
`a patient. Further Dr. Holmlund, Fujikawa's rebuttal witness
`
`acknowledged that the compound did in fact exhibit significant
`
`activity at those levels.
`
`See the Fujikawa record at pages 207 to
`
`209 and 243 (FR 207 to 209 and 243).
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`-23-
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`NCI Exhibit 2020
`Page 23 of 27
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`Interference No. 102,648
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`We do not agree with Fujikawa's position on page 32 of his
`
`main brief that the proofs of Wattanasin fail because a human patient
`
`was not tested. As we noted above, the count embraces the treatment
`
`of mammals. Thus the experiment performed on behalf of Dr.
`
`Wattanasin meets the terms of the count.
`
`It is also Fujikawa's position that the testing of compound
`
`64-935 does not demonstrate a practical utility. This position is
`
`not well taken. The Fujikawa rebuttal evidence is mainly directed to
`
`whether a correlation exists between in vitro activity and in vivo
`
`activity, a matter which is not in issue in this interference. To
`
`the extent that the evidence is relied upon to show that the
`
`Wattanasin record does not demonstrate that the testing establishes a
`
`practical utility for compound 64-935, we are not persuaded thereby.
`
`Fujikawa relies on Dr. Holmlund's testimony at FR 209 that since the
`
`compound was not significantly active at 0.3 milligrams and. that
`
`since he (Dr. Holmlund) could not have obtained the ED50 value on the
`
`basis of WX K-1 in the absence of any reaso.nable dose response curve,·
`
`he could not make any final conclusion on the compound's activity.
`
`In effect, Dr. Holmlund would wan