Petition for Inter Partes Review of USPN...

Petition for Inter Partes Review of USPN 5,856,336

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE_____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD_____________________

Mylan Pharmaceuticals Inc., Petitioner

v.

Nissan Chemical Industries Ltd.Patent Owner

U.S. Patent No. 5,856,336 to Fujikawa et al.Issue Date: January 5, 1999

Title: Quinoline Type Mevalonolactones

_____________________

Inter Partes Review No.: IPR2015-01069

Petition for Inter Partes Review of U.S. Patent No. 5,856,336Under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123

Mail Stop "PATENT BOARD"Patent Trial and Appeal BoardU.S. Patent and Trademark OfficeP.O. Box 1450Alexandria, VA 22313-1450


i

TABLE OF CONTENTS

I. INTRODUCTION ..............................................................................................1

II. MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1))......................................1A. Each Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)) ............................1B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ..............................1

1. Judicial Matters Involving the ’336 patent ..................................12. Administrative Matters .................................................................2

C. Designation of Lead and Back-Up Counsel (37 C.F.R. §42.8(b)(3)) ................................................................................................2

D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)) .......................2

III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A)) ANDPROCEDURAL STATEMENTS......................................................................2

IV. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B)) ANDSTATEMENT OF THE PRECISE RELIEF REQUESTED (37 C.F.R.§ 42.22(A))..........................................................................................................3

V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW .............5

VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED (37C.F.R. § 42.22(A))..............................................................................................5A. Summary of the Argument ......................................................................5B. The Claims of the ’336 Patent.................................................................6C. The Priority Date of the ’336 Patent.....................................................10

1. The Earliest Effective Date for the Challenged Claims ofthe ’336 Patent Is August 3, 1988 ..............................................10

VII. THE ’336 PATENT AND CLAIM CONSTRUCTION................................15A. POSA......................................................................................................15B. Ground 1: Claims 1 and 2 of the ’336 Patent Are Unpatentable

Under 35 U.S.C. § 103 ..........................................................................161. The Scope and Content of the Prior Art ....................................162. Legal Principles Regarding Structural Obviousness.................163. Claim 1 Would Have Been Obvious under 35 U.S.C. §

103................................................................................................174. Claim 2 Would Have Been Obvious Under 35 U.S.C. §

103................................................................................................47


ii

5. Fluvastatin Would Have Been Selected as the LeadCompound for at Least the Following AdditionalReasons ........................................................................................50

6. Any Secondary Considerations Fail to Overcome theShowing of Obviousness ............................................................57

C. Ground 2: Claims 1 and 2 of the ’336 Patent are UnpatentableUnder 35 U.S.C. § 102 in View of the Picard ’419 Patent..................58

VIII. CONCLUSION.................................................................................................60


iii

TABLE OF AUTHORITIES

Page(s)CASES

Abbvie Inc. v. Mathilda & Terence Kennedy Inst. of Rheumatology Trust,764 F.3d 1366 (Fed. Cir. 2014)............................................................................. 59

Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,499 F.3d 1293 (Fed. Cir. 2007).......................................................................42, 43

Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,752 F.3d 967 (Fed. Cir. 2014)........................................................................passim

Daiichi Sankyo Co. v. Matrix Labs., Ltd.,619 F.3d 1346 (Fed. Cir. 2010)............................................................................. 36

Eisai Co. v. Dr. Reddy’s Labs., Ltd.,533 F.3d 1353 (Fed. Cir. 2008)............................................................................. 54

Eli Lilly and Co. v. Zenith Goldline Pharma, Inc.,471 F.3d 1369 (2006) ............................................................................................ 17

In re Aller,220 F.2d 454 (C.C.P.A. 1955) .............................................................................. 49

In re Dillon,919 F.2d 688 (Fed. Cir. 1990)............................................................................... 39

In re Gosteli,872 F.2d 1008 (Fed. Cir. 1989) ............................................................................. 13

In re Ruschig,379 F.2d 990 (C.C.P.A. 1967) .............................................................................. 13

In re Wilder,563 F.2d 457 (C.C.P.A. 1977) .............................................................................. 39

KSR Int’l Co. v. Teleflex, Inc.,550 U.S. 398 (2007)...........................................................................................5, 15

Newell Cos., Inc. v. Kenney Mfg. Co.,864 F.2d 757 (Fed. Cir. 1988)............................................................................... 57


iv

Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,678 F.3d 1280 (Fed. Cir. 2012).................................................................17, 28, 45

Pfizer, Inc. v. Apotex, Inc.,480 F.3d 1348 (Fed. Cir. 2008)......................................................................passim

PowerOasis, Inc. v. T-Mobile USA, Inc.,522 F.3d 1299 (Fed. Cir. 2008) ............................................................................. 13

Schering Corp. v. Geneva Pharm., Inc.,339 F.3d 1373 (Fed. Cir. 2003).......................................................................58, 59

SkinMedica, Inc. v. Histogen, Inc.,727 F.3d 1187 (Fed. Cir. 2013)............................................................................. 48

Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,492 F.3d 1350 (Fed. Cir. 2007)............................................................................. 17

OTHER CASES

Amneal Pharm., LLC v. Supernus Pharm., Inc.IPR2013-00368 ...................................................................................................... 57

Kowa Company, Ltd. et al v. Amneal Pharmaceuticals, LLC,1:14-cv-02758 (S.D.N.Y., Apr. 17, 2014).............................................................. 1

Kowa Company, Ltd. et al v. Aurobindo Pharma Limited et al.,1:14-cv-02497 (S.D.N.Y., Apr. 9, 2014)................................................................ 2

Kowa Company, Ltd. et al v. Mylan, Inc. et al.,1:14-cv-02647 (S.D.N.Y., Apr. 14, 2014).............................................................. 1

Kowa Company, Ltd. et al v. Orient Pharma Co., Ltd.,1:14-cv-02759 (S.D.N.Y., Apr. 17, 2014).............................................................. 1

Kowa Company, Ltd. et al v. Sawai USA, Inc. et al.,1:14-cv-05575 (S.D.N.Y., July 23, 2014) .............................................................. 1

Kowa Company, Ltd. et al v. Zydus Pharmaceuticals (USA) Inc. et al.,1:14-cv-02760 (S.D.N.Y., Apr. 17, 2014).............................................................. 1

Metrics, Inc. v. Senju Pharm. Co.,IPR 2014-01041 ..................................................................................................... 49


v

FEDERAL STATUTES

35 U.S.C. § 102 .....................................................................................................58, 60

35 U.S.C. § 103 ....................................................................................................passim

35 U.S.C. § 112 .......................................................................................................... 13

35 U.S.C. § 119 ........................................................................................................... 11

REGULATIONS

37 C.F.R. § 42.6(d)........................................................................................................ 3

37 C.F.R. § 42.8(a)(1) ................................................................................................... 1

37 C.F.R. § 42.8(b)(1)................................................................................................... 1

37 C.F.R. § 42.8(b)(3)................................................................................................... 2

37 C.F.R. § 42.10(b)...................................................................................................... 3

37 C.F.R. § 42.63(e)...................................................................................................... 3

37 C.F.R. § 42.22(a)...................................................................................................... 3

37 C.F.R. § 42.100(b) ................................................................................................. 15

37 C.F.R. § 42.104(a).................................................................................................... 2

37 C.F.R. § 42.106(a)................................................................................................2, 3


vi

Petitioner’s Exhibit List

Exhibit#

Description

1001 U.S. Patent No. 5,856,336 (“the ’336 patent”)

1002 U.S. Patent No. 5,872,130

1003 U.S. Application Ser. No. 233,752

1004 Japanese Patent Application No. JP 62-207224 with Englishtranslation provided by the ’336 patentee from U.S. Application Ser.07/233,752, related family member of the ’336 patent, withaccompanying sworn declaration provided by the patentee to theUSPTO attesting to the accuracy of the translation.



1007 Curriculum Vitae of Roger Frank Newton, Ph.D.

1008 Declaration of Roger Frank Newton, Ph.D.

1009 Faizulla G. Kathawala, et al., XU 62-320, An HMG-CoA ReductaseInhibitor, More Potent Than Compactin, Abstract for AmericanChemical Society library stamp July 29, 1987

1010 U.S. Patent No. 4,739,073


vii

Exhibit#

Description

1011 R. G. Engstrom et al., Hypolipoproteinemic Effects of a PotentHMG-CoA Reductase Inhibitor, IX International Symposium onDrugs Affecting Lipid Metabolism, Florence (Italy), Oct. 22-25,1986

1012 Jonathan A. Tobert, New Developments in Lipid-Lowering Therapy:The Role of Inhibitors of Hydroxymethylglutaryl-Coenzyme AReductase, 76 CIRCULATION 534 (1987)

1013 Ta-Jyh Lee, Synthesis, SARs and Therapeutic Potential of HMG-CoA Reductase Inhibitors, 8 TRENDS PHARMACOL. SCI. 442 (1987)

1014 Akira Endo et al., ML-236A, ML-236B, and ML-236C, NewInhibitors of Cholesterogenesis Produced by Penicillium Citrinium,29 J. ANTIBIOTICS 1346 (1976)

1015 Declaration of David Gortler, Pharm.D.

1016 U.S. Patent No. 4,647,576

1017 Approved Drug Products with Therapeutic Equivalence Evaluations(“Orange Book”), FOOD AND DRUG ADMINISTRATION,listing for active ingredient “lovastatin,” available athttp://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019643&TABLE1= OB_Disc (last visited April 13, 2015)

1018 U.S. Patent No. 4,613,610

1019 U.S. Patent No. 4,681,893

1020 U.S. Patent No. 4,751,235

1021 U.S. Patent No. 4,761,419

1022 Alfred W. Alberts, Mevinolin: A Highly Potent CompetitiveInhibitor of Hydroxymethylglutaryl-Coenzyme a Reductase and aCholesterol-Lowering Agent, 77 PROC. NAT’L. ACAD. SCI. U.S.A.3957 (1980)


viii

Exhibit#

Description

1023 J.B. Taylor & P.D. Kennewell, Introductory Medicinal Chemistry94 (1981)

1024 Corwin Hansch et al., “Aromatic” Substituent Constants forStructure-Activity Correlations, 16 J. MED. CHEM. 1207 (1973)(“Hansch II”)

1025 European Patent No. 0114027

1026 U.S. Patent No. 4,537,859

1027 Stephen M. Berge, Pharmaceutical Salts, 66 J. PHARM. SCI. 1(1977)

1028 Philip L. Gould, Salt Selection for Basic Drugs, 33 INT. J. PHARM.201 (1986)

1029 John T. Suh et al., Angiotensin-Converting Enzyme Inhibitors NewOrally Active Antihypertensive (Mercaptoalkanoyl)- and[(Acylthio)alkanoyl]glycine Derivatives, 28 J. MED. CHEM. 57(1985)

1030 Michael S. Brown, M.D. et al., Lowering Plasma Cholesterol byRaising LDL Receptors, 305 NEW ENG. J. MED. 515 (1981)

1031 Fujikawa Reply to the Opposition to Fujikawa et al.’s Motion toAdd Counts 3 and 4, received July 21, 1992. U.S. Interference No.102,608 (“Paper No. 32”)

1032 Declaration of Masaki Kitahara, submitted in the ’336 patent, datedMay 25, 1992

1033 O. E. Schultz et al., Schätzung des Verteilungfkoeffizienten mit HilfeQuantenchemischer Molekülgroen, 25 ZEITSCHRIFT FÜR

NATURFORSCHUNG B 1024 (1970), certified English translationincluded


ix

Exhibit#

Description

1034 Corwin Hansch et al., The Effect of Intramolecular HydrophobicBonding on Partition Coefficients, 32 J. ORG. CHEM. 2583 (1967)(“Hansch I”)

1035 European Patent Publication 179,559

1036 I. T. Scoular et al., Human Studies on the Bioavailability of aQuaternary Ammonium Compound, Tiemonium Iodide andTiemonium Methosulphate, 4 CURR. MED. RES. OPIN. 732 (1977)

1037 Curriculum Vitae of David Gortler, Pharm.D.

1038 David J. Shapiro & Victor W. Rodwell, Regulation of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase and CholesterolSynthesis, 246 J. BIOL. CHEM. 3210 (1971)

1039 Yoshio Tsujita et al., CS-514, A Competitive Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase: Tissue-SelectiveInhibition of Sterol Synthesis and Hypolipidemic Effect on VariousAnimal Species, 877 BIOCHIMICA ET BIOPHYSICA ACTA 50 (1986)

1040 G.E. Stokker et al., 3-Hydroxy-3-Methylglutaryl-Coenzyme AReductase Inhibitors. 1. Structural Modification of 5-Substituted3,5-Dihydroxypentanoic Acids and Their Lactone Derivatives, 28 J.MED. CHEM. 347 (1985) (“Stokker I”)

1041 G.E. Stokker et al., 3-Hydroxy-3-Methylglutaryl-Coenzyme AReductase Inhibitors 3. 7-(3,5-Disubstituted [1,1’-biphenyl]-2-yl)-3,5-Dihydroxy-6-Heptenoic Acids and Their Lactone Derivatives,29 J. MED. CHEM. 170, 175 (1986) (“Stokker II”)

1042 Final Hearing, November 22, 1994. U.S. Interference No. 102,608(“Paper No. 122”)


1

I. INTRODUCTION

Mylan Pharmaceuticals Inc. (“Petitioner”) respectfully petitions for Inter

Partes Review (“IPR”) of Claims 1 and 2 (the “challenged claims”) of U.S. Patent

No. 5,856,336 to Fujikawa et al. entitled, “Quinoline Type Mevalonolactones”

(“the ’336 patent”) (EX1001). Based on the records of the U.S. Patent and

Trademark Office (“USPTO”), the ’336 patent is assigned to Nissan Chemical

Industries Ltd.

II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))

A. Each Real Party-in-Interest (37 C.F.R. § 42.8(b)(1))

The real parties-in-interest are Mylan Pharmaceuticals Inc. and Mylan Inc.

B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))

1. Judicial Matters Involving the ’336 patent

Petitioner is a defendant to the following litigation involving the ’336 patent:

Kowa Company, Ltd. et al v. Mylan, Inc. et al., 1:14-cv-02647 (S.D.N.Y., Apr. 14,

2014). Petitioner is aware of at least the following pending judicial matters

involving the ’336 patent: Kowa Company, Ltd. et al v. Sawai USA, Inc. et al.,

1:14-cv-05575 (S.D.N.Y., July 23, 2014); Kowa Company, Ltd. et al v. Zydus

Pharmaceuticals (USA) Inc. et al., 1:14-cv-02760 (S.D.N.Y., Apr. 17, 2014);

Kowa Company, Ltd. et al v. Orient Pharma Co., Ltd., 1:14-cv-02759 (S.D.N.Y.,

Apr. 17, 2014); Kowa Company, Ltd. et al v. Amneal Pharmaceuticals, LLC, 1:14-


2

cv-02758 (S.D.N.Y., Apr. 17, 2014); and Kowa Company, Ltd. et al v. Aurobindo

Pharma Limited et al., 1:14-cv-02497 (S.D.N.Y., Apr. 9, 2014).

2. Administrative Matters

The ’336 patent is a division of U.S. Patent Number 5,872,130, which issued

on December 16, 1999. The ’130 patent is a continuation of U.S. Application No.

07/233,752, filed August 19, 1988, which is abandoned. U.S. Patent No.

5,854,259, a division of the ’336 patent, issued on December 29, 1998.

C. Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))

Lead Counsel Back-Up Counsel

Jitendra MalikReg. No. 55823ALSTON & BIRD LLP4721 Emperor Blvd., Suite 400Durham, North Carolina 27703

Deanne M. MazzochiReg. No. 50158RAKOCZY MOLINO MAZZOCHI SIWIK LLP6 West Hubbard St., Suite 500Chicago, Illinois 60654

D. Notice of Service Information (37 C.F.R. § 42.8(b)(4))

Please direct all correspondence to lead and back-up counsel at the above

address. Petitioner consents to email service at: [email protected],

[email protected], [email protected], [email protected],

[email protected], [email protected] and [email protected].

III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ANDPROCEDURAL STATEMENTS

Petitioner certifies that (1) the ’336 patent is available for IPR; and (2)

Petitioner is not barred or estopped from requesting IPR of any claim of the ’336


3

patent on the grounds identified herein. This Petition is filed in accordance with 37

C.F.R. § 42.106(a). Concurrently filed herewith are a Power of Attorney and an

Exhibit List pursuant to § 42.10(b) and § 42.63(e), respectively. The required fee

is paid when filing the Petition, and the Office is authorized to charge any fee

deficiencies and credit overpayments, to Deposit Acct. No. 160605 (Customer ID

No. 00826).

IV. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ANDSTATEMENT OF THE PRECISE RELIEF REQUESTED (37 C.F.R. §42.22(a))

Petitioner requests inter partes review and cancellation of Claims 1 and 2 of

the ’336 patent under 35 U.S.C. §§ 102 and 103. The ’336 patent is to be reviewed

under pre-AIA §§ 102 and 103. Petitioner’s detailed statement of the reasons for

relief requested is set forth below in the section titled, “Statement of Reasons for

Relief Requested.” Pursuant to 37 C.F.R. § 42.6(d), copies of the exhibits are filed

herewith. In support of the proposed grounds for unpatentability, this Petition is

accompanied by a Declaration of Roger Frank Newton, Ph.D. (EX1008), and a

Declaration of Dr. David Gortler (EX1015).

The challenged claims of the ’336 patent are generally directed to the

calcium salt of compounds having the formula, Z = —CH(OH)—CH2—CH(OH)

—CH2—COO.1/2Ca, including the compound “pitavastatin” and methods of

reducing hyperlipidemia, hyperlipoproteinemia, or atherosclerosis by


4

administering an effective amount of the compound of Claim 1. Claims 1 and 2 of

the ’336 patent are unpatentable based on the following grounds:

Ground References Basis Claims Challenged

11 Kathawala ’073 patent andKathawala Abstract, incombination with Hoefle ’576,Roth ’893, Anderson ’235,Wareing ’610, Hansch II, Suh,Berge, and Gould in view of theknowledge of a POSA.

103 1 and 2

12 Kathawala ’073 patent andKathawala Abstract, incombination with Hoefle ’576,Roth ’893, Anderson ’235,Wareing ’610, Hansch II, Suh,Berge, Gould, Engstrom Abstract,Tobert, Lee, and Picard ’419 patentin view of the knowledge of aPOSA.

103 1 and 2

2 Picard ’419 patent 102 1 and 2

In addition to the primary references listed above, additional prior art

references will provide further background in the art and motivation to combine

the teachings of these references and/or further support why a person of ordinary

1 In the event the Board determines that JP 62-207224 (EX1004), filed August 20,

1987, supports the priority claim of the ’336 patent.

2 In the event the Board determines that JP 62-207224 (EX1004), filed August 20,

1987, does not support the priority claim of the ’336 patent, but that the priority

claim is supported by JP 63-15585 (EX1005), filed January 26, 1988.


5

skill in the art (“POSA”) would have had a reasonable expectation of success in

combining the teachings of the references to arrive at the methods recited in the

challenged claims.

V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW

A petition for IPR must demonstrate “a reasonable likelihood that the

petitioner would prevail with respect to at least one of the claims challenged in the

petition.” 35 U.S.C. § 314(a). This Petition meets this threshold. As explained

below, there is a reasonable likelihood that Petitioner will prevail with respect to at

least one of the challenged claims.

VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED (37C.F.R. § 42.22(a))

A. Summary of the Argument

The claims of the ’336 patent (1 and 2) are unpatentable for failing to satisfy

the nonobviousness requirements of 35 U.S.C. § 103, based on a combination of

the relevant prior art in view of the knowledge of a person of ordinary skill in the

art (“POSA”) and/or as obvious to try, as well as unpatentable for being anticipated

by the prior art under 35 U.S.C. § 102. To this end, the alleged “inventions”

involved no more than selecting an obvious prior art lead compound (fluvastatin),

and routinely modifying it, leading to a predictable result. The claims are not

inventive in any way and are invalid as a matter of law as obvious. KSR Int’l Co.


6

v. Teleflex, Inc., 550 U.S. 398, 417 (2007). Claims 1 and 2 of the ’336 patent also

are invalid as being anticipated under 35 U.S.C. § 102 by the ’419 Picard patent.

B. The Claims of the ’336 Patent

The challenged claims of the ’336 patent are reproduced below:

1. A compound of the formula,

Z = —CH(OH)—CH2—CH(OH) —CH2—COO.1/2Ca.3

2. A method for reducing hyperlipidemia,

hyperlipoproteinemia or atherosclerosis, which comprises

administering an effective amount of the compound of

Formula A as defined in Claim 1.

Claim 1 is purportedly directed to the structure of the calcium salt of a chemical

formula that includes the drug compound “pitavastatin.” Claim 2 is purportedly

3 Petitioner understands that the Patent Owner contends that the “Δ” in Claim 1

represents a cyclopropyl group found in pitavastatin. Although Petitioner disputes

this construction, solely for the purposes of this IPR, Petitioner will accept the

Patent Owner’s construction in evaluating the prior art.


7

directed to a method of reducing hyperlipidemia, hyperlipoproteinemia or

atherosclerosis by administering an effective amount of the compound of Claim 1.

For at least the reasons discussed below, the POSA would have selected the

following prior art compound, also known as fluvastatin, as the lead compound:

(Newton Dec. ¶ 7 (EX1008)). The prior art, such as U.S. patent No. 4,739,073

(“Kathawala ’073 patent”) ((EX1010), filed Mar. 4, 1985, and published Apr. 19,

1988 (102(e) prior art)), at the relevant time showed that fluvastatin possessed

excellent in vitro activity and demonstrated relatively high activity for in vivo

cholesterol biosynthesis inhibition. (Newton Dec. ¶ 8; Kathawala ’073 patent at

col. 33). The prior art disclosed that this compound lowered several lipid

parameters in animals and was used in human clinical trials by at least 1987.

(Newton Dec. ¶ 8; Kathawala Abstract, EX1009 page 5, library stamp July 29,

1987 (102(a) prior art); Engstrom Abstract, EX1011, library stamp Dec. 22, 1987

(102(a) prior art)). In fact, POSAs recognized fluvastatin as one of only five

HMG-CoA reductase inhibitors in clinical trials as of 1987, and as a “particularly

interesting” compound. (Newton Dec. ¶ 9; Tobert, EX1012, library stamp Sept.


8

11, 1987 (102(a) prior art), pages 534-35; Lee, EX1013, available at the National

Library Dec. 2, 1987 (102(a) prior art), page 444). It was also known by 1987 that

HMG-CoA reductase inhibitors were useful in lowering cholesterol. (Gortler Dec.

¶¶ 27, 28 (EX1015)). Indeed, it was public knowledge that several major

pharmaceutical groups were actively researching these compounds by that time.

Thus, the POSA would have been motivated to select fluvastatin as a lead

compound for modification. (Newton Dec. ¶ 10).

In considering further modifications, the POSA would have considered the

logical structural avenues available to further optimize the compound. Within

fluvastatin, both the 4-fluorophenyl group (boxed in green) and isomeric side chain

(boxed in blue) reflected prior efforts to optimize structural groups in comparison

to the early-generation statin molecules (i.e., compactin and mevinolin):

N

CO2Na

F

OHOH

SR

Fluvastatin.

(Newton Dec. ¶ 11). The prior art also taught advantages to incorporating

nitrogen-containing ring systems in the molecule’s core. The POSA would have

been motivated to further optimize the ring system with structural analogs of


9

fluvastatin’s 6,5 indole ring system. A 6,6 quinoline ring would have been an

obvious structural modification the POSA would have reasonably expected to

work (such rings were in fact proposed for use in the relevant time frame in statin

compounds). (Id. ¶ 12). Likewise, the prior art taught interchangeable options for

the isopropyl group, including cyclopropyl. The art further taught a finite number

of salt structures suitable for use with statins, e.g., a calcium salt. Based on these

known strategies, the POSA would have reasonably expected to modify fluvastatin

and arrive at the pitavastatin compound of the ’336 patent. (Id. ¶ 13).

The indole-quinoline modification is a simple structural modification

involving the addition of a single carbon atom that would have been obvious in

light of the prior art. It was also known during the relevant time that cyclopropyl

and isopropyl groups are very similar. (Newton Dec. ¶ 14). This selection of

cyclopropyl was so obvious that even the Patent Owner admitted that doing so

would have been “the next logical, and analogous compound.” Fujikawa Reply to

the Opposition to Fujikawa et al.’s Motion, received July 21, 1992 at 5 (Paper No.

32 (hereinafter “Paper No. 32”)) (EX1031).

With these two structural modifications, the POSA would have had a finite

number of salt options, particularly since the salt had to be a positive cation, and

there were limited cations that were approved by the U.S. Food and Drug

Administration (“FDA”) at the time of the invention. (Newton Dec. ¶ 16).


10

Given that each of the above modifications would have been routine, the

POSA would have arrived at the compound of Claim 1 with a reasonable

expectation of success. Moreover, given the prior art disclosures concerning

biological activity, the POSA would have reasonably expected that such compound

would have been effective in reducing hyperlipidemia and hyperlipoproteinemia as

recited in Claim 2. (Newton Dec. ¶¶ 17, 18).

No evidence of “secondary considerations” would change this conclusion.

The patentee alleged during prosecution that the compounds of the alleged

invention, which contain a cyclopropyl substituent, had unexpected potency over

the isopropyl substituent. However, this difference was within the range the POSA

would have expected when replacing isopropyl with its close analog cyclopropyl,

and would not have been clinically relevant. (Newton Dec. ¶ 15).

The claims of the ’336 patent are further invalid as anticipated by the

teachings of U.S. Patent No. 4,761,419 (“Picard ’419 patent”) ((EX1021), filed

Dec. 7, 1987, and published Aug. 2, 1988 (102(e) prior art)).

C. The Priority Date of the ’336 Patent

1. The Earliest Effective Date for the Challenged Claims of the’336 Patent Is August 3, 1988

Before addressing invalidity, Petitioner addresses the effective filing date of

the ’336 patent for purposes of evaluating the prior art. As explained further

below, the challenged claims are not entitled to the benefit of priority of either JP


11

62-207224 (Aug. 20, 1987) or JP 63-15585 (Jan. 26, 1988) under 35 U.S.C. § 119.

Rather, the earliest effective priority date is that of JP 63-193606, which the face of

the ’336 patent identifies as August 3, 1988.

The ’336 patent issued from U.S. Application Serial Number 883,398 (“the

’398 application”), filed May 15, 1992, which was a division of U.S. Application

Serial Number 631,092 (“the ’092 application”), filed December 19, 1990, now

U.S. Patent Number 5,872,130 (“the ’130 patent”) (EX1002), which was a

continuation of U.S. Application Serial Number 233,752 (“the ’752 application”)

(EX1003), now abandoned. The ’336 patent, the ’130 patent and the ’752

application claim priority to three foreign priority documents:

Japanese Patent Application Number JP 62-207224 “JP 62-207224”

(EX1004), filed August 20, 1987;


(EX1005), filed January 26, 1988; and


(EX1006), filed August 3, 1988.

a) JP 62-207224 Does Not Provide Adequate Support for2-Cyclopropyl Substituents

JP 62-207224 provides no examples or data directed to a pitavastatin

calcium species, and no information justifying its selection or use as a stand-alone

species. JP 62-207224 also provides only one aspirational species example that


12

even includes a cyclopropyl substituent at the 2 position on the quinoline ring.

That aspirational species is not pitavastatin calcium or even a pitavastatin salt;

rather, it is a carboxylic acid version of that compound. (Newton Dec. ¶ 47; JP 62-

207224, at 12, Table 1, last compound). None of the approximately 50 examples

of compounds for which melting points or oil status are described in JP 62-207224

have a cyclopropyl substituent. Additionally, none of the compounds that were

tested biologically have a cyclopropyl substituent. Furthermore, the only

compound utilized in the formulation examples has an isopropyl group (not

cyclopropyl) at the 2 position.4 (Newton Dec. ¶ 48).

Particularly applicable is the Federal Circuit’s discussion in Fujikawa v.

Wattanasin, which concerns the interferences involving applications in the ’336

patent family. 93 F.3d 1559 (Fed. Cir. 1996). In Fujikawa, the ’336 inventors—

the Patent Owner in this proceeding—wanted to bring a subgenus count into U.S.

Interference No. 102,608 (“the ’608 interference”), which included compounds

with a cyclopropyl group and the 4-fluorophenyl group. They argued that their

patent disclosure included cyclopropyl as a possible substituent, and, therefore,

there was written description for the cyclopropyl moiety. Id. at 1569-71. While

4 JP 62-207224 also does not disclose any species of compounds with both a

cyclopropyl group at the 2 position and a salt at the end of the side chain.


13

the USPTO recognized that cyclopropyl was disclosed as part of the broad genus,

it maintained that there was no written description for a narrower genus including

only cyclopropyl at the 2 position. Id. at 1570-71; the ’608 interference Final

Hearing, mailed Apr. 6, 1995, at 2-4 (Paper No. 122) (EX1042). The Federal

Circuit agreed. Fujikawa, 93 F.3d at 1571. Thus, there is no support for any

specific compound with a cyclopropyl group, much less pitavastatin calcium.5 In

re Ruschig, 379 F.2d 990, 994-95 (C.C.P.A. 1967) (using the analogy of marking

trails by making blaze marks). Thus, the challenged claims are not entitled to the

benefit of priority of JP 62-207224 for this reason alone.

b) JP 62-207224 and JP 63-15585 Do Not ProvideAdequate Support for Pitavastatin Calcium

As with JP 62-207224, JP 63-15585 provides no examples or data directed

to a pitavastatin calcium species, and no information justifying its selection or use

as a stand-alone species. Neither JP 62-207224 (Aug. 20, 1987) nor JP 63-15585

5 Claims that are not fully supported by an earlier application may only be entitled

to the effective filing date of a later-filed application that fully supports the claims.

PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1306 (Fed. Cir. 2008).

The disclosure of a foreign application to which a claim of priority is made must

also fully support the claims of the U.S. application within the meaning of 35

U.S.C. § 112, ¶ 1. In re Gosteli, 872 F.2d 1008, 1010 (Fed. Cir. 1989).


14

(Jan. 26, 1988) provides support for a species directed to the calcium salt of

pitavastatin or its isomers—the structure of which the patentee insists is recited in

Claim 1 of the ’336 patent. (Newton Dec. ¶ 50). The genuses disclosed in JP 62-

207224 and JP 63-15585 do not even list calcium salts by name. Instead, when

discussing possible substituents at the end of the side chain in the genus, JP 63-

15585 and JP 62-207224 state “[w]herein M is NH4, a metal capable of forming a

salt which is pharmaceutically acceptable or an amine H.” (JP 63-15585 at 4, ll.

11-12; JP 62-207224 at 4, ll. 4-5). M is further defined as “a metal capable of

forming a pharmaceutically acceptable salt, and it includes, for example, sodium

and potassium.” (JP 63-15585 at 5, ll. 17-19; JP 62-207224 at 5, ll. 1-3). The only

salt species described, made, tested or put into formulation in JP 62-207224 and

JP 63-15585 is sodium salts. (Newton Dec. ¶¶ 51-55).6

6 Unlike JP 62-207224, JP 63-15585 does disclose some species examples of

compounds with a cyclopropyl group. However, no biological data is provided in

JP-15585 for any pitavastatin salts, or any salts of any compounds with a

cyclopropyl group. (Newton Dec. ¶ 52). Preferred examples for the ’336 patent

are not listed until the later-filed, third priority document, JP 63-193606. (Newton

Dec. ¶¶ 53, 54; the ’336 patent, col. 4, l. 59-col. 5, l. 46).


15

Thus, JP 62-207224 and JP 63-15585 lack any blaze marks for a calcium salt

or salt of pitavastatin, much less the calcium salt of pitavastatin and its isomers of

Claim 1. Therefore, JP 62-207224 and JP 63-15585 do not provide adequate

support for the claimed subject matter of the ’336 patent. Accordingly, the

earliest effective priority date for the claimed subject matter of the ’336 patent is

the date of filing of JP 63-193606, i.e., August 3, 1988.

VII. THE ’336 PATENT AND CLAIM CONSTRUCTION

In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be

given their broadest reasonable interpretation in light of the specification of the

’336 patent. Under this standard, no terms or phrases require specific construction

for the purpose of this Petition, assuming the Board accepts the Patent Owner’s

assertion that “Δ” represents a cyclopropyl group such that pitavastatin calcium is

thereby encompassed by the claims.7

A. POSA

A POSA is a hypothetical person who is presumed to be aware of all

pertinent art, follows conventional wisdom in the art, and is a person of ordinary

creativity. KSR, 550 U.S. at 420-21. With respect to the ’336 patent, the POSA

7 Petitioner’s position regarding the scope of the claims should not be taken as an

assertion regarding the appropriate claim scope in other adjudicative forums.


16

would have held an advanced degree, such as an M.S. or a doctorate in one of the

fields of medicinal or synthetic chemistry, pharmacology, pharmacy or medicine,

with several years of experience in one of the fields of medicinal or synthetic

chemistry, pharmacology, pharmacy or medicine. In addition, the POSA would

have either personally possessed, or had access to, knowledge and skills from

medicinal and/or synthetic chemists, as well as biologists, pharmacists and/or

clinicians, including possessing knowledge of statins, their mechanisms of actions,

and other cholesterol treatments. Such person typically would have consulted with

one or more members of a team of experienced professionals in the relevant field

in order to solve a particular problem. (Newton Dec. ¶¶ 34, 35).

B. Ground 1: Claims 1 and 2 of the ’336 Patent Are UnpatentableUnder 35 U.S.C. § 103

1. The Scope and Content of the Prior Art

The scope and content of the prior art will be discussed below in connection

with the state of the art, selection of fluvastatin as the lead compound, as well as

the routine structural modifications to fluvastatin that the POSA would have

recognized as obvious to make.

2. Legal Principles Regarding Structural Obviousness

A prima facie case of obviousness is created by “structural similarity

between claimed and prior art subject matter, proved by combining references or

otherwise, where the prior art gives reason or motivation to make the claimed


17

compositions. . . .” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d

1350, 1356 (Fed. Cir. 2007) (quoting In re Dillon, 919 F.2d 688, 692 (Fed. Cir.

1990) (en banc)). The prior art must also provide “a reasonable expectation of

success, [but] not absolute predictability.” Eli Lilly and Co. v. Zenith Goldline

Pharma, Inc., 471 F.3d 1369, 1377 (2006) (quoting In re Longi, 759 F.2d 887, 896

(Fed. Cir. 1985)). Courts thus apply a two-part inquiry in determining whether a

new chemical compound would have been prima facie obvious over particular

prior art compounds: (1) whether a POSA would have chosen the asserted prior art

compounds as lead compounds (starting points) for further development efforts,

and (2) whether the prior art would have “supplied one of ordinary skill in the art

with a reason or motivation to modify a lead compound to make the claimed

compound with a reasonable expectation of success.” Otsuka Pharm. Co., Ltd. v.

Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012) (citations omitted).

3. Claim 1 Would Have Been Obvious under 35 U.S.C. § 103

Regardless of what priority date is adopted, the prior art at least renders the

Claims 1 and 2 obvious. While Petitioner expects that the Patent Owner will

contest its priority analysis, even the prior art before the earliest priority document,

JP 62-207224 (Aug. 20, 1987), would have rendered Claims 1 and 2 obvious.

Petitioner will first address the relevant prior art that existed prior to JP 62-207224

(Aug. 20, 1987 filing date), in the event the Board determines that the alleged


18

priority application provides support for Claims 1 and 2. Additional prior art

available as of the later priority dates is then discussed in turn in separate sections.

a) Technical background and state of the art prior to JP62-207224

The enzyme known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase

(HMG-CoA reductase) catalyses the conversion of HMG-CoA into mevalonic

acid. This was known by 1980 to be a major rate limiting step in cholesterol

biosynthesis, and thus a prime target for reduction of hypercholesterolemia.

(Newton Dec. ¶ 57; Alberts, EX1022, published July 1980 (102(b) prior art), at

3957). The first HMG-CoA reductase inhibitor was the natural product compactin.

Endo reported compactin’s activity in inhibiting cholesterol synthesis in vitro as

well as in rats in 1976. (Endo, EX1014, published Dec. 1976 (102(b) prior art), at

1347). The disclosure of the activity of an alkyl-substituted version called

mevinolin followed in 1980. (See Endo). These compounds are fungal

metabolites isolated from fungal broths, (Newton Dec. ¶¶ 57, 58):

CH3

O

R

OO

R1CH3

OH O

H

Compactin R = H, R1 = HMevinolin = Lovastatin R = CH3, R1 = H

Simvastatin R = CH3, R1 = CH3

*

**

**

*

*

*

.

After the initial disclosure of compactin (mevastatin) and mevinolin

(lovastatin), many companies, including Merck, Warner-Lambert and Sandoz,


19

began developing new synthetic compounds based on these core structures with

enhanced activity. Before JP 62-207224 was filed, this work began to reveal

patterns for a structure-activity relationship (“SAR”) between the compounds and

expected activity. As the art developed, it confirmed potent HMG-CoA reductase

inhibition activity was retained across a variety of nitrogen ring scaffolds, so long

as a pharmacophore containing a lactone ring or an open heptenoic acid side chain

was flanked on one side by a 4-fluorophenyl group, and on the other side by an

alkyl group, (Newton Dec. ¶ 59):

.

For example, U.S. Patent No. 4,647,576, assigned to Warner-Lambert

(“Hoefle ’576 patent”) (EX1016), was filed December 10, 1984, and published on

March 3, 1987 (102(b) prior art). The Hoefle ’576 patent explained that

compounds of the invention “are potent inhibitors of cholesterol biosynthesis by

virtue of their ability to inhibit . . . (HMG-CoA reductase).” (Hoefle ’576 patent at

col. 1, ll. 65-68). This patent preserved the compactin/mevinolin lactone ring, but

modified it by (a) preparing the compound with an open lactone ring as a side

F

side chain

alkyl


20

chain; (b) changing the ring system to a single 5-membered aromatic nitrogen-

containing ring; and (c) changing the side groups:

(Newton Dec. ¶ 60). Compounds highly potent to inhibiting cholesterol synthesis

resulted; the most potent compounds contained 4-fluorophenyl groups and

isopropyl groups flanking the lactone ring/side chain location. (Hoefle ’576 patent

at Table 1, cols. 19-20; Newton Dec. ¶ 61).

U.S. Patent No. 4,613,610 (“Wareing ’610 patent”) (EX1018), assigned to

Sandoz was filed on June 6, 1985, and published on September 23, 1986 (102(b)

prior art). The Wareing ’610 patent also asserted the disclosed compounds can be

used for “inhibiting cholesterol biosynthesis and lowering the blood cholesterol

level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.”

(Wareing ’610 patent at col. 2, ll. 1-4). Wareing’s compounds differ from the

Hoefle ’576 patent’s in that Wareing’s 5-membered aromatic nitrogen ring has an

additional nitrogen atom added:


21

(Newton Dec. ¶ 62). The Wareing ’610 patent also confirmed that the most potent

compounds possessed a 4-fluorophenyl group and an alkyl in the form of an

isopropyl group flanking the open heptenoic acid side chain, consistent with the

pharmacophore above. (Wareing ’610 patent at cols. 53-54 (Test B), 62, 66, 80-

81) (showing Examples 3, 7, and 14 were more active than mevinolin); Newton

Dec. ¶ 63).

European patent 0114027 (“EP ’027”) (EX1025), dated July 25, 1984

(102(b) prior art), by Kathawala et al. of Sandoz prepared yet another class of

compounds that were indole analogues of mevalonolactone. EP ’027 states that the

compounds disclosed “possess pharmacological activity; in particular they are

inhibitors of . . . (HMG-CoA) reductase and as a consequence inhibitors of

cholesterol biosynthesis as demonstrated in the following three tests. . . .” (EP

’027 at 17, ll. 50-52). (The U.S. version of this application, the Kathawala ’073

patent, is discussed below) (Newton Dec. ¶ 64). Claim 3 of EP ’027 specifically

covers the following structure, showing the modified aromatic nitrogen ring


22

system, again containing the 4-fluorophenyl group and an isopropyl group flanking

the open heptenoic acid side chain and confirming the pharmacophore:

(Newton Dec. ¶ 65).

U.S. Patent No. 4,681,893 (“Roth ’893 patent”) (EX1019), assigned to

Warner-Lambert, was filed May 30, 1986, and published July 21, 1987 (102(b)

prior art). The Roth ’893 patent disclosed compounds that were “potent inhibitors

of cholesterol biosynthesis by virtue of their ability to inhibit . . . (HMG-CoA

reductase).” (Roth ’893 patent at col. 1, l. 67 - col. 2, l. 2). Roth disclosed yet

another series of potent analogues shown below consistent with the

pharmacophore. Notably, in the Roth ’893 patent, trifluoromethyl is substituted

for isopropyl in the pharmacophore, and potent activity is retained:


23

(Newton Dec. ¶¶ 66, 67; Roth ’893 patent at Table 1, cols. 7-10 (Table 1 providing

biological data)).

U.S. Patent No. 4,751,235 (“Anderson ’235 patent”) (EX1020), assigned to

Sandoz, was filed on December 23, 1986, and published on June 14, 1988 (102(e)

prior art). The Anderson ’235 patent confirms the compounds disclosed therein are

“competitive inhibitors of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)

reductase, the rate-limiting enzyme in cholesterol biosynthesis and therefore, they

are inhibitors of cholesterol biosynthesis.” (Anderson ’235 patent at col. 6, ll. 34-

38). The patent also discloses a series of indolizine derivatives, which were

competitive antagonists of HMG-CoA reductase. The Anderson ’235 patent also

discloses detailed biological data for the racemate of the preferred compound of

Example 2 and Claim 15, which again included the 4-fluorophenyl group:


24

.

(Id. at col. 7). This compound put the nitrogen in a different location within the

ring system, and allowed the isopropyl group to attach to a carbon atom within the

nitrogen ring system instead. Activity was retained when the isopropyl group is

attached to a carbon atom. (Newton Dec. ¶ 68).

Thus, the POSA would have recognized not only the strong consistent

preference for the 4-fluorophenyl structure and lactone/side chain for biologically

potent compounds, but also that variation may occur within the nitrogen-containing

ring systems to which these side groups are attached while still preserving

biological activity. (Newton Dec. ¶ 69).

b) The Prior Art Before JP 62-207224 Would Have Ledthe POSA to Select Fluvastatin as a Lead Compound

The POSA would have been motivated to select fluvastatin as a lead

compound for further development because it was unique in the following ways in

the prior art: (1) it possessed the pharmacophore known to optimize activity; (2) it

had proceeded to clinical trials; and (3) it was more than one order of magnitude


25

more potent than both benchmark compounds mevinolin (lovastatin) and

compactin (mevastatin) in vivo. (Newton Dec. ¶ 72).

For example, as discussed below, researchers at Sandoz disclosed the

sodium salt of fluvastatin, also known as SRI-62320, XU 62-320, and [R*, S*-

(E)]-(+-)-Sodium-3,5-dihydroxy-7-[3-(4-fluorophenyl)-1(1-methylethyl)-1H-indol-

2-yl]-hept-6-enoate, as follows, before August 20, 1987:

(See Kathawala Abstract; Newton Dec. ¶ 73). This compound conformed to the

pharmacophore shown to correlate with potent activity, as discussed above. In the

Kathawala Abstract, Sandoz researchers disclosed that fluvastatin was an HMG-

CoA reductase inhibitor, and had entered human clinical trials:

Currently there exists a high level of interest in the

development of safe and effective HMG-CoA reductase

inhibitors. Efforts at Sandoz Research Institute in the

design and synthesis of novel HMG-CoA reductase

inhibitors have led to XU 62-320: [R*, S*- (E)]-(±)-

Sodium-3,5-dihydroxy-7-[3-(4-fluorophenyl)-1(1-

methylethyl)-1H-indol-2-yl]-hept-6-enoate, which is

more potent than compactin in inhibiting HMG-CoA


26

reductase in vitro and cholesterol biosynthesis in vivo.

Design, synthesis and structure activity relationships with

the series of compounds related to XU-62-320, currently

in clinical trials, will be presented.

(Kathawala Abstract; Newton Dec. ¶¶ 74, 75).

In addition, according to the Kathawala ’073 patent (filed March 5, 1985),

“compounds of Formula I are competitive inhibitors of . . . (HMG-CoA)

reductase.” (Kathawala ’073 patent at col. 30, ll. 64-66). As a result, the

compounds are “useful for lowering the blood cholesterol level in animals, e.g.,

mammals, especially larger primates.” (Id. at col. 31, ll. 1-4; Newton Dec. ¶ 76).

Among those compounds disclosed in the Kathawala ’073 patent, the POSA

would have recognized the sodium salt of the racemate of fluvastatin (disclosed as

Example 8) as the best. The structure of Example 8 is shown below:

More specifically, Example 8 possessed the best overall in vitro and in vivo

activity of those compounds disclosed in the Kathawala ’073 patent. In in vitro

Test A concerned an HMG-CoA reductase assay and in vitro Test B concerned a

cholesterol biosynthesis screen in cells, respectively. (See Kathawala ’073 patent


27

at cols. 31-33). Example 8 was the second most potent among all compounds

screened in Test A and B, and the only compound to come in either first or second

in both tests. Example 8 outperformed the only reference comparison in tests A

and B, compactin. (Newton Dec. ¶¶ 77, 78).

Further, the compound of Example 8 was the most potent among all

compounds screened in the more pharmaceutically relevant in vivo Test C

(cholesterol synthesis in male Wistar Royal Hart rats). (Kathawala ’073 patent at

col. 33). It was significantly more potent than both reference compounds (i.e.,

mevinolin and compactin), outperforming both by at least one order of magnitude:

Kathawala ’073 Example 8 ED50 = 0.03 mg/kg

Mevinolin (Lovastatin) ED50 =0.48 mg/kg

Compactin (Mevastatin) ED50 =4.4 mg/kg

(Id.). The POSA would have expected that if he/she separated the racemate of

Example 8 to obtain the biologically active isomer, that compound would have

been even more potent—32 times as potent as mevinolin and about 293 times as

potent as compactin. Example 8 was also the only compound featured in both

capsule and tablet compositions. (Newton Dec. ¶¶ 79, 80; Kathawala ’073 patent

at col. 34, l. 62-col. 35, l. 5; id. at col. 35, ll. 15-21). In fact, the Example 8

compound was recognized as so promising that Sandoz selected it for further

development and clinical trials. (Kathawala Abstract). Thus, at the relevant time,


28

fluvastatin would have been a natural choice for a POSA looking to develop an

HMG-CoA reductase inhibitor to select as a lead compound. Bristol-Myers Squibb

Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014); Otsuka, 678

F.3d at 1294 (explaining that a POSA “would be most attracted to the most potent

compounds in selecting a lead compound for development” (internal quotation and

citations omitted); (Newton Dec. ¶¶ 80-82).

c) It Would Have Been Obvious to Identify Areas ofFluvastatin to Structurally Modify and Improve

After selecting fluvastatin as the lead compound, the POSA would have

routinely identified areas of the fluvastatin structure for obvious and routine

modification. The POSA would have been motivated to develop structurally-

modified HMG-CoA reductase inhibitors in light of the prior art and his/her

experience and knowledge. As discussed herein, POSAs were significantly

interested in developing HMG-CoA reductase inhibitors to treat hyperlipidemia by

modifying existing inhibitors. “[H]igh cholesterol levels in the blood may be one

of the major causes of atherosclerosis and coronary heart disease,” and HMG-CoA

reductase was known as the rate limiting enzyme in the production of cholesterol.

(Endo at 1346; see also Alberts at 3957). Research groups at major

pharmaceutical companies (e.g., Merck, Warner-Lambert, Sandoz) had developed

HMG-CoA reductase inhibitors to lower cholesterol for years prior to the

invention, and synthesized many compounds for this purpose. (Newton Dec. ¶ 83).


29

For instance, Sandoz stated in the Kathawala Abstract: “Currently there

exists a high level of interest in the development of safe and effective HMG-CoA

reductase inhibitors.” (Kathawala Abstract). Merck obtained FDA approval on

August 31, 1987, for the HMG-CoA reductase inhibitor lovastatin, which was

marketed under the trade name Mevacor.8 Merck also reported in Tobert that, by

September 1987, five different HMG-CoA reductase inhibitors had already

progressed to evaluation in the clinic. (Tobert at 534-35). Warner-Lambert stated

in the Hoefle ’576 patent that: “High levels of blood cholesterol and blood lipids

are conditions which are involved in the onset of arteriosclerosis. It is well known

that inhibitors of HMG-CoA reductase are effective in lowering the level of blood

plasma cholesterol.” (Hoefle ’576 patent, col. 1, ll. 24-29). Thus, as evidenced by

the public activities of the industry alone, the POSA would have been motivated to

further develop HMG-CoA reductase inhibitors. In this pursuit, the POSA would

have been motivated to make obvious and routine structural modifications to the

fluvastatin structure, which would have necessarily allowed the POSA to arrive at

the claimed pitavastatin compound. (Newton Dec. ¶¶ 84, 85).

8 Orange Book listing for lovastatin, available at

http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=01964

3&TABLE1= OB_Disc (EX1017).


30

d) Modifying Fluvastatin’s Ring System to a QuinolineRing System Would Have Been Obvious

Having identified fluvastatin as the lead compound, and having established

that the POSA would have been motivated to modify the structure of fluvastatin to

develop HMG-CoA reductase inhibitors, it would have been obvious to the POSA

to add a single carbon to the indole ring of the fluvastatin core to arrive at the

quinoline ring structure of pitavastatin calcium salt. (Newton Dec. ¶ 86).

(1) It Would Have Been Obvious to ModifyFluvastatin’s Ring System to a Quinoline, Priorto JP 62-207224

As noted above, modifying the central nitrogen-containing ring system was

already a well-used strategy by the POSA. The question thus became what would

have been obvious, structurally-similar variants to incorporate into fluvastatin.

The POSA would have found converting the 6,5 indole system in fluvastatin to a

6,6 quinoline ring structure (which contains a 6-membered ring with one nitrogen

atom within the 6-membered ring) an obvious modification for at least three

separate reasons:

First, as with the Hoefle ’576, the Roth ’893, the Anderson ’235, and

Wareing ’610 patents, it was known that the nitrogen ring structure could be

modified while retaining activity, so long as the remaining pharmacophore

structures were retained. This modification thus is justified by the pharmacophore

itself (because such a scaffold would allow for the 4-fluorophenyl and side chain


31

groups to be kept in their same biologically active positions), as well as the

existing trend in the art to make modifications to the nitrogen ring system.

(Newton Dec. ¶¶ 87, 88).

Second, the POSA would have considered the ring system of fluvastatin, and

its corresponding quinoline ring analog, to be similar. In fact, to a POSA, the

existing 6,5 indole ring system in fluvastatin had very similar characteristics to the

6,6 quinoline ring system in terms of similar size, similar shape, and retention of

the ring structure, including aromatic rings. It would have only involved the

inclusion of one extra carbon, and would therefore have not presented any

difficulty from a synthetic chemistry perspective. (Newton Dec. ¶ 89). Further,

nitrogen ring scaffolds, which, unlike fluvastatin, do not incorporate double rings,

had not been reported to have advanced to human clinical trials, and were in some

cases much less active than fluvastatin relative to compactin or mevinolin. (See,

e.g., Roth ’893 patent at Table 1, cols. 7-10; Hoefle ’576 patent at Table 1, cols.

19-20; Newton Dec. ¶ 90). Therefore, a POSA would have favored a nitrogen ring

scaffold more similar to fluvastatin. Fluvastatin (left) and its corresponding

quinoline analog (right) are depicted below:


32


Third, a POSA would have been guided to a quinoline ring system by Log P

calculations that analyze lipophilicity. With fluvastatin in clinical trials, the POSA

would not have wanted to deviate too far from the existing Log P calculations

when making modifications to the central ring system. Log P calculations would

have been routinely used by POSAs at the time of the invention (as they are today).

It would have been immediately apparent to a POSA that he/she could have

achieved a similar Log P with a quinoline ring in fluvastatin. (Newton Dec. ¶ 91).

The Log P value of a quinoline ring structure is 2.02 and an indole ring structure is

2.14. (Schultz, EX1033, published 1970 (102(b) prior art); Hansch I, EX1034,

published 1967 (102(b) prior art)). When the isopropyl group substituent is

considered at the 2 position, the Log P values become 3.55 (quinoline ring

structure) and 3.67 (indole ring structure). Thus, the similarity of the Log P values

would have guided the POSA to a quinoline ring system. (Newton Dec. ¶¶ 91-93).

Moreover, it would have been obvious for the POSA to have incorporated

the isopropyl group on a quinoline carbon atom (at the 2 position), rather than on


33

the nitrogen for at least the following two reasons. First, in the quinoline ring

system the nitrogen atom is part of an aromatic ring and already trivalent.

Locating the isopropyl group on the nitrogen of the quinoline structure would have

resulted in the nitrogen becoming positively charged, and thus, it would have been

expected to be poorly absorbed in the gut. Second, the POSA would have wanted

to maintain the pharmacophore discussed above, and, thus, would have wanted to

maintain the isopropyl group’s position on the core adjacent to the dihydroxy hept-

6-enoate substituent just as it is in the structure of the lead compound, fluvastatin.

As a result, the POSA would not have chosen to locate the isopropyl group on the

nitrogen of the quinoline structure. (Newton Dec. ¶¶ 94-96).

The POSA would have been motivated to modify fluvastatin to arrive at a

quinoline ring scaffold having substituents at the very same positions as those in

Claim 1 of the ’336 patent, not only because of the structural similarity between

that scaffold and fluvastatin’s, but also because it gives the most comparable Log P

value. (Newton Dec. ¶ 97).

In sum, the POSA would have had at least three (3) separate reasons to

modify the indole structure of fluvastatin to arrive at its corresponding quinoline

analog: (1) the prior art had already revealed the trend of, and taught modifications

to, the nitrogen ring scaffold, and further demonstrated that this scaffold could be

modified while retaining activity provided the other key features of the


34

pharmacophore were present; (2) the indole and its corresponding quinoline analog

are very similar in size, shape and other properties; and/or (3) the Log P values are

similar. And, as discussed above, the POSA would have had a reasonable

expectation of success that a quinoline analog would have possessed biological

activity at least similar to fluvastatin. Thus, for at least these reasons, modifying

the indole of fluvastatin to arrive at a quinoline core would have been an obvious

choice. A POSA would have also expected a modification from an indole to a

quinoline core would have retained potent HMG-CoA reductase activity. Bristol-

Myers Squibb, 752 F.3d at 973. (Newton Dec. ¶¶ 98, 99).

e) Substituents on the Quinoline Core

(1) It Would Have Been Obvious to Maintain the 4-Fluorophenyl Group and the Side Chain

The structure of fluvastatin with the 4-fluorophenyl substituent (circled in

green) and the side chain (circled in blue) is provided below (Newton Dec. ¶ 100):

As discussed above, the prior art at the relevant time taught a POSA that a scaffold

that included the 4-fluorophenyl group was known to provide optimal activity;


35

therefore, the POSA would not have looked to modify this group. Likewise, it

would have been necessary to preserve the side chain and its structural

stereochemistry to have a biologically active molecule. Thus, the POSA would

have looked to modify the structure of fluvastatin in areas other than the 4-

fluorophenyl group and would have preserved the side chain structure and

stereochemistry. (Id. ¶ 101).

f) It Would Have Been Obvious to Modify the IsopropylGroup

While fluvastatin contained an isopropyl group, and the pharmacophore

favors an alkyl group structure, the prior art repeatedly taught that variations could

be invoked at this position, as discussed below.

With regard to the isopropyl group, as discussed above, the POSA would

have positioned the isopropyl group in the correct location on the quinoline

structure to ensure a Log P value that remained consistent with fluvastatin’s ring

system, and which did not create a quaternary (or positively charged) nitrogen.

(Newton Dec. ¶¶ 103, 104). The question then became what would be an obvious

modification in this position. The Patent Owner’s own admission evidences, at the

relevant time, the POSA would have modified the isopropyl substituent while

retaining, and possibly even improving upon, HMG-CoA reductase inhibitor

activity because it is the “next logical” analogue. (Paper No. 32 at 5).


36

Separately, the prior art (i.e., Roth ’893 patent) disclosed the substitution of

a trifluoromethyl group for isopropyl at the 2 position. This substitution resulted in

slightly increased activity over the corresponding isopropyl analog and slightly

more potency than compactin. (See Roth ’893 patent at Table 1, cols. 7-10).

Accordingly, a POSA would have been motivated to try modifications at the 2

position with substituents similar to isopropyl. See Daiichi Sankyo Co. v. Matrix

Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) (emphasizing the importance of

potency and promising activity). While several modifications besides

trifluoromethyl could have been made to the isopropyl group at the 2 position of

the quinoline ring, the one that would have particularly stood out from the prior art

would have been the cyclopropyl group. (Newton Dec. ¶¶ 105, 106).

(1) The Patent Owner Admits that Cyclopropyl Isthe Next Logical Choice

The Patent Owner actually provided a very sound rationale for substituting

cyclopropyl for isopropyl during the ’608 interference proceedings:

Having been taught that isopropyl is an acceptable

substituent and within the scope of Wattanasin’s

invention, those of skill in the art would readily arrive at

the selection of cyclopropyl, out of the disclosure of

cycloalkyl of 3-7 carbon atoms, as the next logical, and

analogous compound, isomerically related to exemplified

species. . . . It is well established that isomeric species are


37

expected to behave in similar fashion, in the absence of

evidence to the contrary.

(Paper No. 32 at 5). The Patent Owner further stated that, in a European Patent

Publication 179,559 (“EP ’559”) (EX1035), which contains an equivalent

disclosure to the Hoefle ’576 patent, cyclopropyl and isopropyl “are identified as

equivalent.” Id. at 11-12. Thus, according to the Patent Owner, substituting in a

cyclopropyl is simply an exercise in going to the “next logical” analogue. It was

therefore obvious to do.

(2) The Prior Art Would Have Taught aCyclopropyl Group

The prior art would have taught modifying the isopropyl group to a

cyclopropyl group for at least the following reasons. The Kathawala ’073 patent—

which, as discussed above, would have supported selecting fluvastatin as the lead

compound—includes cyclopropyl as a substituent adjacent to the hept-6-enoate

substituent. According to the Kathawala ’073 patent, compounds of Formula I

include compounds in which one of Ro and R is a substituted phenyl (such as 4-

fluorophenyl), and the other is primary or secondary C1-6alkyl not containing an

asymmetric carbon atom, C3-6 cycloalkyl, or phenyl(CH2)m. (Kathawala ’073

patent at Abstract). The limited members of C3-6 cycloalkyl group include

cyclopropyl. (Newton Dec. ¶¶ 111, 112).


38

In addition, the Hoefle ’576 patent included cyclopropyl groups adjacent to

the lactone ring and the open side chain. A compound with a cyclopropyl

substituent and a 4-fluorophenyl group flanking the lactone ring was included as

one of the 13 “particularly preferred compounds,” (Hoefle ’576 patent col. 2, l. 1–

col. 4, l. 14; id. at col. 8, l. 37-col. 9, l. 6), and a cyclopropyl substituent was

included in the claims, (id. at col. 32, l. 5; Newton Dec. ¶ 113).

Furthermore, the Roth ’893 patent included a cyclopropyl substituent

adjacent to the lactone and open-side chain. Substituents at this position disclosed

in the Roth ’893 patent included an “alkyl of from one to six carbon atoms;

cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl.” The Roth

’893 patent also claimed compounds with a “cyclopropyl substituent.” (Roth ’893

patent at col. 2, ll. 3-44; id. at col. 16, l. 62; Newton Dec. ¶ 114).

Thus, the POSA would have clearly recognized a trend, having a clear

understanding that isopropyl and cyclopropyl groups could readily be substituted

with one another in this position within this drug class. Given that fluvastatin

would have taught a POSA that isopropyl is an acceptable substituent, and that the

prior art taught that cyclopropyl is an acceptable substitution, modifying the

isopropyl to a cyclopropyl group would have been the next logical and analogous

compound. (Newton Dec. ¶¶ 115-117). Indeed, as discussed above, a rationale for

substituting isopropyl was proffered by the Patent Owner during the interference


39

proceedings. (Paper No. 32). As discussed above, the Patent Owner stated that

cyclopropyl and isopropyl “are identified as equivalent” in the prior art. (Id. at 11-

12).

Therefore, in view of the prior art, it would have been obvious to a POSA to

make a substitution at the second position of the quinoline ring to replace the

isopropyl with a cyclopropyl group. See Pfizer, 480 F.3d at 1352-53; In re Dillon,

919 F.2d at 696 (Fed. Cir. 1990) (“if an examiner considers that he has found prior

art close enough to the claimed invention to give . . . motivation to make close

relatives (homologs, analogs, isomers, etc.) of the prior art compound(s), then there

arises . . . a prima facie case of obviousness.”); In re Wilder, 563 F.2d 457, 460-61

(C.C.P.A. 1977). Because several prior art references disclose compounds with a

cyclopropyl substituent as being among compounds that possess HMG-CoA

inhibitory activity, a POSA would have had a reasonable expectation that

modifying the isopropyl in such a way to arrive at a cyclopropyl analog would

have successfully resulted in a compound that retained, or even improved upon,

HMG-CoA reductase inhibitory activity. See Pfizer, 480 F.3d at 1367. In fact, as

discussed below, Suh (EX1029, published Jan. 1985 (102(b) prior art)) shows that,

with respect to inhibition of a different enzyme, the cyclopropyl analog retained,

and improved upon, inhibitory activity. (Newton Dec. ¶¶ 118, 119).


40

(3) Knowledge that Cyclopropyl and IsopropylGroups Are Bioisosteres Would HaveMotivated Modification of Fluvastatin

Alternatively, the POSA would have arrived at substituting isopropyl for

cyclopropyl using bioisosteric principles. Bioisosteric substitution was a well-

established means for making substitutions while preserving biological activity. It

would have been obvious to the POSA that a cyclopropyl substitution of an

isopropyl group would be an interchangeable bioisosteric substitution. (Newton

Dec. ¶ 120). It was well-known that compounds that are bioisosteres can be

interchanged while conserving biological activity. For example, Taylor (EX1023,

published 1981 (102(b) prior art)) states:

One of the fundamental concepts and working

hypotheses of medicinal chemists through the ages has

been that of bioisosterism. Ideally, this involves the

replacement of a fundamental group of moiety in a

specifically active drug molecule for another so that the

biological activity is ameliorated or improved. With the

advent of Hansch analysis it is possible to quantify the

requirements for bioisosterism in terms of the parameters

. . . . Compounds with substituents whose constants have

very similar values and which produce similar biological

responses are called isometric bio-isosteres. Those

substituents may be extensively interchanged whilst

conserving biological activity.


41

(Taylor at 94; see also Newton Dec. ¶ 121).

As noted above, it was well-known that cyclopropyl and isopropyl

substituents are closely-related analogs with very similar steric and electronic

properties. Indeed, the structures of these substituents are very similar:


Importantly, the representations the Patent Owner made concerning the

interchangeability of cyclopropyl and isopropyl (discussed above) are

independently confirmed by other prior art teachings. To this end, Hansch II

(EX1024, published Nov. 1973 (102(b) prior art)) teaches that, relative to other

substituent groups, the constants σm and σp, and the values F, R, MR and MW of

cyclopropyl (47) and isopropyl (55) are very similar. (Hansch II, Table 1 at 1209).

It is notable that the σm values of the isopropyl and cyclopropyl groups are

identical, and that their σp values are very similar. Hansch II explains that σm and

σp values in particular are notable, in part because “it is possible, using only σm

and σp to factor the electronic effect into resonance and non-resonance

components.” (Id. at 1207; see also Newton Dec. ¶ 123).

Further, researchers conducting an SAR analysis (albeit with a different

enzyme) applied the well-known steric and electronic relationship between


42

isopropyl and cyclopropyl, and observed the expected result. (See generally Suh).

Once the Suh authors discovered the activity of a compound with an isopropyl

substituent, they explained that its activity “gave us the incentive to prepare the

cyclopropyl analogue.” (Id. at 59). As the POSA would have expected, the

substitution of a cyclopropyl moiety for the isopropyl moiety retained enzyme

inhibition activity, in fact the cyclopropyl compound was more potent than the

isopropyl analog. (Id.; Newton Dec. ¶ 124).

Thus, setting aside the Patent Owner’s representations and the specific

interchangeability disclosures within the art for this drug class itself, a POSA

would have been motivated to substitute the isopropyl for a cyclopropyl and would

have had a reasonable expectation of success because cyclopropyl and isopropyl

substituents would have been expected to act as nearly interchangeable bioisosteres

in light of the teachings of at least Hansch II and Suh alone. See Aventis Pharma

Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007)

(explaining “it is sufficient to show that the claimed and prior art compounds

possess a sufficiently close relationship to create an expectation, in light of the

totality of the prior art, that the new compound will have similar properties to the

old” (internal quotation and citation omitted)). In sum, a POSA would have had a

reasonable expectation of success that the resulting compound would have

maintained potent HMG-CoA reductase inhibitory activity, particularly because


43

cyclopropyl and isopropyl are nearly interchangeable substituents. See Pfizer, 480

F.3d at 1367; Aventis, 499 F.3d at 1301, Bristol-Myers Squibb, 752 F.3d at 973;

(Newton Dec. ¶¶ 125, 126).

In addition, as there were a finite number of compounds that had similar size

and chemistry to isopropyl, cyclopropyl would have been obvious to try. (Hansch

II at 1209-12); Pfizer, 480 F.3d at 1363. In fact, cyclopropyl would have stood out

from the prior art for the reasons stated above. And a POSA would have been able

to replace the isopropyl group to a cyclopropyl group using routine

experimentation. (Newton Dec. ¶ 127).

g) It Would Have Been Obvious to Prepare SaltDerivatives, Including Calcium Salts

Salts in this class were known, and solid compounds are well-known in the

pharmaceutical industry to have better handling properties. (Newton Dec. ¶¶ 129-

136). As such, after identifying fluvastatin as the lead compound, and making

obvious modifications to arrive at its quinoline, 2-cyclopropyl analog, i.e.,

pitavastatin, the next question became how best to prepare the compound in solid

salt form. It would have been obvious to a POSA to further produce a salt,

including a calcium salt, for at least the following reasons. (Id. ¶ 129).

As discussed above, a POSA would have understood Example 8 of the

Kathawala ’073 patent to have disclosed fluvastatin sodium salt. It would have

been obvious to a POSA to similarly prepare a salt of the quinoline, 2-cyclopropyl


44

derivative of fluvastatin. Because the nature of the side chain dictates that a

cationic salt is required, the POSA would have considered what cationic salts were

available and routinely used. Here, teachings are directed to a calcium salt, and the

motivation to select one is in the prior art. (Newton Dec. ¶ 130). For example, the

Kathawala ’073 patent disclosed calcium salts as potential derivatives for the same

side chain at issue here by stating that R7, located at the distal end of the hept-6-

enoate group, can be “M,” which “may also be divalent or trivalent.” (Kathawala

’073 patent at col. 5, ll. 1-8). Though the Kathawala ’073 patent does not state

calcium by name, the POSA would have recognized that only two such metallic

cations—calcium and magnesium—would likely have been employed in a

pharmaceutical composition. See Pfizer, 480 F.3d at 1367; (Newton Dec. ¶ 131).

In addition, other available art concerning HMG-CoA reductase inhibitors

disclosed the use of calcium salts. For example, the Hoefle ’576 patent discloses

HMG-CoA reductase inhibitors and includes calcium in its list of pharmaceutically

acceptable salts, and notes the salt will arise at the same side chain position as in

fluvastatin. (Hoefle ’576 patent at col. 17, ll. 46-54). U.S. Patent No. 4,537,859

(“Terahara ’859 patent”) ((EX1026), filed Nov. 18, 1982, published Aug. 27, 1985

(102(b) prior art)) also discloses HMG-CoA reductase inhibitors and states that

“sodium, calcium and aluminum salts [are] most preferred” at this same salt


45

location in the side chain. (Terahara ’859 patent at col. 12, ll. 4-5 (emphasis

added); see also Newton Dec. ¶ 132).

Furthermore, there were a finite number of predictable, approved cation

salts. Both Berge (EX1027, published Jan. 1977 (102(b) prior art)) and Gould

(EX1028, published Nov. 1986 (102(b) prior art)) teach that calcium was third in

popularity among just 14 FDA-approved cations available at the time. (Berge at 2;

Gould at 202); Otsuka, 678 F.3d at 1295 (characterizing the court’s earlier

precedent, as dependent in part on a finding that the prior art provided motivation

to narrow a genus of salt-forming anions to a few species). A POSA would have

routinely set up a salt screen to analyze the most common FDA-approved salts and

compared their characteristics. (Newton Dec. ¶ 133).

Therefore, in view of the prior art and his/her knowledge and experience, the

POSA would have had a reasonable expectation of success that the calcium salt

would have maintained potent HMG-CoA reductase inhibitory activity, especially

given that the salt form would not be expected by a POSA to impact potency. See

Bristol-Myers Squibb, 752 F.3d at 973; (Newton Decl. ¶ 134). In addition, it

would have been obvious to the POSA to choose, prefer and try a calcium salt of

the quinoline, 2-cyclopropyl derivative of fluvastatin, with a reasonable

expectation of success. In fact, a POSA would have found replacing the sodium

counterion (as disclosed in the fluvastatin lead compound) to its corresponding


46

calcium counterion a matter of routine experimentation. Having made all of the

above modifications, the POSA would have arrived at a compound purportedly

claimed in Claim 1 of the ’336 patent. (Newton Dec. ¶¶ 135, 136).

h) There Would Have Been a Reasonable Expectation ofSuccess that the Modifications Would Have Resultedin a Compound that Inhibits HMG-CoA Reductase

Prior to JP 62-207224, a POSA would have had a reasonable expectation

that the obvious modifications described herein (i.e., use of a quinoline ring

scaffold and substitution of cyclopropyl for isopropyl at position 2) and the

selection of a calcium salt would have resulted in a compound that retained potent

HMG-CoA reductase inhibitory activity. (Newton Dec. ¶ 137).

As discussed above, the lead compound fluvastatin was disclosed to be a

highly potent HMG-CoA reductase inhibitor, and clinical trials with fluvastatin had

already begun in humans. (See, e.g., Kathawala Abstract; Kathawala ’073 patent at

cols. 31-33, 52). As discussed above, fluvastatin was disclosed to be significantly

more active in vivo than lovastatin, a statin which FDA approved on August 31,

1987. (EX 1017). In addition, a variety of compounds with the same

pharmacophore as fluvastatin, but having different nitrogen ring scaffolds, was

disclosed as having potent HMG-CoA reductase inhibitory activity. For example,

activity was observed in a number of compounds in the Roth ’893 patent (Table 1,

col 7-10), the Wareing ’610 patent (col. 53-54 (Test B), 62, 66, 80-81); and the


47

Hoefle ’576 patent (Table 1, col. 19-20), which possessed the fluvastatin

pharmacophore but different nitrogen ring scaffolds. A POSA would have

expected that substitutions could be made to the nitrogen ring scaffold while

maintaining activity. (Newton Dec. ¶¶ 138, 139). Therefore, in view of the prior

art and his/her knowledge and experience, a POSA would have had a reasonable

expectation of success that a fluvastatin analogue with a quinoline ring scaffold

would have continued to have potent HMG-CoA reductase inhibitory activity and

inhibited cholesterol production in vivo. (Id. ¶¶ 142, 143).

Additionally, the prior art (including the Roth ’893, the Hoefle ’576 and

Kathawala ’073 patents) also taught the cyclopropyl modification. A POSA would

have had a reasonable expectation of success that a cyclopropyl modification

would have produced a compound having equivalent, or even improved upon,

activity. (Newton Dec. ¶ 140; Hansch II at 1209; Suh at 59). This was, in essence,

admitted by the Patent Owner when it averred that isopropyl and cyclopropyl are

“isomerically related to exemplified species” and that “it is well established that

isomeric species are expected to behave in similar fashion, in the absence of

evidence to the contrary.” (Paper No. 32 at 5).

4. Claim 2 Would Have Been Obvious Under 35 U.S.C. § 103

Claim 2 is drawn to a method for reducing hyperlipidemia,

hyperlipoproteinemia or atherosclerosis, by administering an effective amount of


48

the compound of Formula A recited by Claim 1 (i.e., pitavastatin calcium salt).

Since this is a disjunctive element (i.e., “or”), administering an effective amount of

the compound that reduces any of the three recited disease states invalidates the

claim. SkinMedica, Inc. v. Histogen, Inc., 727 F.3d 1187, 1199 (Fed. Cir. 2013).

The compound recited in Claim 2 would have been obvious for at least all of the

reasons set forth above for Claim 1.

The POSA would have expected such a compound to have HMG-CoA

reductase inhibitory activity, and therefore to reduce hyperlipidemia and

hyperlipoproteinemia. “It is well known that inhibitors of HMG-CoA reductase

are effective in lowering the level of blood plasma cholesterol.” (Hoefle ’576

patent, col. 1, ll. 25-35; see also Brown, EX1030, published Aug. 27, 1981 (102(b)

prior art); Alberts; Gortler Dec. ¶ 47). The Wareing ’610 patent states that the

compounds disclosed therein are useful for “inhibiting cholesterol biosynthesis and

lowering the blood cholesterol level and, therefore, in the treatment of

hyperlipoproteinemia and atherosclerosis.” (Wareing ’610 patent, col. 2, ll. 1-5).

The Kathawala ’073 patent further teaches that the compounds disclosed therein


49

(including fluvastatin) are useful “in the treatment of hyperlipoproteinemia and

atherosclerosis.” (Kathawala ’073 patent at col 2. ll. 15-20;9 Newton Dec. ¶ 144).

Indeed, as discussed above, the prior art teaches that such compounds are

effective for inhibiting cholesterol synthesis in vivo. Compounds that inhibit

cholesterol in synthesis in vivo would have been expected to reduce hyperlipidemia

and hyperlipoproteinemia. (Gortler Dec. ¶¶ 39-41). Moreover, a POSA would

have understood that any HMG-CoA reductase inhibitor should be given in an

amount effective to achieve such reduction. Determining an effective amount of

an HMG-CoA reductase inhibitor would have simply been a matter of routine

experimentation for a POSA. In re Aller, 220 F.2d 454, 456-57 (C.C.P.A. 1955);

Metrics, Inc. v. Senju Pharm. Co., IPR2014-01041 [Paper 19, p. 17]. Therefore, a

POSA would also have been motivated to administer the compound of Claim 1 to

subjects having hyperlipidemia, with a reasonable expectation of success in

reducing the severity of the disease. (Newton Dec. ¶¶ 145, 146).

9 If available as a reference, the Picard ’419 patent (discussed below) teaches that

compounds with a quinoline ring scaffold are “potent inhibitors of the enzyme 3-

hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are

useful as hypocholesterolemic and hypolipidemic agents.” (Picard ’419 patent at

Abstract) (EX1021).


50

* * *

The prior art discussed above precedes JP 62-207224 (Aug. 20, 1987).

However, as discussed above, for the reasons discussed above, the Patent Owner

should not be entitled to this early of a priority date. Should the Board find that

indeed JP 62-207224 does not support a claim to priority for the subject matter of

Claims 1 and 2 of the ’336 patent, but that the appropriate priority date is that of JP

63-15585, filed January 26, 1988, then each of the claims is obviated based on

additional prior art.

5. Fluvastatin Would Have Been Selected as the LeadCompound for at Least the Following Additional Reasons

In addition to the disclosures discussed above, Sandoz provided additional

disclosures concerning the sodium salt of fluvastatin, which would have motivated

a POSA to select fluvastatin as the lead compound for further modification. For

example, Sandoz disclosed in the Engstrom Abstract (EX1011) that:

Since the results of Lipid Research Clinic’s Coronary

Primary Prevention Trial with Cholestyramine, there has

been heightened interest in the development of safe and

effective hypolipoproteinemic agents. Efforts at Sandoz

Research Institute in the design and synthesis of Novel

HMG-CoA reductase inhibitors have led to SRI-62320:

[R*, S*-(E)]-(±)-Sodium-3,5- dihydroxy-7-[3-(4-

fluorophenyl)-1(1-methylethyl)-1H-indol-2-yl]- hept-6-

enoate, which shows marked effects in lowering several


51

lipid parameters in rats, dogs and monkeys. The

hypolipoproteinemic properties of SRI-62320, in

comparison to compactin, will be the subject of this

presentation.

(See also Newton Dec. ¶ 147). Scientists in other research groups took notice of

Sandoz’s disclosure of its lead compound fluvastatin before the filing of JP 63-

15585. Tobert identified the sodium salt of fluvastatin (also referred to as SRI-

62320) as one of only five compounds “that have been studied in the clinic”:

(Tobert at 534-35; Newton Dec. ¶ 148).

Among those compounds identified by Tobert, only fluvastatin had the

pharmacophore of a 4-fluorophenyl group and an alkyl group flanking the side

chain taught by the art to have optimal activity. It is particularly noteworthy that

the Kathawala ’073 patent disclosed that fluvastatin was significantly more potent

by an order of magnitude of more than mevinolin and compactin, two of the other


52

four compounds reported by Tobert to be in clinical trials to date. Additionally,

Lee (EX1013), citing the Engstrom Abstract, noted that fluvastatin “appears to be

particularly interesting.” (Newton Dec. ¶¶ 149, 150; Lee at 444).

Therefore, it was known in the prior art that fluvastatin: (1) possessed

potent in vitro and in vivo activity; (2) produced marked effects across a variety of

animal models; (3) was one of only five HMG-CoA reductase inhibitors in clinical

trials; (4) outperformed two of the other four HMG-CoA reductase inhibitors in

clinical trials by at least one order of magnitude in an in vivo screen; (5) was the

only compound that had progressed to clinical trials that had the pharmacophore

having optimal activity; and (6) was considered by researchers outside of Sandoz

to be “particularly interesting.” Thus, fluvastatin’s unique properties would have

made it a natural choice as a lead compound. See Pfizer, 480 F.3d at 1363 (noting

that the prior art provided ample reason to narrow the relevant genus to a few

species, rending the claimed compound obvious); Bristol-Myers Squibb, 752 F.3d

at 973. Therefore, the POSA would have found it obvious to select fluvastatin as a

lead compound for further structural modifications for these additional reasons.

(Newton Dec. ¶¶ 151, 152.)

a) It Would Have Been Obvious to Modify Fluvastatin’sRing System to a Quinoline for at Least the FollowingAdditional Reasons


53

In addition, the Picard ’419 patent, filed Dec. 7, 1987 (102(e) prior art),

confirms that the modification to the quinoline ring structure was in fact done

before January 26, 1988. (Newton Dec. ¶ 153). The Picard ’419 patent discloses

compounds, similar to fluvastatin, but with a quinoline ring structure as discussed

above. In fact, in the case where R1 is a cyclopropyl group at the 2 position, and

R2 is a 4-fluoro phenyl group at the 4 position, R3-R6 are hydrogen groups, and X

is CH=CH, and the compound is the “pharmaceutically acceptable salt” calcium,

the genus of the Picard ’419 patent actually includes pitavastatin calcium. (See,

e.g., Picard ’419 patent at col. 2, l. 9 - col. 3, l. 1; id. at col. 9, ll. 61-68; Newton

Dec. ¶ 154). Further, Example 8 from the Kathawala ’073 patent (i.e., fluvastatin),

discussed at length above, is shown on the left next to the open chain derivative of

Example 3 from the Picard ’419 patent (col. 17) on the right to reveal the

similarities in structure:

.


54

The 4-fluorphenyl group substituent is discussed at length above, and tellingly,

every example disclosed in the Picard ’419 patent has a 4-fluorophenyl at the 4

position. (Newton Dec. ¶¶ 155, 156).

As a POSA would have expected, in the Picard ’419 patent, there are no

examples where a substituent is located on the nitrogen atom of the quinoline ring.

(See, e.g., Picard ’419 patent at cols. 13-17). Thus, the Picard ’419 patent confirms

what a POSA would have already expected, in a quinoline structure, the isopropyl

group should be moved off of the nitrogen ring to avoid giving the nitrogen atom a

positive charge. In addition, as expected, the Picard ’419 patent examples confirm

that a POSA would have maintained the pharmacophore of an alkyl such as

isopropyl and a 4-fluorophenyl group flanking a lactone ring or an open side chain

hept-6-enoate group. (Newton Dec. ¶ 157).

Furthermore, the Picard ’419 patent confirms that the compounds disclosed

therein are “potent inhibitors of . . . (HMG-CoA reductase) and are useful as

hypocholesterolemic and hypolipidemic agents.” (Picard ’419 patent at Abstract).

The Picard ’419 patent provides biological data in columns 11 and 12, showing

that compounds with the quinoline structure, and in particular the compound with

an isopropyl group at the 2 position, have potent HMG-CoA reductase inhibitory

activity. These data confirm that quinoline scaffolding can provide potent

biological activity and the addition of a single carbon in the core ring system


55

would be seen by a POSA as a promising modification of the ring system of

fluvastatin. See Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed.

Cir. 2008). Thus, in addition to the reasons discussed above, it would have been

obvious in light of the Picard ’419 patent to replace the ring of fluvastatin with its

corresponding quinoline analog. (Newton Dec. ¶¶ 158, 159).

b) It Would Have Been Obvious to Modify the Isopropylat the Second Position of the Quinoline Ring for atLeast the Following Additional Reasons

In addition to the reasons discussed above for replacing the isopropyl group

with a cyclopropyl group, the Picard ’419 patent expressly teaches substitution of

both isopropyl and cyclopropyl groups at the 2 position of the quinoline ring

structure. The substituents disclosed in the Picard ’419 patent for R1 and R2

(which correspond to the substituents flanking the side chain) include an “alkyl of

from one to six carbons; trifluoromethyl; cyclopropyl; cyclohexyl

cyclohexylmethyl” along with phenyl substituted groups such as 4-fluorophenyl.

(Picard ’419 patent at col. 2, ll. 30-32). Among the substituents listed in the genus

at the “R2” position in the claims, which are substituted at the 2 position on the

quinoline ring structure, cyclopropyl is identified. (See, e.g., id. at col. 2, l. 9-col.

3, l. 1; id. at col. 18, l. 24; Newton Dec. ¶¶ 160, 161). As the Patent Owner itself

explained:

Having been taught that isopropyl is an acceptable

substituent . . . , those of skill in the art would readily


56

arrive at the selection of cyclopropyl, out of the

disclosure of cycloalkyl of 3-7 carbon atoms, as the next

logical, and analogous compound, isomerically related to

exemplified species.

(Paper No. 32 at 5) (emphasis added). Therefore, from the additional disclosure of

the Picard ’419 patent, which, again, expressly discloses cyclopropyl groups, the

POSA “[h]aving been taught that isopropyl is an acceptable substituent,” would

“readily arrive at the selection of cyclopropyl . . . as the next logical, and analogous

compound.” Id.

Accordingly, in view of at least the additional prior art to JP 63-15585, a

POSA would have been motivated to substitute a cyclopropyl group for an

isopropyl group with a reasonable expectation that the resulting compound would

retain, or even improve upon, HMG-CoA reductase inhibitory activity of

fluvastatin. See Pfizer, 480 F.3d at 1367; (Newton Dec. ¶ 163).

c) It Would Have Been Obvious to Prepare Salts,Including Calcium Salts for at Least the FollowingAdditional Reasons

The Picard ’419 patent discloses salts as all of the examples of synthesized

open chain compounds disclosed therein are salts. (Picard ’419 patent at col. 17).

The Picard ’419 patent states “‘pharmaceutically acceptable metal cation’

contemplates positively charged metal ions derived from sodium, potassium,

calcium, magnesium, aluminum, iron, zinc and the like.” (Id. at col. 9, ll. 65-68


57

(emphasis added)). Therefore, in view of the prior art and his/her knowledge, a

POSA would have been motivated to try preparing a calcium salt of the quinoline,

2-cyclopropyl derivative of fluvastatin—or pitavastatin itself—since pitavastatin is

described within the genus disclosed in the Picard ’419 patent, and would also

have had a reasonable expectation of success. (Newton Dec. ¶¶ 164-166).

6. Any Secondary Considerations Fail to Overcome theShowing of Obviousness

While the Board should consider secondary considerations of

nonobviousness, such indicia do not necessarily control the obviousness

conclusion. Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768 (Fed. Cir.

1988). In fact, a strong case of obviousness, as shown here, cannot be overcome

by objective evidence of non-obviousness. Pfizer, Inc. v. Apotex, Inc., 480 F.3d

1348, 1372 (Fed. Cir. 2008). To the extent the Patent Owner asserts any secondary

considerations of nonobviousness in this proceeding, detailed consideration of the

Patent Owner’s evidence should not be undertaken until Petitioner has had an

opportunity to respond. Amneal Pharm., LLC v. Supernus Pharm., Inc., IPR2013-

00368 [Paper 8, pp. 12-13].

The Patent Owner did, however, allege during the prosecution of the ’336

patent that the compounds of the invention, which contain a cyclopropyl

substituent, had unexpected potency over their isopropyl analogs, showing an

approximately three fold increase in activity in cell culture, with no data in vivo.


58

(Kitahara Dec., EX1032, dated May 25, 1992). However, this difference was

within the range a POSA would have expected when replacing isopropyl with its

close analog cyclopropyl. (Newton Dec. ¶167). Further, a POSA would not have

concluded that this difference in in vitro potency would be clinically significant.

(Id. ¶ 167). Suh demonstrated that an analog having a cyclopropyl group retained

its enzyme inhibition activity. In fact, the cyclopropyl compound was more potent

than the isopropyl analog. (Suh at 60, Table I). Therefore, based on the prior art at

the relevant time, a POSA would have expected that the substitution of a

cyclopropyl substituent for an isopropyl substituent could have resulted in a

compound that exhibits more potent in vitro HMG-CoA reductase inhibitory

activity, as shown in the Kitahara Declaration. (Newton Dec. ¶ 167).

C. Ground 2: Claims 1 and 2 of the ’336 Patent are UnpatentableUnder 35 U.S.C. § 102 in View of the Picard ’419 Patent

A patent claim is said to be anticipated if comparison of the claim with a

prior art reference reveals that every element of the claim is described, either

expressly or inherently, in the prior art reference. See, e.g., Schering Corp. v.

Geneva Pharm., Inc., 339 F.3d 1373, 1377 (Fed. Cir. 2003).

As discussed above, the genus disclosed in the Picard ’419 patent clearly

includes pitavastatin calcium. (See, e.g., Picard ’419 patent (EX1021) at col. 2, l.

9-col. 3, l. 1; id. at col. 9, ll. 61-68; Newton Dec. ¶ 168). The Picard ’419 patent

further provides a small sub genus of just six listed compounds as “particularly


59

preferred.” One of these six compounds is the quinoline analog of fluvastatin. The

sodium salt of this compound is also one of just five synthesis examples presented.

(Picard ’419 patent at col. 4, ll. 57-58; id. at col. 17, ll. 47-66 (Example 3)). As

further discussed above, the Picard ’419 patent teaches that isopropyl and

cyclopropyl are interchangeable and that sodium and calcium salts are

interchangeable.10 As also discussed above, a POSA was well aware that

cyclopropyl and isopropyl were interchangeable bioisosteres; and that calcium and

sodium are among the top three FDA-approved cation salts and were routinely

used. (Newton Dec. ¶¶ 168-170).

Thus, the calcium salt of the cyclopropyl analog of the “particularly

preferred” compound – the quinoline analog of fluvastatin – anticipates claim 1 of

the ’336 patent. “Anticipation does not require the actual creation or reduction to

practice of the prior art subject matter; anticipation requires only an enabling

disclosure.” Schering v. Geneva, 339 F.3d at 1380 (Fed. Cir. 2003) (citing In re

Donohue, 766 F.2d 531, 533 (Fed. Cir.1985)); Abbvie Inc. v. Mathilda & Terence

Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1379 (Fed. Cir. 2014).

10 Two position substituents on the quinoline ring include “cyclopropyl,”

“pharmaceutically acceptable metal cation[s]” include “calcium.” (Picard ’419

patent at col. 2, ll. 30-32; id. at col 9, ll. 65-68).


60

Further, the Picard ’419 teaches the remaining limitations of dependent

Claim 2 (e.g., method for reducing hyperlipidemia, hyperlipoproteinemia or

atherosclerosis and administering an effective amount). (Picard ’419 patent at

Abstract (“potent inhibitors of . . . (HMG-CoA reductase) and are useful as

hypocholesterolemic and hypolipidemic agents”); id. at col. 20, ll. 52-56 (claim 15)

(disclosing administration); id. at col. 3, ll. 58-62 (“administering”); id. at col. 3, ll.

51-57 (disclosing “[e]ffective amount of a compound”); id. at col. 12, ll. 52-58)

(disclosing effective dosage ranges for compounds “[i]n therapeutic use as

hypolipidemic or hypocholesterolemic agents”); see also (Newton Decl. ¶¶ 171-

173). Thus, the Picard ’419 patent also anticipates the ’336 patent.

VIII. CONCLUSION

Petitioner has demonstrated by a preponderance of the evidence that Claims

1 and 2 of the ’336 patent are unpatentable under 35 U.S.C. § 103 and under 35

U.S.C. § 102 and respectfully requests that the Board so finds.

RESPECTFULLY SUBMITTED,

ALSTON & BIRD LLP

Date: 18th April, 2015 /s/Jitendra Malik /

Lead Counsel for PetitionerMylan Pharmaceuticals Inc.

LEGAL02/35454033v1

CERTIFICATION OF SERVICE ON PATENT OWNER

Pursuant to 37 C.F.R. §§ 42.6(e), 42.8(b)(4) and 42.105, the

undersigned certifies that on the 18th day of April 2015, a complete copy of

the foregoing Petitioner’s Petition for Inter Partes Review of U.S. Patent

No. 5,856,336, Power of Attorney, and all supporting exhibits were served

via United States Postal Service to the Patent Owner, including by serving

the correspondence address of record for the ’336 patent:

David G. Conlin ([email protected])Kathleen B. Carr ([email protected])Adam P. Samansky ([email protected])MINTZ LEVIN COHN FERRIS GLOVSKY AND POPEO, P.C.One Financial CenterBoston, Massachusetts 02111(617) 542-6000 (telephone)

and

Arthur I. NeustadtOblon, Spivak, McClelland, Maier & Neustadt, P.C.1940 Duke StreetAlexandria, Virginia 22314

Respectfully submitted,

ALSTON & BIRD LLP

By: /Jitendra Malik/

Jitendra MalikReg. No. 558234721 Emperor Blvd., Suite 400Durham, North Carolina 27703Telephone: 919-862-2200


2LEGAL02/35454033v1

Fax: [email protected]

Deanne M. MazzochiReg. No. 50158RAKOCZY MOLINO MAZZOCHI

SIWIK LLP6 West Hubbard St., Suite 500Chicago, Illinois 60654312-222-6305

Attorneys for MylanPharmaceuticals Inc.

Petition for Inter Partes Review of USPN...

Documents

Transcript of Petition for Inter Partes Review of USPN...