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Paper No.

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

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
1. The 208 Specification ..................................................................... 3
2. The 208 Claims ............................................................................... 5
3. The 208 Prosecution History ........................................................ 10
4. The Certificate of Correction ......................................................... 12
B. Claim Construction of Challenged Claims........................................... 13
1. 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4c]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

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ii

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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

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iii

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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

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iv

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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
Exhibit 1003

Excerpts from the File History of U.S. Patent No. 6,967,208.


Published PCT Application WO 00/39131 titled Nitrogen
Containing Heterobicycles as Factor Xa Inhibitors, published on
July 6, 2000 (Fevig I).
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 1004

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Exhibit 1005

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

Exhibit 1006
Exhibit 1007

Published PCT Application WO 95/01980 titled Bicyclic


Tetrahydro Pyrazolopyridines, filed July 3, 1993. (Duplantier)
Reserved

Exhibit 1008

Expert Declaration of George Burton

Exhibit 1009

Prescribing Information Eliquis FDA Label

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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. 31119 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

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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

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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 twright@cunninghamswaim.com. 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
lgopalakrishnan@winstead.com. 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

1.

The 208 Specification

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

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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: 2125. 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
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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.
2.

The 208 Claims

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 subunits of the overall molecular structure that is claimed. As with any claimfunnel, 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

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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:
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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

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:
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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
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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
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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-(4methoxyphenyl)-7-oxo-6-4[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro1Hpyrazolo-[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 abovedescribed 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.
3.
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The 208 Prosecution History


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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-(4methoxyphenyl)-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
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with rings P and M defined as two specific systems:

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.
4.

The Certificate of Correction

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
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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 mayissue
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
Owners 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

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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-1piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4c]pyridine-3-carboxamide
The term 1-( 4-methoxyphenyl)-7-oxo-6-[ 4-(2-oxo-1piperaziny 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:
O

H 2N
N
N
N
N
O
O

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
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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
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).
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)
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).
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)

C.

Exhibit No.
1003

1004

1003
1004

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.

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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

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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 Patents 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.

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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
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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, 137980 (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 Bachelors or

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Masters 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

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

H 2N
N
N
N
N
O
O

Structure 3 apixaban

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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. 9:811)
D

I
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II
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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:
Z

B
N

N
O

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.
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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= CC(O)NH2. Id. Substituting this Z into Structure 5 results in:
N
O
B
N
N

N
O

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 02 R4. Ex 1003 at pg. 12:20. So a C6 carbocycle, e.g. a phenyl ring, with zero R4
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substitutions is a disclosed alternative. Ex. 1008 at 73. Substituting this alternative


for A gives the structure:
N

N
N

B
O

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:
O

H 2N
N
N
N
N
O
O

Structure 8

Structure 8, which was constructed of specifically disclosed alternative


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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.
2. Anticipation of Claim 8 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-4,5,6,7tetrahydro-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
patents claimed genus reads on the generic claim and anticipates.).
There is no question that claim 8 is a Markush claim. Ex. 1008 at 78.
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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.
3. Anticipation of Claim 1 by 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

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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:
R1a

N
N

M4

G1
O

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
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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:
D

IIa

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IIb

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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:
N
O
B
N
N

N
O

Structure 6

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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:
N

N
N

B
O

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]
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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:
O

H 2N
N
N
N
N
O
O

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 patents claimed genus reads on the generic
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claim and anticipates.).


4. Anticipation of Claim 2 by Fevig I.
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

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


5. Anticipation of Claim 3 by Fevig I.
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.
6. Anticipation of Claim 4 by Fevig I.
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

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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.
7. Anticipation of Claim 5 by Fevig I.
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:

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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.
9. Anticipation of Claim 7 by Fevig I.
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.
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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

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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 applicants (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:

[Type text]

[Type text]

39

[Type text]

H 2N
N
N
N
N
O
O

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:
D

I
[Type text]

II
[Type text]

40

[Type text]

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

B
N

N
O

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 8:89. 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:
[Type text]

[Type text]

41

[Type text]

N
O
B
N
N

N
O

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:
N

N
N

B
O

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
[Type text]

[Type text]

42

[Type text]

embodiments results in the full structure of apixaban disclosed and claimed in the
challenged claims of the 208 Patent. Namely:
O

H 2N
N
N
N
N
O
O

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-oxo1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3carboxamide, 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
[Type text]

[Type text]

43

[Type text]

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
patents 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
[Type text]

[Type text]

44

[Type text]

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
Claim 1
A compound of

WO 00/39131 Fevig I
[I]n a first embodiment,
the present invention
provides a novel
compound selected from
the group [containing]:

US 6,413,980 Fevig II
[I]n a first embodiment,
the present invention
provides a novel
compound selected from
the group [containing]:

(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

[Type text]

[Type text]

45

[Type text]

(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 4
Structure 2
Ex. 1008 at 45

G is a group of Formula
IIa or IIb

[Type text]

Structure 4

(Ex. 1003 pg 3:24-25


and pg 4 first structure,
left, top of page)

(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 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.

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. 1003 pg. 9:811)
[Type text]

46

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

[Type text]

D
D

Formula I

Formula I

Formula IIa
D
D

Formula II

Formula II

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).

[Type text]

The description goes


on to state that
alternatively, ring D is
absent. (Ex 1003 at
pg. 10:15.)

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 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 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

When this G ring is


substituted into
Structure 4 (with s =
0), the resulting
structure is

[Type text]

47

[Type text]

B
N

B
N

N
N

Ex. 1008 at 66-70

[Type text]

Structure 5

Results in

Structure 5
Ex. 1008 at 109-113

When the Z moiety for


When the Z moiety for Structure 4 is defined as
Structure 4 is defined as N or CR1a " (Ex. 1004
N or CR1a " (Ex 1003
col 7:64) and the CR1a
pg. 10:29) and the CR1a alternative is chosen with
alternative is chosen
R1a defined as, among
with R1a defined as,
other alternatives, among other alternatives, (CH2)r-R1 (Ex. 1004 col
-(CH2)r-R1 (Ex. 1003
8:1) , r is defined as
pg. 11:3), r is defined equaling 0 (Ex. 1004 col
as equaling 0 (Ex 1003
10:19) meaning that Z
pg 15:7) meaning that
= CR1. When R1 is
Z = CR1. When R1 is C(O)NR2R2a (Ex. 1004
C(O)NR2R2a (Ex.
col 8:8-9) where both R2
1003 pg. 11:9) where
and R2a are hydrogen (H)
both R2 and R2a are
atoms (Ex. 1004 col
hydrogen (H) atoms (Ex. 8:17; col 8:25) gives Z=
1003 pg 11:17 and pg.
C-C(O)NH2. Placing this
11:22) gives Z= CZ into Structure 5
C(O)NH2. Placing this
results in
Z into Structure 5
results in

[Type text]

48

[Type text]

O
B

B
N
N

B
N

N
O

Structure 6

Structure 6

Structure 6

Ex. 1008 at 71

Ex. 1008 at 83-87

Ex. 1008 at 114

When A is
specifically defined as
a C3-10 carbocyclic
residue substituted with
0-2 R4 (Ex. 1003 pg.
A can be a C3-C10
carbocycle substituted with 12:20) where a six
0 [zero] - R4 (Ex. 1001 col membered carbon ring,
238: 20-21). For apixaban, e.g. a C6 carbocycle is a4
when the carbocycle is a C6 phenyl ring with zero R
substitutions and is
phenyl ring, the resulting
disclosed as
structure is:

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

N
N

N
N

O
B

O
O

B
O

Structure 7

Structure 7
Ex. 1008 at 73

[Type text]

[Type text]

49

Structure 7
Ex. 1008 at 115

[Type text]

B is defined as

Structure 12
(Ex. 1001 Col 238:22-28)

B is defined as a 5-10
membered heterocyclic
and the A-X-N moiety
system containing 1-4
forms other than a N-N-N
group, where Q1 is C=O, heteroatoms selected
from the group
and where ring Q is a six
membered monocyclic ring consisting of N, O, and4a S
wherein 0 [no] double bond substituted with 0-2 R .
(Ex. 1003 pg 12:24-28)
is present within the ring
So a C6 heterocycle
and the ring is and is
4a
substituted with 0-2 R and made up of five carbons
X is absent. (Ex. 1001 col and one nitrogen atom
will satisfy the ring
238:30-36 and COC pg 2
4a
correcting col 238: lines 33 alternative and R
defined as a carbonyl
and 34). A saturated sixoxygen =O (Ex. 1003 pg.
membered lactam ring
attached to A through the 13:24) results in
lactam-nitrogen atom meets
these limitations for B.
Apixaban has zero R4a
substituents resulting in
O

H 2N

H 2N

H 2N
N

N
N
N

N
N

N
O

apixaban
Ex. 1008 at 80-91

O
O

N
N

[Type text]

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 74-75

[Type text]

50

apixaban
Ex. 1008 at 116

[Type text]

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
Claims 9 and 20-27 depend
from claims 1-8, and 13,
respectively.

WO 00/39131 Fevig I
It is another object of
the present invention to
provide pharmaceutical
compositions
A pharmaceutical
comprising a
composition, comprising: a
pharmaceutically
pharmaceutically acceptable acceptable carrier and a
carrier and a therapeutically therapeutically effective
effective amount of a
amount of at least one of
compound of [the antecedent the compounds of the
claim] or a pharmaceutically present invention or a
acceptable salt form thereof. pharmaceutically
acceptable salt or
prodrug form thereof.
(Ex. 1003 pg. 3:5-8)
Claims 10, 34, 37, 40, 43,
It is another object of
46, 49, 52, and 55 depend
the present invention to
from claims 1-8 and 13,
provide a method for
respectively.
treating thromboembolic
disorders comprising
A method for treating a
administering to a host
thromboembolic disorder,
in need of such
comprising: administering to treatment a
a patient in need thereof a
therapeutically effective
therapeutically effective
amount of at least one of
amount of a compound of
the compounds of the
[the antecedent claim] or a
present invention or a
[Type text]

[Type text]

51

US 6,413,980 Fevig II
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)
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
[Type text]

pharmaceutically acceptable
salt form thereof.

pharmaceutically
acceptable salt or
prodrug form thereof.
(Ex. 1003 pg 3 :9-13)
Claims 11, 35, 38, 41, 44,
The compounds of this
47, 50, 53, and 56 depend
invention are useful as
from claims 10, 34, 37, 40,
anticoagulants for the
43, 46, 49, 52, and 55,
treatment or prevention
respectively.
of thromboembolic
disorders in mammals.
A method according to [the The term
antecedent claim], wherein
"thromboembolic
the thromboembolic disorder disorders" as used herein
is selected from the group
includes arterial or
consisting of arterial
venous cardiovascular or
cardiovascular
cerebrovascular
thromboembolic disorders,
thromboembolic
venous cardiovascular
disorders (Ex. 1003
thromboembolic disorders,
pg 263:1-5)
and thromboembolic
disorders in the chambers of
the heart.
Claims 12, 36, 39, 42, 45,
The compounds of this
48, 51, 54, and 57 depend
invention are useful as
from claims 10, 34, 37, 40,
anticoagulants for the
43, 46, 49, 52, and 55,
treatment or prevention
respectively.
of thromboembolic
disorders in mammals.
A method according to [the The term
antecedent claim], wherein
"thromboembolic
the thromboembolic disorder disorders" as used herein
is selected from unstable
includes arterial or
angina, an acute coronary
venous cardiovascular or
syndrome, first myocardial
cerebrovascular
infarction, recurrent
thromboembolic
myocardial infarction,
disorders, including, for
ischemic sudden death,
example, unstable
transient ischemic attack,
angina, first or recurrent
stroke, atherosclerosis,
myocardial infarction,
peripheral occlusive arterial ischemic sudden death,
[Type text]

[Type text]

52

acceptable salt or
prodrug form thereof.
(Ex. 1004 col 2: 51-56)
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)
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,
[Type text]

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)

The compounds of this


58. A method according to
invention are useful as
claim 55, wherein the
anticoagulants for the
thromboembolic disorder is treatment or prevention
an acute coronary syndrome. 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.
59. A method according to
The compounds of this
[Type text]

[Type text]

53

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)

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.
The compounds of this
[Type text]

claim 55, wherein the


thromboembolic disorder is
stroke.

60. A method according to


claim 55, wherein the
thromboembolic disorder is
deep vein thrombosis.

61. A method according to


claim 55, wherein the
thromboembolic disorder is
pulmonary embolism.

C.

[Type text]

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)
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 pulmonary
embolisms. (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)
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)
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)

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).
[Type text]

54

[Type text]

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
[Type text]

[Type text]

55

[Type text]

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
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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
[applicants] generic claims and it is of a class of chemicals used for the same
purpose as [applicants] 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
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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


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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
twright@cunninghamswaim.co

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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

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