UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`COALITION FOR AFFORDABLE DRUGS IX LLC,
`Petitioner, v.
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`BRISTOL-MYERS SQUIB PHARMA COMPANY,
`Patent Owner.
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` IPR2015-_______
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` Patent 6,967,208
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`DECLARATION OF GEORGE BURTON, Ph.D.
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`CFAD EX 1008
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`TABLE OF CONTENTS
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`I.  
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`II.  
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`III.  
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`IV.  
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`TABLE OF CONTENTS ................................................................................... ii  
`Introduction and Bases for Opinions ............................................................ 1  
`A.   Qualifications ............................................................................................... 1  
`B.   Materials Reviewed ...................................................................................... 2  
`C.   Legal Principles Used In Analysis ................................................................ 9  
`Background ................................................................................................ 15  
`A.   Overview of the ’208 Patent ....................................................................... 15  
`1.   The ’208 Specification ......................................................................... 15  
`2.   The ’208 Claims ................................................................................... 16  
`3.   The ’208 Prosecution History .............................................................. 20  
`4.   The Certificate of Correction ............................................................... 23  
`5.   Applicant’s Admitted Prior Art ............................................................ 24  
`6.   Person of Ordinary Skill in the Art (POSA) ......................................... 24  
`Claim Construction ..................................................................................... 25  
`A.   “1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-
`4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide” ............... 25  
`B.   “Pharmaceutically Acceptable Salt” .......................................................... 26  
`The Invalidity Grounds ............................................................................... 27  
`A.   Overview of the Cited Art .......................................................................... 27  
`1.   PCT Publication No. WO 00/39131 (Ex. 1003) ................................... 27  
`2.   Level of Skill in the Art ........................................................................ 30  
`B.   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). ................................................... 31  
`1.   Anticipation of Claim 13 ...................................................................... 33  
`C.   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). ........................................................................... 49  
`1.   Anticipation of Claim 13 ...................................................................... 50  
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`2.   Anticipation of Claim 8 ........................................................................ 54  
`3.   Anticipation of Claim 1-7 .................................................................... 55  
`D.   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). ............................................................................................. 66  
`E.   Secondary Considerations of Non-Obviousness Do Not Rebut the
`Prima Facie Case of Obviousness .............................................................. 68  
`Conclusion .................................................................................................. 70  
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`V.  
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`I, George Burton, Ph.D., declare and state as follows:
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`I.
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`Introduction and Bases for Opinions
`1. My name is George Burton, and I reside in Douglassville, PA. I
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`have been retained by Cunningham Swaim LLP on behalf of the Coalition for
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`Affordable Drugs IX LLC (“CFAD” or “Petitioner”) and understand that I am
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`submitting this Declaration in connection with the above-referenced request for
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`inter partes review (IPR) proceeding.
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`2.
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`Specifically, I have been requested to evaluate certain claims of U.S.
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`Patent No. 6,967,208 (“the ’208 Patent”) Ex. 1001. As detailed in this
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`Declaration, it is my opinion that claims 1-13, 20-27, and 34-61 are anticipated or
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`rendered obvious by prior art references that predate the ’208 Patent. If
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`requested by the parties to this proceeding or the Patent Trial and Appeal Board
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`(“Board”), I will testify about my opinions expressed herein.
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`3.
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`I reserve the right to modify or supplement my opinions, as well as
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`the basis for my opinions, based on the nature and content of the documentation,
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`data, proof, and other evidence or testimony that other experts may present or
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`based on any additional discovery or other information provided to me or found
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`by me in this matter.
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`A. Qualifications
`4.
`I have over 40 years of educational and work experience in the fields
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`of organic chemistry, pharmaceutics, pharmacology, and pharmacokinetics. I have
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`attached my Curriculum Vitae as Ex. 1009.
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`5.
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`I am being compensated at a rate of $500 per hour for my
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`work in this matter. My compensation is not conditioned on the outcome
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`of this matter.
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`B. Materials Reviewed
`6.
`In preparing this Declaration, I reviewed the following materials:
`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
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`Exhibit 1006 Published PCT Application WO 95/01980 titled Bicyclic
`Tetrahydro Pyrazolopyridines, filed July 3, 1993. (Duplantier)
`Exhibit 1007 Mark-up showing Claim 1 of the ‘208 Patent as corrected in the
`Certificate of Correction.
`Exhibit 1009 Eliquis Prescribing Information
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`C. Legal Principles Used In Analysis
`7.
`I have been asked to provide my opinions as to whether certain
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`claims of the ’208 Patent would have been anticipated or obvious to a person of
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`ordinary skill in the art (“POSA”) at the time of the invention. I understand
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`that a POSA is a hypothetical person who is presumed to have known the
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`relevant art at the time of the invention.
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`8.
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`I also understand that this hypothetical person is a person of
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`ordinary creativity, and that this person in many cases will be able to fit the
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`teachings of multiple patents together like pieces of a puzzle. I also understand
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`that the inferences and creative steps that a POSA would employ may be
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`considered in an obviousness analysis.
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`9.
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`I provide my opinions in this Declaration based on the following
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`legal principles that were provided to me by counsel for Petitioner.
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`10.
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`I understand that my analysis requires an understanding of the
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`scope of claims 1-8 and 13 (and claims 9-12, 20-27, and 34-61 which depend
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`from them) of the ’208 Patent. I understand that each patent claim subject to
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`inter partes review (“IPR”) is given its “broadest reasonable construction in
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`light of the specification of the patent in which it appears.” 42 C.F.R. §
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`42.100(b).
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`11.
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`I understand that, pursuant to 35 U.S.C. § 311(b), a petitioner in an
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`IPR may request to cancel, as unpatentable, one or more claims of a patent only
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`on a ground that could be raised under 35 U.S.C. § 102 (anticipation) or 35
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`U.S.C. § 103 (obviousness), and only on the basis of prior art consisting of
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`patents or printed publications.
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`12.
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`I understand that a claim is unpatentable under 35 U.S.C. § 102 if it
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`is anticipated. I understand that the anticipation analysis involves comparing a
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`claim to a prior art reference to determine whether each and every element of the
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`claimed invention is disclosed in a single prior art reference, either expressly or
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`inherently. I also understand that material not expressly recited in a single prior
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`art document may still be considered for purposes of anticipation if that material
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`is incorporated by reference into the document. I further understand that an
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`anticipation analysis may include one or more extra references when the extra
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`references are cited to:
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`(A) prove the primary reference contains an “enabled disclosure”; (B) explain
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`the meaning of a term used in the primary reference; or (C) show that a
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`characteristic not disclosed in the reference is inherent.
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`13.
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`I understand that a claim is unpatentable under 35 U.S.C. § 103 if the
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`differences between the invention and the prior art are such that the subject matter
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`as a whole would have been obvious at the time the alleged invention was made
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`to a POSA to which the subject matter pertains. I understand that the obviousness
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`analysis involves a consideration of the scope and content of the prior art, the
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`level of ordinary skill in the pertinent art, and the differences between the
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`claimed invention and the prior art. I also understand when a POSA would have
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`reached the claimed invention through routine experimentation, the invention
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`may be deemed obvious.
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`14.
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`I also understand that obviousness can be established by combining
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`or modifying the teachings of the prior art. Specific teachings, suggestions, or
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`motivations to combine any prior art reference with additional prior art references
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`can be explicit or implicit. I understand that the references themselves may be
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`one source of a specific teaching or suggestion to combine features of the prior
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`art, but that such suggestions or motivations to combine art may come from other
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`sources as well. Specifically, the source may include logic, judgment, and
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`common sense available to a person of ordinary skill rather than explicit
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`statements in the prior art. For example, I understand that, in claims directed to a
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`combination of two known pharmaceutical compositions, increasing patient
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`compliance provides a motivation to combine the two compositions.
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`15.
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`I further understand that whether there is a reasonable expectation
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`of success from combining references in a particular way is also relevant to the
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`analysis. I understand there may be a number of rationales that may support a
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`reasonable expectation of success, including:
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`combining prior art elements according to known methods to
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`yield predictable results;
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`substitution of one known element for another to obtain
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`predictable results;
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`use of a known technique to improve similar devices (methods,
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`or products) in the same way;
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`applying a known technique to a known device (method, or
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`product) ready for improvement to yield predictable results;
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`“obvious to try,” in other words, choosing from a finite number
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`of identified, predictable solutions with a reasonable
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`expectation of success;
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`when a work is available in one field of endeavor, design incentives
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`and other market forces can prompt variations of it, either in the
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`same field or a different one; and
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`a teaching, suggestion, or motivation to modify or combine
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`references.
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`16.
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`I understand that an invention may be unpatentable when it is
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`“obvious to try.” For example, when there is a design need or market pressure
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`to solve a problem and there are a finite number of identified, predictable
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`solutions, a person of ordinary skill has good reason to pursue the known
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`options within his or her technical grasp. If this leads to the anticipated success,
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`it is likely the product not of innovation but of ordinary skill and common sense.
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`In that instance the fact that a combination was obvious to try might show that it
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`was obvious under § 103. I understand that for a claimed invention to be
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`“obvious to try,” the number of options to try should be small or easily tested,
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`with a reasonable expectation of success.
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`17.
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`I understand that when a patent claim arranges prior art elements in
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`a new combination, with each element performing the same function it had been
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`known to perform and yielding no more than one would expect from such an
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`arrangement, the combination is obvious.
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`18.
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`I understand that it is not proper to use hindsight to combine
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`references or elements of references to reconstruct the invention using the
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`claims as a guide. My analysis of the prior art is based on what a POSA would
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`have understood prior to September 21, 2000, i.e., the date one year before the
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`earliest claimed priority date for the ’208 Patent.
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`19.
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`I understand that secondary considerations may be relevant to the
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`determination of whether a claim is obvious should Patent Owner raise such
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`allegations or evidence. Such secondary considerations can include evidence of
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`commercial success caused by an invention, evidence of a long-felt need that was
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`solved by an invention, evidence that others copied an invention, evidence that
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`the prior art teaches away, or evidence that an invention achieved an unexpected
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`result. I understand that such evidence must have a nexus, or causal relationship
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`to the elements of a claim, in order to be relevant to the obviousness or
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`nonobviousness of the claim. I am unaware of any such secondary considerations
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`of nonobviousness having a nexus to the claims at issue in this proceeding.
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`20.
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`I understand that it may not be proper to combine references when
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`the prior art teaches away from such a combination. However, a reference’s
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`mere disclosure of more than one alternative does not constitute teaching away
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`from any of these alternatives.
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`21.
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`I understand that it may not be proper to combine references when
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`the claimed invention possessed some superior property or advantage that the
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`POSA would have found surprising or unexpected (“unexpected results”). I
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`understand that the results must be shown to be unexpected compared with the
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`closest prior art and be a difference in kind not one of degree.
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`22.
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`I understand that for a reference to be used to show a claim is
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`obvious, the reference must be analogous art to the claimed invention. I
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`understand that a reference is analogous to the claimed invention if the reference
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`is from the same field of endeavor as the claimed invention, even if it addresses a
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`different problem, or the reference is reasonably pertinent to the problem faced
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`by the inventor, even if it is not in the same field of endeavor as the claimed
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`invention. I understand that a reference is reasonably pertinent based on the
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`problem faced by the inventor as reflected in the specification, either explicitly or
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`implicitly.
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`II.
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`Background
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`A. Overview of the ’208 Patent
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`1.
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`The ’208 Specification
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`23. The ’208 Patent was filed on September 17, 2002 and claims benefit
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`of provisional applications Nos. 60/324,165 and 60/402,317, for which the earliest
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`filing date is September 21, 2001. Ex. 1001 Front Cover.
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`24. The ‘208 patent is titled “Lactam-Containing Compounds and
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`Derivatives thereof as Factor Xa Inhibitors,” and it describes and claims
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`compositions “which are inhibitors of trypsin-like serine protease enzymes,
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`especially factor Xa, pharmaceutical compositions containing the same and
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`methods of using the same as anticoagulant agents for treatment of
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`thromboembolic disorders.” Id. at 1: 21-25. The ‘208 specification acknowledges
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`that Factor Xa inhibitors containing moieties closely related to those claimed in the
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`‘208 were known in the art at the time of filing. Id. at 1:27-5:22. Thus the only
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`alleged improvement of the ‘208 patent is the preparation and use of “efficacious
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`and specific inhibitors of factor Xa.” The patent does describe the synthesis of
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`numerous alleged factor Xa inhibitors, but there are not any working examples
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`showing administration of any of the disclosed compounds to a patient, or any in
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`vitro or in vivo testing to prove efficacy, pharmacokinectics, and the like. Thus
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`there is no disclosure that any of the compounds described in the ‘208 patent is an
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`actual Xa inhibitor, much less an “efficacious” one.
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`25. Further, since there is no pharmacological data presented in the
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`specification, there is no information that establishes the inhibiting properties of
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`any of the enormous number of claimed compounds, or whether any of them are
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`more effective inhibitors than any of the others. In other words, there are no
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`distinguishing characteristics that would lead one of ordinary skill in the art to
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`choose any particular combination of moiety/moieties to form any one of the
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`specific compound(s) as claimed for any reason. Rather a person of ordinary skill
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`would recognize all of the disclosed compounds as reasonable candidates for the
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`stated purpose of being Factor Xa inhibitors absent further guidance and
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`disclosure.
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`2.
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`The ’208 Claims
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`26. The claims at issue here can be summarized as a typical funnel that
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`begins with an enormous number of alternatives in the only independent claim
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`(claim 1) of 103 claims, composed of Markush group alternatives for different sub-
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`units of the overall molecular structure that is claimed. As with any claim-funnel,
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`the scope of the independent claim is further limited through a chain of dependent
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`claims. In this case, the total number of claimed variations or alternatives is
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`decreased until a single molecular formula is claimed, inter alia, in claim 13. The
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`reduction in claim scope is accomplished not through the addition of new claim
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`elements, but through the successive reduction in the number of alternative
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`formulations possible under each dependent claim.
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`27. Claim 13 depends, ultimately from claim 1. Due to the chain of
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`claim dependency (i.e., claim 13 depends from claim 8 and claim 8 depends from
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`claim 1) the patent owner cannot deny that the single compound of claim 13 is
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`claimed in each of the earlier claims in that chain since a dependent claim must
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`contain all of the elements of any claim from which it depends. MPEP
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`608.01(i)(c) (“Claims in independent form shall be construed to include all the
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`limitations of the claim incorporated by reference into the dependent claim”).
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`28. The claims at issue here do nothing more than progressively restrict
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`the large number of alternative compounds claimed in claim 1 until they are
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`reduced to a few (claims 2-7) or a single molecule (e.g.claim 13). Further, I
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`understand that if claim 13 is determined to have been taught in the prior art, no
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`antecedent claims can be found nonobvious.
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`29. What follows is a general description of the claims that are at issue
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`in this IPR:
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`30. Claim 1, the only independent claim in the ’208 patent, recites a
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`generic claim for a compound of the formula:
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`The components of this generic formula are set forth as a massive listing
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`of nested chemical moieties in the form of multiple Markush groups that takes
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`up over five columns of the patent consisting of inestimable combination. The
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`claim concludes with “or a pharmaceutically acceptable salt thereof.” (Id. at
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`237:1-242:23.)
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`31. Claim 2 depends from claim 1 and recites a subset of the enormous
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`range of compounds in claim 1 by listing alternatives for a subunit (labeled G) of
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`the P4 moiety and a subunit (labeled A) of the M4 moiety of the formula provided
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`above. Id. at 242:24-245:29 and Cert. of Cor. pg 2-3 correcting columns 243 and
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`244. Even this “narrowing” would results in, still, millions of potential
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`combinations.
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`32. Claim 3 depends from claim 2 and defines a list of 168 alternatives
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`for moiety G in the form of structural formulae. In the alternative it provides that
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`“G1 is absent or selected from” a list of generic formulae, each with multiple
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`variations and further limits moiety “A”. Id. at 242:30-254:41 and Cert. of Corr.
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`pg 3-5 correcting columns 246, 248, 249, 251-254.
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`33. Claim 4 depends from claim 3 and narrates 96 alternative structural
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`variations for the “G” moiety, a subset of the 168 in claim 3. Claim 4 also
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`includes the alternative that “G1” is absent or chosen form another list of
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`alternatives that themselves include variations chosen from one or more of 12
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`groups of additional variables. Id. at 254:42-259:67 and Cert. of Corr. pg 5-6
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`correcting columns 255, 256, 258 and 259.
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`34. Claim 5 depends from claim 4, and recites 58 alternatives for the
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`“G” moiety as structural formulas (a subset of the 96 listed in claim 4) and number
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`of additional alternatives including the “A” and “B” moieties. Id. at 260:-263:44.
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`and Cert. of Corr. pg 6-7 correcting columns 261-263.
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`35. Claim 6 depends from claim 5, again reciting a subset of structural
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`alternatives in which G1 is absent with 27 alternatives for moiety G and two
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`alternatives for –A-B. Id. at 263:45-265:28 Cert. of Corr. pg 7 correcting col 265
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`lines 20-25..
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`36. Claim 7 depends from claim 6 and defines a single alternative for a
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`moiety labeled “-A-B.” The “-A-B” structural unit is included in all of the claims
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`that are at issue in this IPR, but is never shown in any of the structural diagrams or
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`demonstrated in the specifications with particularity. It is merely defined in the
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`claims. Id. at 265:29-265:38 and Cert. of Cor. pg 7 correcting line 35 by deleting
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`the second structure.
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`37. Claim 8 depends from claim 1, and claims “a compound according
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`to claim 1 wherein the compound is selected from” a group of 65 specific
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`compounds “or a pharmaceutically acceptable salt form thereof” admitted to being
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`covered by the generic formula of claim 1. Id. at 265:39-268:41and see also Cert.
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`of Corr. pg 7 correcting line 66 from “…pyrazole-…” to “…pyrazolo-…” as well
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`as numerous other corrections.
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`38. Claim 13 depends from claim 8, and recites a single compound, 1-
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`(4-methoxyphenyl)-7-oxo-6-4[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-
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`1Hpyrazolo-[3,4-c]pyridine-3-carboxamide or a pharmaceutically acceptable salt
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`form thereof, which is the ninth compound of the 65 compounds listed in claim 8.
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`Id. at 269:1-6 and see also Cert. of Corr. pg 10 correcting Line 4 from
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`“…pyrazole-…” to “…pyrazolo-…” as well as other corrections.
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`39. Claims 9-12, 20-27, and 34-61 all depend from one of the above-
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`described claims and add nothing of patentable distinction, but rather simply
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`recite, for example, a specific condition for which one or more the compounds
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`claimed in the claims above may be administered.
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`3.
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`The ’208 Prosecution History
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`40. The application that led to the ‘208 patent was filed on September
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`17, 2002 and contained 30 claims. A restriction requirement was issued on
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`September 29, 2003. In issuing the restriction requirement the examiner stated
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`that all 30 claims were generic and that an election of a single species for
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`examination was required. In response the applicant elected 2(1-(4-
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`methoxyphenyl)-3-[(methylamino)methyl]-6-[-4-(2-oxo-1-piperdinyl)phenyl]-
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`1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one.
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`41. The first, and only, substantive office action on the merits was
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`issued on October 23, 2003. In the action claims 1-21 were rejected and claims
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`22-30 were withdrawn for being drawn to non-elected subject matter. The
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`rejected claims were characterized as constituting an improper Markush group.
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`The variables “P” and “M” that made up the two core rings of the generic formula
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`were originally submitted as follows”
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`P4-P-M-M4
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`42. The examiner then requested changes “in the core of the compound
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`that determines classification” for the purposes of examination.
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`43. A response was filed on November 9, 2003 that cancelled claims 9-
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`15 and 2-30 that left claims 1-8, and 16-19 pending. Claims 31-121 were then
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`added. Claim 1 was amended such that the generic formula above was replaced
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`with the formula illustrated here
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`with rings P and M defined as two specific systems:
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` “P” “M”
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`44. The amendment of claim 1 resulted in the issuance of a Notice of
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`Allowance on March 11, 2004. An amendment and Request for Continued
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`Examination was filed on September 16, 2004 that also added claims 122-133.
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`45. When the “P” and “M” rings defined in the amendment are fused
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`via the dangling bonds of the individual rings (represented by the zig-zagging
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`lines, above in “P and “M” separately), the result is a fused two-ring system of
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`Structure 1, below.
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`
`R1a
`
`N
`
`N
`
`G1
`
`G
`
`N
`
`M4
`
`O
`
` 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:
`
`Structure 2
`
`
`
`Structure 2 appears in the ‘208 Patent at 134:60 (where R1
`
`a = H).
`
`
`
`  
`
`4.
`
`The Certificate of Correction
`
`46. A 13 page Certificate of Correction that was filed by the patent
`
`owner. The corrections resulted in numerous changes to the claims. In addition
`
`to the above-mentioned definition of “M4” as “A-B,” the other changes
`
`specifically relevant to this IPR are correction of the spelling of the names of the
`
`compound in claim 13, and the correction of that same compound name in the list
`
`of compounds in claim 8 by replacing “pyrazole” with “pyrazolo”.
`
`23
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`5.
`
`Applicant’s Admitted Prior Art
`
`47. The Background of the Invention in the ’208 section acknowledges
`
`that WO 00/39131 (Ex. 1003, Fevig I) belonging to the Patent Owner, and relied
`
`upon by me to demonstrate that the ‘208 is both anticipated and made obvious by
`
`Fevig I (and Fevig II as set forth below) in this request for IPR is prior art. Ex.
`
`1001, col. 2:54-63. That same passage also states that compounds described in the
`
`Fevig I “are not considered to be part of the present invention,” but I understand
`
`that this is irrelevant to whether Fevig I actually disclosed the subject matter of
`
`the Challenged Claims in this request for IPR, and as demonstrated below, it does.
`
`  
`
`6.
`
`Person of Ordinary Skill in the Art (POSA)
`
`48.
`
`I understand that a POSA is one who is presumed to be aware of all
`
`pertinent art, thinks in line with conventional wisdom in the art, and is a person of
`
`ordinary creativity.
`
`49. 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 Ph.D. in organic
`
`chemistry, pharmacy, pharmacology, or a related discipline; or a Bachelor’s or
`
`Master’s degree in organic chemistry or a related field with at least four years
`
`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
`
`  
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`24
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`  
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`medicines.
`
`III. Claim Construction
`
`
`50.
`
`I reviewed Petitioner’s proposed claim constructions for this
`
`proceeding, and, as discussed below, I agree that those constructions reflect the
`
`broadest reasonable construction in light of the specification of the ’208 Patent. I
`
`understand that the Board has not yet construed the claims in this proceeding. I
`
`reserve the right to supplement this declaration based on alternative constructions
`
`proposed by Patent Owner, based on alternative construction proposed by the
`
`Board, and based on an earlier invention date if the Patent Owner establishes such
`
`a date.
`
`
`
`A.
`“1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-
`4,5,6,7-tetrahydro-1Hpyrazolo-[3,4-c]pyridine-3-carboxamide”
`
`51. Claim 13 specifically claims this compound in the form written
`
`above. Compound 13 depends from claim 8, which in turn depends from 7, and so
`
`forth such that claims 2-8 and 13 all ultimately depend from claim 1 and thus all of
`
`the Challenged Claims cover this specific compound. This compound is known by
`
`its commercial brand name as the drug “Eliquis,” and it is listed in the FDA’s
`
`“Orange Book.” The compound is also known by the trivial name “apixaban.”
`
`52.
`
`I have used readily available software as well as my knowledge of
`
`IUPAC naming conventions to confirm that the structural formula for the named
`
`  
`
`25
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`

`
`  
`
`compound above is:
`
`O
`
`H2N
`
`N
`
`N
`
`N
`
`O
`
`N
`
`O
`
`
`
`
`
`O
`
`
`
`B.
`
`“Pharmaceutically Acceptable Salt”
`
`53. All of the Challenged Claims cover one or more specific compounds
`
`
`
`
`
`for which various constituent moieties are selected from various alternatives. Each
`
`of the claims also specifically claims a ‘pharmaceutically acceptable salt” of any
`
`compound that can be constructed from the presented alternatives. To the extent
`
`construction of this term is deemed necessary, a definition has been provided by
`
`the Patent Owner in the ‘208 patent at col 116: 40-47, specifically, it is defined as
`
`“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 other problem or complication, commensurate with a reasonable benefit/risk
`
`ratio.” As a person of skill in the art and based on my experience in the field of
`
`pharmaceuticals, I concur and believe that this is an accurate statement of what
`
`constitutes a “pharmaceutically acceptable salt to one of ordinary sill in the art of
`
`the invention under discussion.
`
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`IV. The Invalidity Grounds
`
`
`A. Overview of the Cited Art
`
`
`
`54. 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. 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. 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)
`
`55.
`
`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, I understand that 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.
`
`56. Fevig I is mentioned in the ‘208 Patent, and was submitted on an
`
`IDS disclosing 63 prior art document references during the prosecution of the
`
`  
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`27
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`  
`
`application leading to the ‘208 Patent but Fevig I was not substantively considered
`
`by the Examiner during prosecution of the ‘203 patent. The ‘208 Patent does not
`
`claim priority to Fevig I . Despite the fact that Fevig I was disclosed to the
`
`examiner in an expansive list of prior art during prosecution of the ‘208 Patent, it
`
`is undeniable that