Kyle Bass IPR against Bristol-Myers

Paper No. 1

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

COALITION FOR AFFORDABLE DRUGS IX LLC,

Petitioner

v.

BRISTOL-MYERS SQUIBB PHARMA COMPANY

Patent Owner

IPR2015-___________

Title: LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR XA

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,967,208

[Type text] [Type text] [Type text]

ii

TABLE OF CONTENTS TABLE OF AUTHORITIES ................................................................................... iv LIST OF EXHIBITS ................................................................................................. v

I. Introduction ................................................................................................... 1 II. Grounds for Standing .................................................................................... 1 III. Mandatory Notices ....................................................................................... 1

A. Real Party-In-Interest ............................................................................. 1 B. Related Matters ...................................................................................... 2 C. Lead and Back-Up Counsel, and Service Information ........................... 3

IV. Payment of Fees ........................................................................................... 3 V. Identification of Challenge ........................................................................... 3

A. Overview of the ’208 Patent ................................................................... 3 The ’208 Specification ..................................................................... 3 1. The ’208 Claims ............................................................................... 5 2. The ‘208 Prosecution History ........................................................ 10 3. The Certificate of Correction ......................................................... 12 4.

B. Claim Construction of Challenged Claims ........................................... 13 1. “1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-

piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide” ............................................................ 14

2. “Pharmaceutically acceptable salt” ................................................ 14 3. Claims for Which Review Is Requested ........................................ 15 4. Statutory Grounds of Challenge ..................................................... 15

C. Overview of the Cited Art .................................................................... 15 1. PCT Publication No. WO 00/39131 (Ex. 1003) .............................. 16 2. U. S. Patent 6,413,980 (Ex. 1004) ................................................. 17

D. Level of Skill in the Art ........................................................................ 19 VI. Detailed Explanation of the Challenge ...................................................... 20


iii

A. Ground 1: PCT Published Application WO 00/39131 to Fevig et al. (“Fevig I”) (Ex. 1003) anticipates claims 1-13, 20-27, and 34-61 of US 6,967,208 under 35 U.S.C. § 102(b). ............................... 20 1. Anticipation of Claim 13 by Fevig I. ............................................. 22 2. Anticipation of Claim 8 by Fevig I. ............................................... 27 3. Anticipation of Claim 1 by Fevig I. ............................................... 28 4. Anticipation of Claim 2 by Fevig I. ............................................... 34 5. Anticipation of Claim 3 by Fevig I. ............................................... 35 6. Anticipation of Claim 4 by Fevig I. ............................................... 35 7. Anticipation of Claim 5 by Fevig I. ............................................... 36 8. Anticipation of claim 6 by Fevig I. ................................................ 36 9. Anticipation of Claim 7 by Fevig I. ............................................... 37 10. Anticipation of claims 9-12, 20-27, and 34-61 by Fevig I. ........... 38

B. Ground 2: U.S. Patent 6,413,980 to Fevig et. al (“Fevig II”) (Ex. 1004) anticipates claims 1-13, 20-27, and 34-61 of U.S. 6,967,208 under 35 U.S.C. § 102(e). .................................................... 38 1. Anticipation of Claim 13 by Fevig II. ............................................. 39 2. Anticipation of Claim 8 Fevig II. .................................................... 43 3. Anticipation of Claim 1-7 Fevig II. ................................................. 44 4. Anticipation of claims 9-12, 20-27 and 34-61. ............................... 51

C. Grounds 3 and 4: Fevig I and Fevig II, each in its own right, renders the challenged claims of the ‘208 Patent obvious under 35 U.S.C. 103(a). .................................................................................. 54

D. Secondary Considerations of Non-Obviousness Do Not Rebut the Prima Facie Case of Obviousness .................................................. 58

VII. Conclusion .............................................................................................. 60 CERTIFICATE OF SERVICE ................................................................................ 61


iv

TABLE OF AUTHORITIES Cases App. of Susi

440 F.2d 442; 169 U.S.P.Q. 423 (CCPA, 1971) ......................................... 21, 57 Application of Ruff

256 F.2d 590 (CCPA 1958) ............................................................ 21, 27, 34, 44 Atlas Powder Co. v. Ireco, Inc.

190 F.3d 1342, 51 U.S.P.Q.2d (BNA) 1943 (Fed. Cir. 1999) ........ 21, 27, 34, 44 Calloway Golf Company v. Acushnet Company

576 F.3d 1331 (Fed. Cir. 2009) ........................................................................... 6 In re Swanson

540 F.3d 1368 (Fed. Cir. 2008) ........................................................................ 19 Merck v Biocraft Labs.

874 F2d 804; 10 U.S.P.Q. 2d 1843 (Fed. Cir. 1989) ........................................ 57 Ruiz v. A.B. Chance Co.

234 F.3d 654 (Fed. Cir. 2000) ........................................................................... 59 Upsher-Smith Labs., Inc. v. Pamlab, L.L.C. 412 F.3d 1319 (Fed. Cir. 2005) ......... 30 Verdegaal Bros. v. Union Oil Co. of California

814 F.2d 628 (Fed. Cir. 1987) ........................................................................... 20 Statutes 35 U.S.C. 102(e)(2) ................................................................................................ 18 35 U.S.C. 303(a) ..................................................................................................... 19 Regulations 37 C.F.R. § 42.100(b) ............................................................................................. 14


v

LIST OF EXHIBITS

Exhibit 1001 U.S. 6,967,208 to Pinto et. al, titled, “Lactam Containing Compounds and Derivatives Thereof as Factor Xa Inhibitors,” filed on September 17, 2002, and issued on November 22, 2005 (“the ’208 Patent”).

Exhibit 1002 Excerpts from the File History of U.S. Patent No. 6,967,208. Exhibit 1003 Published PCT Application WO 00/39131 titled Nitrogen

Containing Heterobicycles as Factor Xa Inhibitors, published on July 6, 2000 (“Fevig I”).

Exhibit 1004 U.S. Patent 6,413,980 to Fevig et. al, titled Nitrogen Containing Heterobicycles as Factor Xa Inhibitors, filed on December 22, 1999. (“Fevig II”)

Exhibit 1005 Excerpts from the File History of U.S. Patent 6,413,980

Exhibit 1006 Published PCT Application WO 95/01980 titled Bicyclic Tetrahydro Pyrazolopyridines, filed July 3, 1993. (Duplantier)

Exhibit 1007 Reserved

Exhibit 1008 Expert Declaration of George Burton Exhibit 1009 Prescribing Information– Eliquis FDA Label


1

I. Introduction

Petitioner Coalition For Affordable Drugs IX LLC (“CFAD”), requests an

Inter Partes Review (“IPR”) of Claims 1-13, 20-27, and 34-61 (collectively, the

“Challenged Claims”) of U.S. Patent No. 6,967,208 (the “’208 Patent”) (Ex. 1001)

in accordance with 35 U.S.C.§§ 311–19 and 37 C.F.R. §§ 42.100 et seq.

II. Grounds for Standing

Petitioner certifies that the ’208 Patent is available for IPR and that the

Petitioner is not barred or estopped from requesting IPR challenging the claims of

the ’208 Patent on the grounds identified in this petition.

III. Mandatory Notices

A. Real Party-In-Interest

Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Coalition For

Affordable Drugs IX LLC (“CFAD IX ”), Hayman Credes Master Fund, L.P.

(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman Capital

Master Fund, L.P. (“HCMF”), Hayman Capital Management, L.P. (“HCM”),

Hayman Offshore Management, Inc. (“HOM”), Hayman Investments, L.L.C.

(“HI”), nXn Partners, LLC (“nXnP”), IP Navigation Group, LLC (“IPNav”), J.

Kyle Bass, and Erich Spangenberg are the real parties in interest (collectively,

“RPI”). The RPI hereby certify the following information: CFAD IX is a wholly

owned subsidiary of Credes. Credes is a limited partnership. HOF is a segregated


2

portfolio company. HCMF is a limited partnership. HCM is the general partner and

investment manager of Credes and HCMF. HCM is the investment manager of

HOF. HOM is the administrative general partner of Credes and HCMF. HI is the

general partner of HCM. J. Kyle Bass is the sole member of HI and sole

shareholder of HOM. CFAD IX, Credes, HOF and HCMF act, directly or

indirectly, through HCM as the general partner and/or investment manager of

Credes, HOF and HCMF. nXnP is a paid consultant to HCM. Erich Spangenberg is

the Manager and majority member of nXnP. IPNav is a paid consultant to nXnP.

Erich Spangenberg is the Manager and majority member of IPNav. Other than

HCM and J. Kyle Bass in his capacity as the Chief Investment Officer of HCM and

nXnP and Erich Spangenberg in his capacity as the Manager/CEO of nXnP, no

other person (including any investor, limited partner, or member or any other

person in any of CFAD IX, Credes, HOF, HCMF, HCM, HOM, HI, nXnP or

IPNav) has authority to direct or control (i) the timing of, filing of, content of, or

any decisions or other activities relating to this Petition or (ii) any timing, future

filings, content of, or any decisions or other activities relating to the future

proceedings related to this Petition. All of the costs associated with this Petition

will be borne by HCM, CFAD IX, Credes, HOF and/or HCMF.

B. Related Matters

The Petitioner has found no record of the ’208 Patent having been


3

involved in any related matters in any United States District Court or in the U.S.

Patent and Trademark Office.

C. Lead and Back-Up Counsel, and Service Information

Lead counsel is Thomas C. Wright, Reg. No. 47189, of CUNNINGHAM

SWAIM LLP, 7557 Rambler Road, Suite 440, Dallas, TX 75231, P:

469.729.7010/F: 214.613.1163 [email protected]. Back-up counsel

is Lekha Gopalakrishnan, Reg. No. 46,733, of Winstead P.C., 500 Winstead Bldg.,

2728 Harwood Street, Dallas, TX 75201, P: 214.745.5356/F: 214.745.5390

[email protected]. Petitioner consents to electronic service.

IV. Payment of Fees

The required fees are submitted herewith in accordance with 37 C.F.R. §§

42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the

Office is authorized to charge such fees to Deposit Account No. 506787.

V. Identification of Challenge

A. Overview of the ’208 Patent

The ’208 Specification 1.

The ’208 Patent was filed on September 17, 2002 and claims benefit of

provisional applications Nos. 60/324,165 and 60/402,317, for which the earliest

filing date is September 21, 2001. (Ex. 1001 Front Cover.)

The ‘208 Patent is titled “Lactam Containing Compounds and Derivatives


4

thereof as Factor Xa Inhibitors,” and it describes and claims compositions “which

are inhibitors of trypsin-like serine protease enzymes, especially factor Xa,

pharmaceutical compositions containing the same and methods of using the same

as anticoagulant agents for treatment of thromboembolic disorders.” Id. at 1: 21-

25. The ‘208 specification acknowledges that Factor Xa inhibitors containing

moieties closely related to those claimed in the ‘208 were known in the art at the

time of filing. Id. at 1:27-5:22. Thus the only alleged improvement of the ‘208

Patent is the preparation and use of “efficacious and specific inhibitors of factor

Xa.” Ex. 1008 at 24. But while the patent does describe the synthesis of

numerous alleged factor Xa inhibitors, there is not a single working example

showing administration of any of the disclosed compounds to a patient, or any in

vitro or in vivo testing to prove efficacy, pharmacokinectics, and the like. Id.

Thus there is no disclosure that any of the compounds described in the ‘208 Patent

is an actual Xa inhibitor, much less an “efficacious” one. Id.

The ‘208 Patent is an extreme example of the abuse of the use of Markush

groups in claims drafting. The ‘208, with its sprawling and outlandish claims,

teaches absolutely nothing with specificity with respect to any particular

compound. Therefore any and all possibilities for any and all structures are as

equally likely to be chosen by a person of ordinary skill, as not, from the starting

Markush group in the single, independent claim 1 since nothing is claimed with


5

any specificity or with any certainty.

Further, since there is no pharmacological data presented in the

specification, there is no information that establishes the inhibiting properties of

any of the enormous number of claimed compounds, or whether any of them are

more effective inhibitors than any of the others. In other words, there are no

distinguishing characteristics that would lead one of ordinary skill in the art to

choose any particular combination of moiety/moieties to form any one of the

specific compound(s) as claimed for any reason. Rather a person of ordinary skill

would recognize all of the disclosed compounds as reasonable candidates for the

stated purpose of being Factor Xa inhibitors absent further guidance and

disclosure. Id.

The ’208 Claims 2.

The claims at issue here can be summarized as a typical funnel that begins

with an enormous number of alternatives in the only independent claim (claim

1) of 103 claims, composed of Markush group alternatives for different sub-

units of the overall molecular structure that is claimed. As with any claim-

funnel, the scope of the independent claim is further limited through a chain of

dependent claims. In this case, the total number of claimed variations or

alternatives is decreased until a single molecular formula is claimed, inter alia,

in claim 13. The reduction in claim scope is accomplished not through the


6

addition of new claim elements, but through the successive reduction in the

number of alternative formulations possible under each dependent claim. Id. at

26.

Claim 13 depends, ultimately from claim 1. Due to the chain of claim

dependency (i.e., claim 13 depends from claim 8 and claim 8 depends from

claim 1) the patent owner cannot deny that the single compound of claim 13 is

claimed in each of the earlier claims in that chain since a dependent claim must

contain all of the elements of any claim from which it depends. Id. at 27. MPEP

608.01(i)(c) (“Claims in dependent form shall be construed to include all the

limitations of the claim incorporated by reference into the dependent claim”).

The claims at issue here do nothing more than progressively restrict the

large number of alternative compounds claimed in claim 1 until they are reduced

to a few (claims 2-8) or a single molecule (e.g. claim 13). Ex. 1008 at 28.

Further, if claim 13 is determined to have been taught in the prior art, no

antecedent claims can be found nonobvious. Calloway Golf Company v.

Acushnet Company, 576 F.3d 1331, 1344 (Fed. Cir. 2009) (“A broader

independent claim cannot be nonobvious where a dependent claim stemming

from that independent claim is invalid for obviousness”).

What follows is a general description of the claims that are at issue in this

IPR petition:


7

Claim 1, the only independent claim in the ‘208 Patent, recites a generic

claim for a compound of the formula:

wherein P4 is further defined as -G1-G and M4 is –A-B1 . Ex. 1001 237: 3-10 and

1 When the “P” and “M” rings defined in the amendment are fused via the

dangling bonds of the individual rings (represented by the zig-zagging lines,

above in “P and “M” separately), the result is a fused two-ring system of

Structure 1, below.

Structure 1

Where P4 is replaced by “G1-G” as defined in claim 1 of the ‘208 Patent. “M4”

was further defined in the Certificate of Correction for claim 1 to be the “A-B” unit

which results in the structure of the ring system being:


8

Cert. of Cor. pg 2 correcting line 34. The components of this generic formula are

set forth as a massive listing of nested chemical moieties in the form of multiple

Markush groups that take up over five columns of the patent consisting of

inestimable combinations. The claim concludes with “or a pharmaceutically

acceptable salt thereof.” Ex. 1001 at 237:1-242:23 and Cert. of Cor. pg 1-2

correcting multiple entries in all of columns 237-242; Ex. 1008 at 30.

Claim 2 depends from claim 1 and recites a subset of the enormous range

of compounds in claim 1 by listing alternatives for a subunit (labeled G) of the

P4 moiety and a subunit (labeled A) of the M4 moiety of the formula provided

above. Id. at 242:24-245:29 and Cert. of Cor. pg 2-3 correcting columns 243

and 244. Even this “narrowing” would results in, still, millions of potential

combinations. Ex. 1008 at 31.

Claim 3 depends from claim 2 and defines a list of 168 alternatives for

moiety G in the form of structural formulae. In the addition it provides that “G1

is absent or selected from” a list of generic formulae, each with multiple

variations and further limits moiety “A”. Ex. 1001 at 245:30-254:41 and Cert.

Structure 2

Structure 2 appears in the ‘208 Patent at 134:60 (where R1a = H). Ex. 1008 at 45


9

of Corr. pg 3-5 correcting columns 246, 248, 249, 251-254; Ex. 1008 at 32.

Claim 4 depends from claim 3 and narrates 96 alternative structural

variations for the “G” moiety, a subset of the 168 in claim 3. Claim 4 also

includes the alternative that “G1” is absent or chosen form another list of

alternatives that themselves include variations chosen from one or more of 12

groups of additional variables. Id. at 254:42-259:67 and Cert. of Corr. pg 5-6

correcting columns 255, 256, 258 and 259; Ex. 1008 at 33.

Claim 5 depends from claim 4, and continuing with the theme of claims 3

and 4, recites 58 alternatives for the “G” moiety as structural formulae (a subset

of the 96 listed in claim 4) and number of additional alternatives including the

“A” and “B” moieties. Id. at 260:1 -263:44 and Cert. of Corr. pg 6-7 correcting

columns 261-263; Ex. 1008 at 34.

Claim 6 depends from claim 5, and, again recites a vast subset of

structural alternatives in which G1 is absent with 27 alternatives for moiety G

and two alternatives for –A-B. Id. at 263:45-265:28 and Cert. of Corr. pg 7

correcting col 265 lines 20-25; Ex. 1008 at 35.

Claim 7 depends from claim 6 and defines a single alternative for the

moiety labeled “-A-B.” The “-A-B” structural unit is included in all of the

claims that are at issue in this IPR, but is never shown in any of the structural

diagrams or demonstrated in the specifications with particularity. It is merely


10

defined in the claims. Id. at 265:29-39 and Cert. of Cor. pg 7 correcting line 35

by deleting the second structure; Ex. 1008 at 36.

Claim 8 depends from claim 1, and claims “a compound according to

claim 1 wherein the compound is selected from” a group of 65 specific

compounds “or a pharmaceutically acceptable salt form thereof” admitted to

being covered by the generic formula of claim 1. Ex. 1001 at 265:39-268:41 and

see also Cert. of Corr pg 7 correcting col 655 line 66 from “…pyrazole-…” to

“…pyrazolo-…” as well as other numerous corrections; Ex. 1008 at 37.

Claim 13 depends from claim 8, and recites a single compound, 1-(4-

methoxyphenyl)-7-oxo-6-4[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-

1Hpyrazolo-[3,4-c]pyridine-3-carboxamide or a pharmaceutically acceptable

salt form thereof, which is the ninth compound of the 65 compounds listed in

claim 8. Id. at 269:1-6 and see also Cert. of Corr. page 10 correcting col 269

line 4 from “…pyrazole-…” to “…pyrazolo-…” as well as other corrections;

Ex. 1008 at 38.

Claims 9-12, 20-27, and 34-61 all depend from one of the above-

described claims and add nothing of patentable distinction, but rather simply

recite, for example, a specific condition for which the compounds claimed in the

claims above may be administered Ex. 1001 passim; Ex. 1008 at 39.

The ‘208 Prosecution History 3.


11

The application that led to the ‘208 Patent was filed on September 17,

2002 and contained 30 claims. A restriction requirement was issued on

September 29, 2003. In issuing the restriction requirement the examiner stated

that all 30 claims were generic and that an election of a single species for

examination was required. In response the applicant elected 2(1-(4-

methoxyphenyl)-3-[(methylamino)methyl]-6-[-4-(2-oxo-1-piperdinyl)phenyl]-

1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one.

The first, and only, substantive office action on the merits was issued on

October 23, 2003. In the action claims 1-21 were rejected and claims 22-30

were withdrawn for being drawn to non-elected subject matter. The rejected

claims were characterized as constituting an improper Markush group. The

variables “P” and “M” that made up the two core rings of the generic formula

were originally submitted as follows:

P4-P-M-M4

The examiner then requested changes “in the core of the compound that

determines classification” for the purposes of examination. Ex. 1002 at 4.

A response was filed on November 19, 2003 that cancelled claims 9-15

and 2-30 that left claims 1-8 and 16-19 pending. Claims 31-121 were then

added. Claim 1 was amended such that the generic formula above was replaced

with the formula illustrated here


12

with rings P and M defined as two specific systems:

“P” “M”

Ex. 1002 at 7-8

The amendment of claim 1 resulted in the issuance of a Notice of Allowance

on March 11, 2004. No reason for allowance was given. An Amendment and

Request for Continued Examination was filed on September 16, 2004 and

September 22, 2004 that added claims 122-133. A second Notice of Allowance

was issued on October 13, 2004 for the amendments. Another RCE was filed

November 3, 2004 with a third Notice of Allowance issued December 8, 2004.

The Certificate of Correction 4.

Perhaps the most significant event in the prosecution of the ‘208 was the 13

page Certificate of Correction that was filed by the patent owner. The corrections

resulted in numerous changes to the claims Ex. 1001 Cert. of Corr. pg 1-13. In

addition to the above-mentioned definition of “M4” as “A-B,”(Cert. of Corr. pg 2)

the other changes specifically relevant to this IPR are correction of the spelling of


13

the name of the compound in claim 13, and the correction of that same compound

name in the list of those in claim 8 by replacing “pyrazole” with “pyrazolo”. Ex

1001, Cert. of Corr. at pg 7 and 10; Ex. 1008 at 46. It should be noted that while

this request for an IPR is limited to validity challenges for anticipation and

obviousness, the Certificate of Correction for the ‘208 Patent raises serious

questions about the validity of the ‘208 claims under 35 U.S.C. §112. The

“corrections” go well beyond fixing typographical errors and the like, as is

appropriate in a Certificate of Correction. MPEP 1481 (“the Director may…issue

a certificate of correction, if the correction does not involve such changes in the

patent as would constitute new matter or would require examination”) These

changes did indeed add new matter and substantive language to the claims that was

never considered by any examiner. Further, many of the corrections go to

renaming previously “examined” compounds. For example, the Certificate reads,

“’P4 is –G1-G;’ should read –M4 is –A-B; P4 is G1-G; “Ex1001 Cert. of Corr. at 2.

As set forth below, the “A-B” units added as a “correction” do appear in the Patent

Owner’s own prior art relied upon in this request. The corrections improperly

added new, unexamined, chemical structures into the patent without the benefit of

any prior art analysis. Id.

B. Claim Construction of Challenged Claims

A claim subject to IPR receives the “broadest reasonable construction in


14

light of the specification of the patent in which it appears.” 37 C.F.R. §

42.100(b). Unless otherwise noted below, Petitioner accepts, for purposes of

IPR only, that the claim terms of the ‘208 Patent are presumed to take on their

ordinary and customary meaning that they would have to one of ordinary skill

in the art.

1. “1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide”

The term 1-( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-1-

piperaziny l)pheny 1 ]-4,5,6, 7-tetrahydro-1H -pyrazolo

[3,4-c ]pyridine-3-carboxamide (Ex. 1001 Example 97 - col 208:51-55)

corresponds to the structure:

Structure 3

which is also known as apixaban or by the commercial brand of Eliquis. Ex. 1009 pg. 12 section 11 “Description” and Ex. 1008 at 51-52.

2. “Pharmaceutically acceptable salt”

The term “pharmaceutically acceptable salt” means: those compounds,

materials, compositions, and/or dosage forms which are, within the scope of

sound medical judgment, suitable for use in contact with the tissues of human

beings and animals without excessive toxicity irritation, allergic response, or

O

OO

N

H2N

O

NN

N


15

other problem or complication, commensurate with a reasonable benefit/risk

ratio” Ex. 1001 116:40-47, Ex.1008 at 53.

Statement of Precise Relief Requested for Each Claim Challenged

3. Claims for Which Review Is Requested

Petitioners request IPR under 35 U.S.C. § 311 of claims 1-13, 20-27 and

34-61 of the ‘208 Patent, and such cancellation of said claims as unpatentable.

4. Statutory Grounds of Challenge

Claims 1-13, 20-27, and 34-61 are unpatentable under 35 U.S.C. §§ 102

and/or 103 for the following reasons:

Ground Proposed Rejections for the ‘208 Patent Exhibit No. 1 Claims 1-13, 20-27, and 34-61 are anticipated

under 35 U.S.C. § 102(b) by the publication of PCT Application WO 00/39131A1 (Fevig I).

1003

2 Claims 1-13, 20-27, and 34-61 are anticipated under 35 U.S.C. 102(e) by United States Patent 6,413,980 (Fevig II)

1004

3 Claims 1-13, 20-27, and 34-61 3 are obvious under 35 U.S.C. § 103(a) in view of the publication of PCT application WO 00/39131A1 (Fevig I).

1003

4 Claims 1-13, 20-27, and 34-61 are obvious under 35 U.S.C. § 103(a) in view of United States Patent 6,413,980 (Fevig II)

1004

C. Overview of the Cited Art

The references relied upon to establish the invalidity of the ‘208 Patent are a

published PCT application belonging to the Patent Owner as well as the U.S.


16

version of that PCT application filed in the U.S. without claiming priority to the

PCT. Both the PCT application and the U.S. Patent claim priority to the same two

U.S. Provisional Applications, US 60/127,633 and US 60/113,628. The published

application is prior art under 35 USC 102(b) and the U.S. Patent is prior art under

35 USC 102(e)(2).

1. PCT Publication No. WO 00/39131 (Ex. 1003)

International Publication No. WO 00/39131 (here after “Fevig I”) entitled

“Nitrogen Containing Heterocycles of Factor Xa Inhibitors” was published on

July 6, 2000. It does not designate the United States and was filed before

November 29, 2000. Therefore, Fevig I is 102(b) prior art as of its publication

date. MPEP 2136.03 II(B). The publication date of the Fevig I application, July

6, 2000, is more than one year before September 21, 2001, the earliest priority

date of the ‘208 Patent. Ex 1001 Front Cover. Fevig I is over 300 pages long

and, like the ‘208 Patent, discloses an enormous number of compounds claimed to

be Factor Xa inhibitors. Ex. 1003 passim; Ex. 1008 at 55.

Fevig I is mentioned in the ‘208 Patent, and was submitted on an IDS

disclosing prior art document references during the prosecution of the application

leading to the ‘208 Patent but Fevig I was not substantively considered by the

Examiner during prosecution of the ‘208 Patent. Despite the fact that Fevig I was

disclosed to the examiner in an expansive dump of prior art during prosecution of


17

the ‘208 Patent, it is undeniable that the compound disclosed in claim 13 of the

‘208 Patent is also explicitly disclosed in Fevig I. The examiner, who was

undoubtedly under time constraints, would not have the time to appreciate the fact

that the claims of the ‘208 are covered by the disclosure of Fevig I given the

enormously complicated Markush structure of the both Fevig I and the ‘208

Patent.

Apparently acknowledging the substantial overlap between the disclosure

of Fevig I and the ‘208 Patent, the Patent Owner, in describing the scope of Fevig

I in the Background of the Invention section of the ‘208 Patent states

“[c]ompounds specifically described in WO 00/39131 are not considered to be

part of the present invention.” Ex. 1001 at 2:62 Regardless of what the Patent

Owner believes to be part of the ‘208 Patent’s inventions, the Patent Owner

cannot disclaim what its own prior art publication actually discloses. There is

nothing inventive about claiming compounds identical to those found in the prior

art.

2. U. S. Patent 6,413,980 (Ex. 1004)

U.S. Patent 6,413,980 (Ex. 1004, here after “Fevig II”) has the identical

specification as Fevig I. Ex. 1008 at 57. It was filed on December 22, 1999,

which was five days after the filing of the Fevig I application and almost two years

before September 21, 2001, the earliest potential priority date for the ‘208 Patent.


18

Pre-AIA 35 U.S.C. 102(e)(2) states in pertinent part that a reference is prior art to

an invention if:

the invention was described in a patent granted on an application for

patent by another filed in the United States before the invention by the

applicant for patent.

The inventive entity of the Fevig II is different from that of the ‘208,

therefore it qualifies as “by another” under the Patent Act. MPEP 2136.04(I) (“If

there is any difference in the inventive entity, the reference is ‘by another’”).

Fevig II and the ‘208 Patent have four inventors in common, Han, Lam, Pinto, and

Pruitt. Fevig II also lists as inventors Fevig, Cacciola, Clark, Pruitt, and Rossi,

who are not inventors on the ‘208 Patent. Conversely, the ‘208 Patent lists Orwat,

Li, Qiao and Koch as inventors who are not inventors on Fevig II. Ex 1001 and

1004 front pages. Thus, the ‘980 meets the requirements of prior art under 35 USC

102(e) by virtue of its filing date “by another.” It is worth noting that since there is

a time bar under 35 USC 102(b) by virtue of the Fevig I publication, Fevig II

cannot be overcome as prior art by establishing that it is the work of one of the

inventors of the ‘208. MPEP 2136.05(II) (stating that an inventor may overcome a

102(e) rejection based on his or her own work, “unless there is a time bar under

pre-AIA 35 USC 102(b)”).

Like Fevig I, Fevig II was disclosed to the examiner during prosecution, but


19

again, there is no evidence of substantive consideration of Fevig II by the examiner

and, as with Fevig I, the complexity of the claim structure of Fevig II does not

make it more likely that an examiner in the ordinary course of his or her duties

would have had the time to do a proper comparison of the complicated claims of

the ‘208 with the equally complicated structure of the Fevig II disclosure. Ex.

1008 at 59.

The examiner never rejected the ‘208 Patent over Fevig I or II, and there is

no evidence that either was actually considered. Similarly, Patent Owner never

made any statements regarding Fevig I or II that are of record and were relied upon

by the examiner. Accordingly, the appearance of Fevig I and II in the record of the

‘208 sheds no light on their applicability as prior art in this request for IPR. Id. As

noted by the Federal Circuit in the context of reexamination, 35 U.S.C. 303(a)

“mandates that ‘the existence of a substantial new question of patentability is not

precluded by the fact that a patent or printed publication was previously cited by or

to the Office or considered by the Office.’” In re Swanson, 540 F.3d 1368, 1379-

80 (Fed. Cir. 2008).

D. Level of Skill in the Art

The level of skill in the art is apparent from the cited art. Further, a person

having ordinary skill in the art would have either a Pharm. D. or a Ph.D. in organic

chemistry, pharmacy, pharmacology, or a related discipline; or a Bachelor’s or


20

Master’s degree in organic chemistry or a related field with at least four years of

experience relating to compounds that are or may be Factor Xa inhibitors. A person

of ordinary skill in the art would have collaborated with others having expertise in,

for example, methods of treating diseases and administering medicines. Ex. 1008 at

61.

VI. Detailed Explanation of the Challenge

A. Ground 1: PCT Published Application WO 00/39131 to Fevig et al. (“Fevig I”) (Ex. 1003) anticipates claims 1-13, 20-27, and 34-61 of US 6,967,208 under 35 U.S.C. § 102(b).

To anticipate a claim, a prior art reference must disclose every limitation of

the claimed invention, either explicitly or inherently. Verdegaal Bros. v. Union Oil

Co. of California, 814 F.2d 628, 631 (Fed. Cir. 1987). As set forth below, the

specific compound claimed in claim 13 of the ‘208 Patent, the same compound

claimed as an alternative in claim 8, and the same compound from a larger number

of alternatives in claims 1-7 was disclosed in Fevig I more than one year before the

earliest priority date of the ‘208 Patent, and therefore those claims of the ‘208 are

anticipated under 35 U.S.C. 102(b).

Claim 1 of the ‘208 Patent is extraordinarily long. It covers almost 6

columns of the patent. Additionally, significant changes were made to the claim in

a 13-page Certificate of Correction. Ex 1001. Large portions of the claim are

extended lists of molecular subunits written in Markush form, e.g. moieties


21

“selected from” the list. There are 34 such lists of subunits from which to “select

from” in claim 1 alone. Ex. 1008 at 63.

Rather than first attacking the tremendous breadth of claim 1 to demonstrate

that it and the other claims at issue in this request for IPR are anticipated

specifically by Fevig I, Petitioner will instead begin by showing that the single

compound of claim 13 in the ‘208 Patent is specifically disclosed in Fevig I. Once

this has been established Petitioner will proceed to show that that same compound

is specifically claimed in each of the other challenged claims. Demonstration of the

presence of this single compound in any of claims 1-8 is sufficient to invalidate

each of those claims since each is a Markush-style claim and anticipation of a single

member anticipates the entire group. Application of Ruff, 256 F.2d 590, 593

(CCPA 1958); Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1346, 51

U.S.P.Q.2d (BNA) 1943 (Fed. Cir. 1999) (“In chemical compounds, a single prior

art species within the patent’s claimed genus reads on the generic claim and

anticipates.”).

Additionally, as will be discussed below in more detail, the case law

supports the presented arguments for anticipation and obviousness based on a

broad prior art genus anticipating specific compounds or rendering later generic

claims obvious. App. of Susi, 440 F.2d 442; 169 U.S.P.Q. 423 (CCPA, 1971)

(endorsed by the Federal Circuit in Merck v Biocraft Labs., 874 F2d 1843, 1846;


22

10 U.S.P.Q. 2d 1843 (Fed. Cir. 1989). Most importantly, in the prosecution of

Fevig II discussed below, the Patent Owner acknowledged this very law as cited

by the examiner when it amended the claims to avoid the cited art. The prior art

genus of both Fevig I and Fevig II reads directly on the challenged claims of the

‘208 and thus they are anticipated.

1. Anticipation of Claim 13 by Fevig I.

Claim 13 of the ‘208: A compound according to claim 8 wherein the compound is “1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide”

Claim 13 depends from Claim 8. Claim 8 is nothing more than a long list of

65 specific compounds presented in the alternative (i.e. that can be “selected

from”) and thus there are no additional elements that are included from the

underlying claim since the broader antecedent claim funnels down to the single

compound of claim 13 that includes all of the preceding elements. The structure

of the compound recited in claim 13 is referred to hereafter as Structure 3 or

“apixaban”:

Structure 3 “apixaban” O

OO

N

H2N

O

NN

N


23

Apixaban can be represented by the general formula from Fevig I:

Structure 4

Ex. 1008 at 66.

This exact formula of Structure 4 appears in Fevig I as the first structure on

the left at the top of page 4 (there are no line numbers on that page). Ex 1003 at

pg. 4; Ex. 1008 at 67. Petitioner will take each variable in Structure 4, above, in

turn and show that the appropriately disclosed alternative for each variable of the

structure results in anticipating the apixaban structure from Fevig I.

Variable “s”

Fevig I defines “s” as “at each occurrence, is selected from 0, 1, 2 or 3.”

Ex. 1003 at 15:9 . For the apixaban structure, “s” equals zero, such that “G” is

attached directly to the nitrogen atom with no intervening spacer groups. Ex. 1008

at 68.

Variable “G”

In Fevig I, “G” is defined as “a group of formula I or II” (Ex. 1003 pg. 9:8-

11)

I II D E D E


24

The description goes on to state that “alternatively, ring D is absent.” Ex. 1003 at

pg. 10:15. In the case of apixaban, ring D is absent Ex. 1008 at 70. When ring D

is absent, “ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and ring

E is substituted with R” and R’.” Ex. 1003 at 10:17-18. For the apixaban

structure, E is the phenyl alternative. Ex. 1008 at 70. Further to the apixaban

structure, R’ is H (taught specifically at Ex. 1003 pg. 10:24) and R” is methoxy

(as specifically taught within “C1-3 alkoxy” alternatives as the C1 alkoxy at Ex.

1003 pg10:20). Ex. 1008 at 70. These selections result in a “G” component that

is a methoxy-phenyl group. Id. When this “G” ring is substituted into Structure 4

(with “s” = 0), the structure looks like this:

Structure 5

Id.

Variable “Z”

The “Z” moiety is defined as “N or CR1a ". Ex. 1003 at p 10:29. For the

apixaban structure, the CR1a alternative is chosen with R1a defined as, among

other alternatives, -(CH2)r-R1’. Ex 1003 at pg. 11:3. Ex. 1008 at 71. Continuing

the nested definition, “r” is defined as equaling 0, 1, 2 or 3. Ex. 1003 at pg. 15:7.

Z

N

N

N

O

O

A

B


25

For the apixaban structure the alternative “r” = 0 is appropriate. Ex. 1008 at 71.

This selection means that “Z” = CR1’. Id. A number of alternatives for R1’ are

provided. Ex 1003 at 11:6-12. For the apixaban structure R1’ is the “C(O)NR2R2a

alternative. Ex 1003 at 11:9; Ex. 1008 at 71. Continuing the solution of the

apixaban puzzle, Fevig I provides appropriate alternatives from the list provided.

Ex. 1003 at 11:17-25. To demonstrate the apixaban structure both R2 and R2a are

hydrogen (H) atoms, which are specifically set out in the list of alternatives. Ex.

1003 at 11:17 and 11:22; Ex. 1008 at 71. Combining these subunits gives Z= C-

C(O)NH2. Id. Substituting this “Z” into Structure 5 results in:

Structure 6

A comparison of Structure 6 with apixaban (Structure 3) shows that they are

identical except for the denotation of the of the generic “A-B” subunits of

Structure 6. Ex. 1008 at 72.

Variable “A”

“A” is specifically defined as “a C3-10 carbocyclic residue substituted with 0-

2 R4.” Ex 1003 at pg. 12:20. So a C6 carbocycle, e.g. a phenyl ring, with zero R4

N

N

N

O

O

N

O

A

B


26

substitutions is a disclosed alternative. Ex. 1008 at 73. Substituting this alternative

for “A” gives the structure:

Structure 7

Variable “B”

“B” is defined as a “5-10 membered heterocyclic system containing 1-4

heteroatoms selected from the group consisting of N, O, and S substituted with 0-2

R4a.” Ex. 1003 at pg. 12:27-28. So a C6 heterocycle made up of five carbons and

one nitrogen atom will satisfy the ring alternative. Ex. 1008 at 73. R4a is defined in

Fevig I by a long list of alternatives, one of which is a carbonyl oxygen =O. Ex

1003 at 13:24. Attaching this alternative for “B” to Structure 7 results in this

structure:

Structure 8

Structure 8, which was constructed of specifically disclosed alternative

N

N N

O

O

NO

B

O

OO

N

H2N

O

NN

N


27

components in Fevig I is identical to Structure 3, which is the claimed compound

of claim 13 of the ‘208 Patent. Ex. 1008 at 74-75. As such, it is plainly evident

that claim 13 is anticipated by Fevig I.


Claim 8 is directed to “a compound according to claim 1, wherein the

compound is selected from the group….” wherein the “group” is a list of 65

individual compounds taking up approximately 3 columns of the ‘208 Patent.

Reproducing the listing of compounds here would serve little purpose. The

significant observation regarding claim 8 is that the single compound claimed in

claim 13, 1-(4-methoxyphenyl)-7-oxo-6-4[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-

tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide, is among the compounds

listed. Ex. 1001 at 265:65; Ex. 1008 at 76.

The anticipation analysis of Claim 8 is identical to that of claim 13 with

respect to this particular compound, vida supra. As set forth above, the case law

is clear that when one member of a Markush group is anticipated, the entire

group is anticipated. Application of Ruff, 256 F.2d 590, 593 (CCPA 1958); Atlas

Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1346, 51 U.S.P.Q.2d (BNA) 1943

(Fed. Cir. 1999) (“In chemical compounds, a single prior art species within the

patent’s claimed genus reads on the generic claim and anticipates.”).

There is no question that claim 8 is a Markush claim. Ex. 1008 at 78.


28

MPEP 2173.05(H)(“Markush claim’ means any claim that recites a list of

alternatively useable species regardless of format”). The analysis of claim 13

plainly demonstrates that the claim is anticipated by the disclosure of Fevig I.

Claim 8 merely places the compound of claim 13 into a listing of a specific

species of compounds presented as a choice of 65 compounds. As cited above,

the case law is clear that the entire group in claim 8 is anticipated by the

disclosure of one of the compounds presented in the alternative, in this case,

apixaban in Fevig I.


Petitioner began by showing anticipation of the compound of claim 13,

apixaban, because of the brevity of that claim and the clarity of what was claimed.

The discussion of claim 8 followed because of the specific claiming of apixaban,

albeit as a selection from a Markush group. Petitioner will now demonstrate that

apixaban is presented as one of an enormous number of possibilities in the

expansive Markush style of claim 1. Petitioner expects that the patent owner may

argue that claim 1 is not anticipated by this compound because there are so many

choices that no one of skill in the art would be able to appreciate that this specific

compound is claimed. Such an argument is disingenuous since it is unquestionable

that the patent owner would attempt to enforce the ‘208 Patent against any infringer

that was making or selling apixaban. And more to the point, anticipation is based on


29

disclosure and there is no question that apixaban is one of the specifically claimed

alternatives in claim 1 of the ‘208 Patent. Finally, the complexity of Fevig I is

entirely due to the conscious decisions of the Patent Owner, and thus there is no

equitable justification for allowing it to be saved by unnecessary clutter of its own

creation.

As with all of the challenged claims in this IPR, the claimed compounds of

claim 1 are represented by Structure 4:

Structure 4

This structure is further limited by claim 1 to be of the general

formula:

Structure 1

Ex. 1008 at 80-81.

As was evident from the discussion set forth above regarding claim 13, the

use of a traditional claim chart to show anticipation of the challenged claims in

this case is not effective given the nesting and multiple interrelated claim

N

O

N

N

G1

R1a

M4

G


30

elements. Ex. 1008 at 82. Rather, Petitioner feels having shown with specificity

that the Fevig I reference specifically discloses and claims apixaban, petitioner

need only show that apixaban is claimed in each of the other challenged claims in

order to establish that they too are anticipated. Upsher-Smith Labs., Inc. v.

Pamlab, L.L.C., 412 F.3d 1319, 1322 (Fed. Cir. 2005)(“a product which would

literally infringe if later in time anticipates if earlier”). The claiming of apixaban

in claims 1-7 of the ‘208 Patent is set forth below.

As a preliminary matter, this demonstration is unnecessary by virtue of the

chain of dependent claims created by the patent owner. Claim 13 ultimately

depends from claim 1 and thus patent owner admits that claim 1 covers apixaban.

Claim 8 also depends from claim 1, and thus there is further admission that

apixaban is covered by claim 1. Finally claims 2-7 all depend, or ultimately

depend, from claim 1 and since they are narrowed, not by the addition of new

elements, but by reducing the number of alternative compounds claimed, each of

them also covers apixaban and is thus anticipated by Fevig I. Ex. 1008 at 83.

Claim 1 defines moiety “G” of Structure 1 as one of these two ring systems,

“G is a group of Formula IIa or IIb”:

IIa IIb

D E D E


31

Ex 1001 at 237:35-45. It also defines the G1 spacer of Structure 1 as alternatively

“absent.” Id. at 238:38. In the case of apixaban, G1 is absent. Ex. 1008 at 83-84.

As was the case with the anticipating Fevig I reference (Ex 1003 at 10:15),

claim 1 also states that “alternatively, ring D is absent.” Ex. 1001 at 237:57. In

the case of apixaban, ring D is absent. Ex. 1008 at 85. Claim 1 goes on to mirror

Fevig I (Ex. 1003 at 10:17-18) and states that when D is not present, “Ring E is

selected from phenyl,” among other choices. Ex. 1001 at 237:58. It also requires

that “ring E be substituted with 1-2 R ” Ex. 1001 at 237:57-61. In the case of

apixaban, Ring E is phenyl substituted with a methoxy group alternative for R.

Ex. 1001 at 238:5; Ex. 1008 at 85.

Still referring to Structure 1 above, For R1a, apixaban is –(CR3R3a)r-R1b (Ex.

1001 col 238:62-63) where r is 0 (Ex. 1001 col 242:18) and where R1b is

C(O)NR2R2a (Ex. 1001 col 239:19) with both R2 and R2a as H. Ex. 1001 col

239:34 and 239:40.

This selection of specific alternatives results in a compound of this structure:

Structure 6

N

N

N

O

O

N

O

A

B


32

The fused pyrazole-lactam ring system is defined in the corrected claim 1. Ex.

1001, Cert. of Corr. at pg 2; Ex. 1008 at 86-87.

Accordingly, Petitioner need now only demonstrate the presence of “A” and

”B” in claim 1 to complete the structure of apixaban. Ex. 1008 at 89.

The corrected claim 1 defines M4 of Structure 1 as “A-B.” Ex 1001 Cert. of

Corr. at pg. 2 (“M4 is –A-B”). A is defined as a C3-C10 carbocycle substituted with

0-2 R4. Ex 1001 238 a:20-21. One of the alternatives for R4 is zero. For

apixaban, when R4 is zero and the carbocycle is a C6 phenyl ring, the resulting

structure is:

Structure 7

B is defined in claim 1 as:

Ex. 1001 at 238:22-28; Ex.1008 at 90.

Where “the A-X-N moiety forms other than a N-N-N group,” where “Q1 is

C=O,” and where “ring Q is a six membered monocyclic ring wherein 0 [no]

N

N N

O

O

NO

B


33

double bond is present within the ring and the ring is substituted with 0-2 R4a and

X is absent.” (Ex. 1001 col 238:30-36 and Cert. of Corr. pg 2 correcting col 238:

lines 33 and 34). A saturated six-membered lactam ring attached to “A” through

the lactam-nitrogen atom meets these limitations for “B”. Apixaban has zero R4a

substituents. Ex. 1008 at 91. A saturated six-membered lactam ring attached to

“A” through the lactam-nitrogen atom meets these limitations for “B”. Id.

Plugging in this disclosed structural limitation for B results in the complete

structure of apixaban:

Structure 3 “apixaban”

Ex. 1008 at 91.

Accordingly, claim 1 of the ‘208 Patent claims apixaban, which was

disclosed in Fevig I. Ex. 1008 at 92. Claim 1 of the ‘208 is anticipated by virtue

of the fact that a single member of the genus claimed in claim 1 was disclosed

more than a year before the earliest priority date of the ‘208. Application of Ruff,

256 F.2d 590, 593 (CCPA 1958); Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342,

1346, 51 U.S.P.Q.2d (BNA) 1943 (Fed. Cir. 1999) (“In chemical compounds, a

single prior art species within the patent’s claimed genus reads on the generic

O

OO

N

H2N

O

NN

N


34

claim and anticipates.”).


In what has already been explained as a continuing reduction in the number

of alternatives for the various moieties of the claimed compounds of the ‘208

Patent, claim 2 begins the process of reducing the vast number of compounds

identified and claimed in claim 1. Claim 2 leaves out the definition of the primary

ring system of claim 1 and starts with the definition of the D-E ring system. This

structure as far as the disclosure of apixaban is concerned is identical to the

description of the D-E system in claim 1. Ex. 1001 242:23 et seq.; Ex. 1008 at

93.

Claim 2 again allows for ring D to be “absent,” and in such circumstances

“E is selected from phenyl,” among other choices, just as in claim 1, where E is

further substituted with “1-2 R”. Ex. 1001 at 242:47-49. ). In term of the target

structure, apixaban, ring E is phenyl substituted with a methoxy group (R). Ex.

1001 col 242:58; Ex. 1008 at 94.

“A” is defined in claim 2 as a “C5-10 carbocycle substituted with 0-2 R4”

substituents. Ex. 1001 243:1-2. Apixaban has C6 carbocycle with zero R4. Claim 2

is silent as to B, thus claim 2 carries the same limitations of B as claim 1. When

combined with the underlying elements of claim 1, the above-described

components result in a claiming of the complete apixaban structure and is


35

therefore anticipated just as in independent claim 1. Ex. 1008 at 95.


Claim 3 depends from claim 2 and begins by further claiming the “G” group

as selected from a number of structural formulae similar to claim 2. The very first

structure claimed is a methoxy-phenyl group. Ex. 1001 245:35-40. Claim 3 also

defines G1 as alternatively absent. (Id. at 252:65) as in claim 1. Id. 238:38; Ex.

1008 at 96.

Claim 3 also states “A is phenyl substituted with 0-2 R4.” Id. 253:10 For

apixaban, A is phenyl with zero R4. Claim 3 is silent as to B, thus claim 3 carries

the same limitations of B as claim 2. Accordingly, it adds nothing that alters the

analysis presented for claim 2 above, and thus the apixaban structure is

specifically claimed in claim 3. Ex. 1008 at 97.


Claim 4 depends from claim 3 and begins by presenting a “reduced

number”, (only four columns), of alternatives structures for the “G” unit. Once

again, the “G” unit of apixaban, the methoxy-phenyl, is the first one shown in

claim 4. Ex 1001 at 254:45-53. The only other structural unit defined in claim 4

is “G1” albeit with a large number of choices. The only choice relevant to the

anticipating apixaban structure is where G1 is “absent.” Ex 1001 at 258:50. Ex.

1008 at 99. As the two defined portions of the apixaban structure claimed in


36

claim 4 are identical to those two units (G and G1) as claimed in claim 3, claim 4,

like claim 3 is anticipated, by the disclosure of the apixaban structure in the Fevig

I reference. Id.


Claim 5 depends from claim 4 and again starts by again defining the “G”

unit as methoxy-phenyl, among others. Ex. 1001 at 260:5-11. The claim also

defines the “A” unit as “phenyl” among other choices. Id. at 262:31. Finally

claim 5 defines the “B” unit as the moiety found in the apixaban structure

substituted with R4a. Id. at 262 37-43 (first structure on the left; also Cert. of

Corr. pg 6-7 correcting column 262). R4a in the apixaban structure is H as

claimed in claim 5. Id. at 263:24 first structure; Ex.1008 at 100.

8. Anticipation of claim 6 by Fevig I.

Claim 6 depends from claim 5 and begins by claiming the generic structure:

Where “P4 is G” Ex 1001 at 263:48-56. It further defines “G” (similar to claims

1, 3, etc.) as a methoxy-phenyl structure. Id. at 263: 59-65 first structure. It then

defines “A-B” (Id. 265:10-20, first structure) as:


37

These are the “A” and “B” rings that Petitioner has previously identified as being

disclosed by Fevig I and claimed in all of the challenged claims in this IPR. Ex.

1008 at 78. The chain of dependency for claim 6 goes all the way back to claim 1

and thus includes all the limitations of all of the underlying claims. Claim 1

defined M4 as A-B. Id. 237:34-35 and Cert. of Corr. at page 2. So replacement of

P4 with methoxy-phenyl and M4 with –A-B produces a compound that is identical

with that of Structure 3, apixaban, except that it contains the variable R1a. Ex.

1008 at 103. To complete the apixaban structure R1a needs to be an amide moiety.

Claim 5 defines R1a as an amide group, among others and as claim 6 depends from

claim 5 and claim 6 is silent as to the R1a , the R1a is carried into claim 6. Ex 1001

at 262:61; Ex. 1008 at 103. Accordingly, apixaban is claimed in claim 6.


Claim 7 depends from claim 6 and further defines the “A-B” unit. The

claim provides A-B as

Ex. 1001265: 31-39 and Cert. of Corr. pg. 7 correcting column 265:30 and 35.


38

Thus claim 7 is limited to the apixaban structure. Ex. 1008 at 104.

10. Anticipation of claims 9-12, 20-27, and 34-61 by Fevig I.

Fevig I (and Fevig II) anticipate, almost verbatim, claims 9-12, 20-27, and

34-61. For ease of reference and to conserve space, a claim chart illustrating the

anticipation of claims 9-12, 20-27, and 34-61 by Fevig I is presented later in

Section B(4), below.

B. Ground 2: U.S. Patent 6,413,980 to Fevig et. al (“Fevig II”) (Ex. 1004) anticipates claims 1-13, 20-27, and 34-61 of U.S. 6,967,208 under 35 U.S.C. § 102(e).

As set forth in Section V(D)(2) above, Fevig II qualifies as prior art under

35 U.S.C. 102(e)(2). Also, as explained above, the specification of Fevig II is

identical to Fevig I. Accordingly, Petitioner need not repeat the reasoning set forth

for why Fevig I anticipates the challenged claims of the ‘208 Patent, but rather

only need provide the specific cites to Fevig II for the identical disclosure cited for

Fevig I.

Before pointing out the relevant portions of Fevig II that establish

anticipation of the challenged claims of the ‘208, it should be noted that a broad

genus of the type asserted in this petition against the ‘208 was also asserted against

Fevig II during its prosecution.

The examiner rejected claims 1, 8, 10 and 11 of the application for Fevig II

over Duplantier, WO 95/01980. Ex. 1005 p. 369. Specifically, the examiner


39

found anticipation by example 59 of Duplantier. Id.; Ex 1006 at 20. The cited

Duplantier example 59 is a compound selected from a broad genus by selecting

variables within the disclosed genus, just as was done above to establish that Fevig

I is anticipating. Id. There is nothing in Duplantier to suggest that the compound

of example 59 is any better or worse for the stated purpose than any of the other

compounds within the disclosed genus. Id.; Ex. 1008 at 107. Patent Owner

acknowledged in prosecution of the Fevig II that a broad genus can anticipate a

specific compound and the same genus, if it covers the applicant’s (i.e. the Patent

Owner in this petition) claimed compounds. Patent Owner amended its claims in

the prosecution of Fevig II to place the claimed compounds outside of the genus

disclosed by the prior art. Ex. 1006 at p. 20.

1. Anticipation of Claim 13 by Fevig II.

As set forth above, Claim 13 depends from Claim 8. Claim 8 is nothing

more than a long list of 65 specific compounds presented in the alternative (i.e.

that can be “selected from”) and thus there are no additional elements that are

included from the underlying claim since the broader antecedent claim funnels

down to the single compound of claim 13 that includes all of the preceding

elements. The structure of the compound recited in claim 13 is referred to

hereafter as Structure 3 or “apixaban”:


40

Ex. 1008 at 108. Structure 3

As previously discussed the generalized formula for apixaban is:

Structure 4

This exact structure appears in Fevig II. Ex. 1004 at 3:6-15 first structure on

the left of column 3. Substituting the variables with specifically disclosed options

produces the structure of apixaban. Ex. 1008 at 110.

Variable s

As was the case with the identical disclosure in Fevig I, the “s” group in

Fevig II is defined “at each occurrence” to be “selected from 0, 1 and 2.” Ex 1004

at 10:21. For the target compound apixaban, “s” is zero. Ex. 1008 at 111.

Variable G

Variable G is defined as the same two bicyclic ring systems as also found in

Fevig 1 as well as the ‘208 Patent, namely:

I II

O

OO

N

H2N

O

NN

N

D E D E


41

Ex 1004 at 7:24-35; Ex. 1008 at 112. The description goes on to state that

“alternatively ring D is absent Id. at 7:50. As with Fevig I, when ring D is absent,

“ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and ring E is

substituted with R” and R’.” (Ex 1004 col 7:51-53). For the apixaban structure, E

is the phenyl alternative, R” is methoxy as specifically taught within “C1-3 alkoxy”

alternatives as a C1 alkoxy (Ex. 1004 col 7:54) and R’ is H (Ex. 1007 col 7:58).

When this “G” ring is substituted into Structure 4 (with “s” = 0), the resulting

structure is

Ex. 1008 at 113. Structure 5

Variable Z

As in Fevig I, “Z” is defined as being selected from “N or CR1a ” . (Ex.

1004 col 7:64. R1a is defined, among others, as –(CH2)-R1’. Id. at 8:1. In the

continuing nesting of variables, r is defined as 0, 1, 2 or 3. Id. at 10:19. For

apixaban, r = zero. R1’ is further defined as C(O)NR2R2a, among others. Id. at 8:8-

9. R2 and R2a are each defined in the alternative as H. Id. at 8:17 and 8:25. With

this selection of alternatives the structure disclosed becomes:

Z

N

N

N

O

O

A

B


42

Structure 6

Ex. 1008 at 114.

Variables “A” and “B”

As was done in the discussion of Fevig I above, “A” is defined as “a C3-10

carbocyclic residue with 0-2 R4 groups.” Id. at 8:58. A C6 carbocycle is a phenyl

ring with zero R4 substitutions. Id. Adding “A” results in:

Structure 7

Similarly, “B” is defined is defined as a “5-10 membered heterocyclic

system containing 1-4 heteroatoms selected from the group consisting of N, O, and

S substituted with 0-2R4a.” Id. at 8:62-67. “B” as a C6 heterocycle made with five

carbons and with an N hetero atom will satisfy the ring alternative. R4a is defined

as a carbonyl oxygen =O within the parameters of the disclosure of Fevig II Id. at

9:33. Replacing “A” and ”B” of the structure above with these disclosed

N

N

N

O

O

N

O

A

B

N

N N

O

O

NO

B


43

embodiments results in the full structure of apixaban disclosed and claimed in the

challenged claims of the ‘208 Patent. Namely:

Ex. 1008 at 115-16.

Thus, exactly as was the case with Fevig I, Fevig II anticipates the

challenged claims of the ‘208 Patent by disclosing, among other compounds,

apixaban, which is explicitly disclosed by name in claims 13 and 8 and generically

in claims 1-7.

2. Anticipation of Claim 8 Fevig II.

As set forth in the discussion of Fevig I, Claim 8 is directed to “a compound

according to claim 1, wherein the compound is selected from the group.” Wherein

the “group” is a list of 65 individual compounds taking up approximately 3

columns of the ‘208 Patent. Reproducing the listing of compounds here would

serve little purpose. The significant observation regarding claim 8 is that the

single compound claimed in claim 13, 1-(4-methoxyphenyl)-7-oxo-6-4[4-(2-oxo-

1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-

carboxamide, is among the compounds listed. Ex. 1001 at 265:65. Ex. 1008 at

118.

The anticipation analysis of Claim 8 is identical to that of claim 13 with

O

OO

N

H2N

O

NN

N


44

respect to this particular compound, vida supra. As set forth above, the case law

is clear that when one member of a Markush group is anticipated, the entire

group is anticipated. Application of Ruff, 256 F.2d 590, 593 (CCPA 1958); Atlas

Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1346, 51 U.S.P.Q.2d (BNA) 1943

(Fed. Cir. 1999) (“In chemical compounds, a single prior art species within the

patent’s claimed genus reads on the generic claim and anticipates.”).

There is no question that claim 8 is a Markush claim. MPEP 2173.05(H)

(“’Markush claim’ means any claim that recites a list of alternatively useable

species regardless of format”). The analysis of claim 13 plainly demonstrates

that the claim is anticipated by the disclosure of Fevig II. Claim 8 merely places

the compound of claim 13 into a listing of a specific species of compounds

presented as a choice of 65 compounds. Ex. 1008 at 120. As cited above, the case

law is clear that the entire group in claim 8 is anticipated by the disclosure of one

of the compounds presented in the alternative, in this case, apixaban in Fevig II.

3. Anticipation of Claim 1-7 Fevig II.

As was done for Fevig I, Petitioner has established that claims 13 and 8 are

anticipated by Fevig II. The analysis for the remainder of the challenged claims

of the ‘208 is accomplished by showing that the scope of each of claims 1-7

covers apixaban, and thus they too are anticipated by the disclosure of apixaban in

Fevig II. Since the disclosures of Fevig I and II are identical, Petitioner presents


45

the following table that shows the correlation of the elements of claim 1 of the

‘208 Patent with their location in both Fevig I and II. The same correlation holds

true for the rest of the Challenged Claims, and they are not presented here since

the complete overlap of the disclosure if Fevig I and Fevig II is undeniably

demonstrated by this table. Ex. 1008 at 121.

US 6,967,208 WO 00/39131 Fevig I US 6,413,980 Fevig II

Claim 1 “A compound of “

(Ex. 1001 col 237:2-10) with rings P and M are defined as two specific systems: ”ring M, including P1, P2, and M1, and M2 is substituted with 0-2 R1a and is

(Ex. 1001 COC pg 1 correcting col 237:15-20) ”And ring P, including P1, P2 and P3, is ”

“[I]n a first embodiment, the present invention provides a novel compound selected from the group [containing]:”

[I]n a first embodiment, the present invention provides a novel compound selected from the group [containing]”:


46

(Ex. 1001COC pg. 1-2 correcting col 237:25-30) Where “P4 is –G1-G” (Ex. 1001 col 237:35) and “M4 is -A-B” (Ex. 1001 COC pg 2 correcting col 237:33-34) Resulting in this structure:

Structure 2

Ex. 1008 at 45 “G is a group of Formula IIa or IIb

Structure 4

(Ex. 1003 pg 3:24-25 and pg 4 first structure, left, top of page) Where variable “s” “at each occurrence, is selected from 0, 1, 2 or 3” (Ex 1003 at pg. 15:9). For the apixaban structure, “s” equals zero, such that “G” is attached directly to the nitrogen atom with no intervening spacer groups.

Further, “G” is defined as “a group of formula I or II” (Ex. 1003 pg. 9:8-11)

Structure 4

(Ex. 1004 col 3:6-15; first structure on the left col 3) Where variable “s” “at each occurrence, is selected from 0, 1, 2 or 3” (Ex 1004 col 10:21). For the apixaban structure, “s” equals zero, such that “G” is attached directly to the nitrogen atom with no intervening spacer groups.

Further, “G” is defined as “a group of formula I or II” (Ex. 1004 col 7:24-35)


47

Formula IIa

Formula IIb

Ex. 1001 Col 237:35-45 Where “G1 is absent” (Ex. 1001 col 238:38), and “alternatively ring D is absent and ring E is … phenyl … with ring E substituted with 1-2 R” (237:57-61). In term of the target structure, apixaban, ring E is phenyl substituted with a methoxy group (R) (Ex. 1001 col 238:5). For R1a, apixaban is –(CR3R3a)r-R1b (Ex. 1001 col 238:62-63) where r is 0 (Ex. 1001 col 242:18) and where R1b is (C(O)NR2R2a (Ex. 1001 col 239: 19) with both R2 and R2a as H (Ex. 1001 col 239:34 and 239: 40).

Formula I

Formula II

The description goes on to state that “alternatively, ring D is absent.” (Ex 1003 at pg. 10:15.) When ring D is absent, “ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and ring E is substituted with R” and R’.” (Ex 1003 at 10:17-18). For the apixaban structure, E is the phenyl alternative, R” is methoxy as specifically taught within “C1-3 alkoxy” alternatives as a C1 alkoxy (Ex. 1003 pg 10:20) and R’ is H (Ex. 1003 pg 10:24).

When this “G” ring is substituted into Structure 4 (with “s” = 0), the resulting structure is

Formula I

Formula II

The description goes on to state that “alternatively, ring D is absent.” (Ex 1004 col 7:50)

When ring D is absent, “ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and ring E is substituted with R” and R’.” (Ex 1004 col 7:51-53). For the apixaban structure, E is the phenyl alternative, R” is methoxy as specifically taught within “C1-3 alkoxy” alternatives as a C1 alkoxy (Ex. 1004 col 7:54) and R’ is H (Ex. 1007 col 7:58).

When this “G” ring is substituted into Structure 4 (with “s” = 0), the resulting structure is

D E

D E

D E

D E

D E

D E


48

Results in

Structure 5

Ex. 1008 at 66-70

When the “Z” moiety for Structure 4 is defined as “N or CR1a " (Ex 1003 pg. 10:29) and the CR1a alternative is chosen with R1a defined as, among other alternatives, -(CH2)r-R1’ (Ex. 1003 pg. 11:3), “r” is defined as equaling 0 (Ex 1003 pg 15:7) meaning that “Z” = CR1’. When R1’ is “C(O)NR2R2a ” (Ex. 1003 pg. 11:9) where both R2 and R2a are hydrogen (H) atoms (Ex. 1003 pg 11:17 and pg. 11:22) gives Z= C-C(O)NH2. Placing this “Z” into Structure 5 results in

Structure 5 Ex. 1008 at 109-113 When the “Z” moiety for Structure 4 is defined as “N or CR1a " (Ex. 1004 col 7:64) and the CR1a alternative is chosen with R1a defined as, among other alternatives, -(CH2)r-R1’ (Ex. 1004 col 8:1) , “r” is defined as equaling 0 (Ex. 1004 col 10:19) meaning that “Z” = CR1’. When R1’ is “C(O)NR2R2a ” (Ex. 1004 col 8:8-9) where both R2 and R2a are hydrogen (H) atoms (Ex. 1004 col 8:17; col 8:25) gives Z= C-C(O)NH2. Placing this “Z” into Structure 5 results in

Z

N

N

N

O

O

A

B Z

N

N

N

O

O

A

B


49

Structure 6 Ex. 1008 at 83-87 “A” can be a “C3-C10 carbocycle substituted with 0 [zero] - R4 “ (Ex. 1001 col 238: 20-21). For apixaban, when the carbocycle is a C6 phenyl ring, the resulting structure is:

Structure 7

Structure 6

Ex. 1008 at 71 When “A” is specifically defined as “a C3-10 carbocyclic residue substituted with 0-2 R4 ” (Ex. 1003 pg. 12:20) where a six membered carbon ring, e.g. a C6 carbocycle is a phenyl ring with zero R4 substitutions and is disclosed as

Structure 7 Ex. 1008 at 73

Structure 6

Ex. 1008 at 114 When “A” is specifically defined as “a C3-10 carbocyclic residue substituted with 0-2 R4 ” (Ex. 1004 col 8:58) where a six membered carbon ring, e.g. a C6 carbocycle is a phenyl ring, with zero R4 substitutions and is a disclosed as

Structure 7

Ex. 1008 at 115

N

N

N

O

O

N

O

A

B

N

N N

O

O

NO

B

N

N

N

O

O

N

O

A

B

N

N N

O

O

NO

B

N

N

N

O

O

N

O

A

B

N

N N

O

O

NO

B


50

B is defined as

Structure 12

(Ex. 1001 Col 238:22-28) and the “A-X-N moiety forms other than a N-N-N group,” where “Q1 is C=O,” and where “ring Q is a six membered monocyclic ring wherein 0 [no] double bond is present within the ring and the ring is and is substituted with 0-2 R4a and “X is absent.” (Ex. 1001 col 238:30-36 and COC pg 2 correcting col 238: lines 33 and 34). A saturated six-membered lactam ring attached to “A” through the lactam-nitrogen atom meets these limitations for “B”. Apixaban has zero R4a

substituents resulting in

apixaban

Ex. 1008 at 80-91

“B” is defined as a “5-10 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a.” (Ex. 1003 pg 12:24-28) So a C6 heterocycle made up of five carbons and one nitrogen atom will satisfy the ring alternative and R4a defined as a carbonyl oxygen =O (Ex. 1003 pg. 13:24) results in

apixaban

Ex. 1008 at 74-75

“B” is defined as a “5-10 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a.” (Ex. 1004 col 8:62-67) So a C6 heterocycle made up of five carbons and one nitrogen atom will satisfy the ring alternative and R4a is defined as a carbonyl oxygen =O (Ex. 1004 col 9:33) results in

apixaban

Ex. 1008 at 116

O

OO

N

H2N

O

NN

N

O

OO

N

H2N

O

NN

N

O

OO

N

H2N

O

NN

N


51

4. Anticipation of claims 9-12, 20-27 and 34-61.

Fevig II repeats the disclosures of Fevig I as discussed above. Likewise, the

limitations of claims 9-12, 20-27 and 34-61 of the ‘208 Patent are anticipated by

Fevig II as well by virtue of the fact that the ‘208 claims read on Fevig II almost

verbatim. The details for the anticipatory citations from both Fevig I and Fevig II

may be found in the accompanying claim chart for ease of reference.

US 6,967,208 WO 00/39131 Fevig I US 6,413,980 Fevig II Claims 9 and 20-27 depend from claims 1-8, and 13, respectively. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of [the antecedent claim] or a pharmaceutically acceptable salt form thereof.

“It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.” (Ex. 1003 pg. 3:5-8)

“It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.” (Ex. 1004 col 2:45-50)

Claims 10, 34, 37, 40, 43, 46, 49, 52, and 55 depend from claims 1-8 and 13, respectively. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of [the antecedent claim] or a

“It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a

“It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically


52

pharmaceutically acceptable salt form thereof.

pharmaceutically acceptable salt or prodrug form thereof.” (Ex. 1003 pg 3 :9-13)

acceptable salt or prodrug form thereof.” (Ex. 1004 col 2: 51-56)

Claims 11, 35, 38, 41, 44, 47, 50, 53, and 56 depend from claims 10, 34, 37, 40, 43, 46, 49, 52, and 55, respectively. A method according to [the antecedent claim], wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders…” (Ex. 1003 pg 263:1-5)

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders (Ex. 1004 col 213:21-25)

Claims 12, 36, 39, 42, 45, 48, 51, 54, and 57 depend from claims 10, 34, 37, 40, 43, 46, 49, 52, and 55, respectively. A method according to [the antecedent claim], wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death,

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death,


53

disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms.” (Ex. 1003 pg 263:2-9)

transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms.” (Ex. 1004 col 213:21-31)

58. A method according to claim 55, wherein the thromboembolic disorder is an acute coronary syndrome.

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke,” (Ex. 1003 pg 263:2-9) all of which may be characterized as different types of an acute coronary syndrome.

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke,” (Ex. 1004 col 213:21-31) all of which may be characterized as different types of an acute coronary syndrome.

59. A method according to “The compounds of this “The compounds of this


54

claim 55, wherein the thromboembolic disorder is stroke.

invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … stroke… (Ex. 1003 pg 263:2-9)

invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … stroke… (Ex. 1004 at 213:21-28)

60. A method according to claim 55, wherein the thromboembolic disorder is deep vein thrombosis.

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … deep vein thrombosis… (Ex. 1003 pg 263:2-9)

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … deep vein thrombosis… (Ex. 1004 col 213:21-29)

61. A method according to claim 55, wherein the thromboembolic disorder is pulmonary embolism.

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … pulmonary embolisms. (Ex. 1003 pg 263:2-9)

“The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes … pulmonary embolisms. (Ex. 1004 at 213:21-31)

C. Grounds 3 and 4: Fevig I and Fevig II, each in its own right, renders the challenged claims of the ‘208 Patent obvious under 35 U.S.C. 103(a).


55

While Petitioner feels that the detailed explanation offered for Grounds 1

and 2 clearly establishes that the challenged claims of the ‘208 Patent are

anticipated under 102(b) for Fevig I and under 102(e)(2) for Fevig II, if this Board

does not reach the same conclusion, then it should at least conclude that, based on

the above-presented evidence, that both the Fevig I and Fevig II references render

the challenged claims obvious under 103(a) on Grounds 3 and 4.

Both prior art references and the patent for which review is sought belong to

the same assignee, Bristol-Myers Squib. And all three documents disclose the

compound Petitioner has chosen to use to establish the invalidity of the ‘208

Patent, namely apixaban.

It is anticipated that the Patent Owner will argue against this Petition by

asserting that the genera of the Fevig prior art is too vast and undifferentiated to

steer one of ordinary skill to pick one particular compound, thus there is no

anticipation or obviousness with respect to the challenged claims. Patent Owner

may also argue that the disclosures that it created are so broad and so convoluted

that one of ordinary skill would not be motivated to ferret out any specific

compound.

If the Board sees fit to allow Patent Owners to create absurdly complicated

claim schemes and then to argue that the very schemes and disclosures that they

created, and had the opportunity to simplify, are immune from use as prior art, it is


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allowing a manipulation of the patent system that was never contemplated or

authorized and that is contrary to law. See below.

As mentioned above, claims of the Fevig II reference were rejected over a

generic disclosure of Duplantier. Ex. 1005 p. 370. In making that rejection based

on a broad genus in the prior art the examiner stated, “Duplantier teaches a generic

group of compounds which embraces applicants instantly claimed compounds.”

Id. The Examiner went on to state, “One of ordinary skill in the art would have

been motivated to select the claimed compounds from the genus in the reference

since such compounds would have been suggested by the reference as a whole.”

Id.

Finally, the examiner stated correctly, “[i]t has been held that a prior art

disclosed genus of useful compounds is sufficient to render prima facie obvious a

species falling within that genus.” He then cited to In re Susi, 440 F.2d 442; 169

U.S.P.Q. 423 (CCPA, 1971), which was endorsed by the Federal Circuit in Merck

v Biocraft Labs., 874 F2d 804, 807; 10 U.S.P.Q. 2d 1843 (Fed. Cir. 1989).

This case is directly analogous to the facts in Merck. In that case the

Federal Circuit stated, the fact that the prior art reference “discloses a multitude of

effective combinations does not render any particular formulation less obvious.”

It went on to note “[t]his is especially true because the claimed composition is

used for the identical purpose taught by the prior art.” Merck at 807. The Federal


57

Circuit cited to Susi for support of these positions and characterized the holding in

Susi as an “obviousness rejection affirmed where the disclosure of the prior art

was ‘huge,’ but it undeniably include[d] at least some of the compounds recited in

[applicant’s] generic claims and it is of a class of chemicals used for the same

purpose as [applicant’s] additives.” Merck at 807.

That is precisely the situation in this case. Fevig I and II disclose a vast

number of compounds that undeniably includes apixaban, a compound admitted

by Patent Owner to be covered by generic claim 1 of the ‘208 Patent, and from

which all of the challenged claims ultimately depend. The compounds disclosed

in the Fevig references are “Factor Xa inhibitors,” which are identical to the

nature of the compounds claimed in the ‘208 Patent. Ex. 1008 at 123-26.

In Merck, Plaintiff had argued that the prior art did not suggest that the

compounds within the claimed genus were preferred embodiments, and therefore

did not render the later claimed compounds obvious. Merck at 807. In response

the Federal Circuit said that with respect to an analysis under section 103, “all

disclosures of the prior art, including unpreferred embodiments, must be

considered.” Merck at 708.

It has been demonstrated with respect Grounds 1 and 2 with regard to

anticipation by Fevig I and II that the broad genus of claim 1 of the ‘208 Patent

(and all of the remaining challenged claims that depend from it) reads on the prior


58

art. An obviousness analysis starts with the same conclusion. It is important to

note that it is not necessary to alter or combine the prior art to establish

obviousness in this case. The apixaban compound is in the prior art and it is in the

challenged claims, so no alteration or supplementation from another source is

needed. As set forth above, the other requirements of obviousness under 103 are

satisfied under Federal Circuit authority.

In the prosecution of Fevig I the Patent Owner did not argue that

Duplantier did not render obvious the claims of the application that lead to Fevig

I. Rather, after an interview with the examiner the claims were amended such

that the generic disclosure of Duplantier no longer covered the claimed genus of

compounds. Ex. 1008 at 128. That is not the situation here. The prior art Fevig

references disclose apixaban, which is claimed individually and as a generic

compound in the ‘208 Patent.

Finally, it should also be noted that the ‘208 Patent could have claimed

priority to Fevig I, but the Patent Owner made a tactical decision not to do so.

They should not be allowed now to assert that their own identical disclosures do

not render their later filing of the same subject matter either not anticipated or

non-obvious over their own disclosure.

D. Secondary Considerations of Non-Obviousness Do Not Rebut the Prima Facie Case of Obviousness

Objective indicia of non-obviousness, also referred to as “secondary


59

considerations,” must be considered in an obviousness determination. See, e.g.

Ruiz v. A.B. Chance Co., 234 F.3d 654, 667 (Fed. Cir. 2000). Such secondary

considerations can include a long-felt but unresolved need, unexpected results,

commercial success and a teaching away by others.

None of these secondary considerations is applicable here to overcome the

prima facie case of obviousness set forth above since the prior art discloses the

same genera and the same compounds as the ‘208 Patent. So there can be no long

felt need that was filled by the ‘208 that was not also fulfilled earlier by the Fevig

references. Ex. 1008 at 130-131. Similarly, there can be no unexpected results for

any particular compound because the ‘208 makes no attempt to differentiate any

individual claimed compound from any of its others in terms of efficacy or any

other chemical property. Id.

A similar analysis follows for both “commercial success” and any alleged

“teaching away by others.” Since the broad genus of the Fevig references cover at

least a significant portion, if not the entirety of the claimed genera of the ‘208, any

commercial success of the compounds of ‘208 is indistinguishable from the success

of those same compounds as disclosed and claimed in the prior art Fevig references,

especially apixaban, since it is taught by both Fevig references and claimed in the

‘208. Similarly, disclosure of the same compounds cannot legitimately be

characterized as teaching away, since the prior art teaches the same compounds. Ex.


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1008 at 131.

VII. Conclusion

As set forth in detail above, apixaban, the specific compound claimed in

claim 13 of the ’208 Patent is claimed in each of the challenged claims. There is no

argument that all of the moieties that the patent owner chose to break apixaban into

in order to claim them as separate variables are not present in each challenged claim

(other than 13 which only claims apixaban). The only potential roadblock to

reaching this conclusion comes from having to piece together apixaban via a

labyrinth of nested components with variations on variations.

Respectfully submitted,

/s/ Thomas C. Wright Thomas C. Wright State Bar No. 24028146 Cunningham Swaim, LLP 7557 Rambler Road, Suite 440 Dallas, Texas 75231 Telephone: 214-646-1495 Direct: 469-729-7010 Facsimile: 214-613-1163 [email protected]


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CERTIFICATE OF SERVICE

Pursuant to 37 C.F.R. § 42.6(e), I hereby certify that on August 12, 2015 a

copy of the foregoing Petition for Inter Partes Review of U.S. Patent No. 6,967,208 was

provided via FedEx, overnight delivery, to the Patent Owner by serving the

correspondence address of record for the ’208 Patent:

Henry Renk Fitzpatrick Cella Harper & Scinto 1290 Avenue of the Americas New York, NY 10104-3800

Date: August 12, 2015 /s/ Thomas C. Wright Thomas C. Wright Lead Counsel for Petitioner

Coalition for Affordable Drugs IX LLC

Kyle Bass IPR against Bristol-Myers

Documents

Transcript of Kyle Bass IPR against Bristol-Myers