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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________________________________________
`
`LIFESCAN GLOBAL CORPORATION
`Petitioner
`
`v.
`
`IKEDA FOOD RESEARCH, LTD., and PHC CORPORATION
`Patent Owners
`
`
`
`
`
`Patent No. 9,976,125
`Issue Date: May 22, 2018
`Title: FAD-CONJUGATED GLUCOSE DEHYDROGENASE GENE
`__________________________________________________________________
`
`DECLARATION OF JEFFREY T. LA BELLE, PHD
`IN SUPPORT OF LIFESCAN GLOBAL CORPORATION’S
`PETITION FOR POST-GRANT REVIEW OF U.S. PATENT 9,976,125
`
`Case No.: PGR2019-_______
`__________________________________________________________________
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`I, Jeffrey T. La Belle, PhD, hereby declare and state as follows:
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`
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`I.
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`Introduction
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`1. My name is Jeffrey T. La Belle, and I am an Assistant Professor in the
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`School of Biological & Health Systems Engineering of the Harrington Program of
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`Biomedical Engineering at Arizona State University. I am submitting this
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`declaration on behalf of LifeScan Global Corporation (“LifeScan”) in the Petition
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`for Post-Grant Review of U.S. Patent 9,976,125 ("the '125 patent").
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`2.
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`I have reviewed the ’125 patent and its claims. I am a technical expert
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`in the subject matter areas relevant to the '125 patent, including the field of protein
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`chemistry and biosensors. I am familiar with the development of enzyme-based
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`glucose sensors. I have more than 60 publications in the relevant areas. I have
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`been asked to consider the validity of the claims of the '125 patent in light of the
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`publications of Tsuji, Machida, Omura, and Senior. (Exs. 1007, 1006, 1010, and
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`1004). I have read and understood the content of each of the publications
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`referenced in the Petition. This declaration provides my expert opinion regarding
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`the subject matter addressed below.
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`3.
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`This declaration is based on the information currently available to me.
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`To the extent that additional information becomes available, I reserve the right to
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`continue my investigation and study, which may include review of document and
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`information that may be produced, as well as testimony from depositions that have
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`not yet been taken.
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`
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`II. Background and Qualifications
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`4.
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`A copy of my curriculum vitae, which fully describes my
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`qualifications as an expert in this matter, is found at Exhibit 1027. In addition, I
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`have set forth some of my qualifications in the paragraphs below that may be
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`particularly relevant here.
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`5.
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`I hold B.S. and M.S. Degrees in Electrical Engineering from Western
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`New England University and M.S. and Ph.D. degrees in Bioengineering from
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`Arizona State University.
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`6.
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`I have been active in the field of biosensor development and protein
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`chemistry for over 18 years and have published over 60 journal articles in the
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`relevant areas. I am an inventor on 30 patent applications and 8 issued patents in
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`the United States and a member of the National Academy of Inventors. I teach
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`university and graduate level courses in the areas of physical prototyping,
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`biosensors, electrochemical biosensors, and medical device design at Arizona State
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`University and the medical technology venture program in conjunction with
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`Maricopa County Industrial Development Award Office.
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`7.
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`I sit on various review committees and industry organizations and
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`have been nominated for several awards as indicated in my attached curriculum
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`vitae.
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`
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`III. Legal Standards
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`8.
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`I have been instructed by Petitioner’s Counsel that, when construing
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`claim terms in an unexpired patent, a claim subject to post-grant review receives its
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`ordinary and customary meaning. Petitioner’s Counsel has further informed me
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`that the ordinary and customary meaning is the meaning that the term would have
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`had to a person of ordinary skill in the art in question at the time of the invention.
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`9.
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`Petitioner’s Counsel has advised that for a claim to satisfy the written
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`description requirement of 35 U.S.C. § 112(a) or 35 U.S.C. §112 (Pre-AIA), first
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`paragraph, the specification must reasonably convey to those skilled in the that the
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`inventor had possession of the claimed subject matter as of the filing date.
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`10. Petitioner’s Counsel has further advised that for a claim to satisfy the
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`separate enablement requirement of 35 U.S.C. § 112(a) or 35 U.S.C. §112 (Pre-
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`AIA), first paragraph, the specification must teach those skilled in the art how to
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`make and use the full scope of the claimed invention without undue
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`experimentation.
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`11.
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`I understand that in order for a patent claim to be valid, it must recite a
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`novel invention. Petitioner’s Counsel has further advised that, if the ’125 patent is
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`not entitled to claim the benefit of an earlier priority date, the novelty of its claims
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`will be determined by AIA 35 U.S.C. § 102.
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`12.
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`I understand that, under AIA 35 U.S.C. § 102(a)(1), if a prior art
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`disclosure that is in public use, on sale, or otherwise available to the public before
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`the effective filing date of a claimed invention satisfies every element of a claim,
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`the claim is anticipated and is not patentable. AIA 35 U.S.C. § 102(b) provides
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`certain exceptions to § 102(a) — for example, where the public use, sale, or public
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`availability of the prior art system was from one of the patent’s named inventors or
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`where the prior art system was developed pursuant to a joint research agreement.
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`13.
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`I have also been instructed by Petitioner’s Counsel that obviousness
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`under AIA 35 U.S.C. § 103 is a basis for invalidity for patents filed after March 16,
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`2013 and that are not entitled to the benefit of an earlier effective filing date. I
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`understand that if a prior art reference does not disclose all of the limitations of a
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`given patent claim, that patent claim is nonetheless invalid if the differences
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`between the claimed subject matter and the prior art are such that the claimed
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`subject matter as a whole would have been obvious to a person of ordinary skill in
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`the art. I have been further advised that obviousness can be based on a single piece
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`of prior art or a combination that either expressly or inherently disclose all
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`limitations of the claimed invention.
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`
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`IV. Materials Considered
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`14.
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`I have considered the following materials in preparing the opinions set
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`forth in this declaration:
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`(a) the ’125 patent, including the specification and claims;
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`(b) the prosecution history of the ’125 patent in the United
`States Patent & Trademark Office (“the PTO”); and
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`(c) any documents cited in this declaration.
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`
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`I also relied on my own training, knowledge, and experience in the field to
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`which the '125 patent is directed, along with my understanding of how one of
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`ordinary skill in the art would have understood the disclosure of the '125 patent.
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`V. The Level of Skill in the Art to Which the '125 Patent Pertains
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`15.
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`It is my understanding that I must address the issues set forth in this
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`declaration from the viewpoint of a person of ordinary skill in the art (POSA) to
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`which the '125 patent pertains at the time of the invention.
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`16.
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`In my opinion, one of ordinary skill in the art to which the '125 patent
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`pertains would have had a PhD in molecular biology (or a related discipline, such
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`as biochemistry) with at least 2 years of post-doctoral experience, or an equivalent
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`amount of combined education and laboratory experience. The POSA would have
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`also had experience using recombinant DNA techniques to express proteins and a
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`familiarity with protein chemistry and biosensors.
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`
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`VI. The '125 Patent
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`17.
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`I have read and reviewed the ’125 patent and its prosecution history. I
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`understand that the ’125 patent pertains to glucose biosensors that use FAD-linked
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`GDH enzymes. In particular, I understand the ’125 patent is directed to the use of
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`recombinant FAD-conjugated glucose dehydrogenase having an amino acid
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`sequence with at least 90% identity to SEQ ID NO: 1 disclosed in the ’125 patent
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`which is identical to the amino acid sequence of the FAD-conjugated glucose
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`dehydrogenase from Aspergillus oryzae as provided in Tsuji and Machida.
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`18. The '125 patent includes a single independent claim (claim 1),
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`directed to, “a biosensor comprising a recombinant FAD-conjugated glucose
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`dehydrogenase, wherein the recombinant FAD-conjugated glucose dehydrogenase
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`is selected from: (a) a polypeptide which comprises the amino acid sequence
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`represented by SEQ ID NO: 1; and (b) a polypeptide which comprises an amino
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`acid sequence having a homology of 90% or more to the amino acid sequence (a)
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`and has an FAD-conjugated glucose dehydrogenase activity; wherein the
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`recombinant FAD-conjugated glucose dehydrogenase has a value of enzymatic
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`activity for maltose of 10% or less with a value of enzymatic activity for D-glucose
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`taken as 100%; and wherein the biosensor is capable of detecting glucose."
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`19.
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`I understand that a dependent claim is narrower than the claims from
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`which it depends because it includes additional limitations. Thus, claims 2-10,
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`which depend, either directly, or ultimately, from independent claim 1, are
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`narrower in scope than claim 1.
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`
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`VII. Claim Construction
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`20. A POSA at the time of the invention of the ’125 patent would have
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`understood homology to refer to the existence of shared ancestry between sources
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`of protein sequences as potentially inferred from amino acid sequence similarity or
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`identity. Based on the context of the claims and their designation of a percentage
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`homology however, a POSA would interpret the recitation of a percentage
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`homology to refer to a percentage identity or similarity between sequences.
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`21. A POSA at the time of the invention of the ’125 patent would have
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`understood FAD-conjugated glucose dehydrogenase activity to refer to the reaction
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`mechanism in which the glucose dehydrogenase enzyme effects oxidation of
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`glucose.
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`VII. Grounds of Unpatentability
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`22.
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`I reviewed the '125 patent, including the specification and claims, the
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`prosecution history of the '125 patent in the USPTO, as well as the Tsuji, Machida,
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`Omura, and Senior references. Based on my independent review of the '125 patent,
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`its prosecution history, and the other materials referenced in this declaration, along
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`with my own experience and expertise, I agree that claims 1-10 of the '125 patent
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`should not have issued, as argued in the Petition for Post-Grant Review submitted
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`on behalf of LifeScan.
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`
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`A.
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`The Pre-AIA Application does not Provide Proper Written Description
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`for the Glucose Dehydrogenase of Claims 1-10 of the ‘125 patent
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`23. The specification of the ’125 patent and the earlier 12/866,071
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`application to which it claims priority do not reasonably convey to those skilled in
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`the art that the inventor had possession of the claimed subject matter as of the
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`filing date.
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`24. Applying the ordinary and customary meaning to the limitations
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`emphasized in claim 1, a POSA would have understood claim 1 to cover a
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`biosensor capable of detecting glucose that includes a recombinant glucose
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`dehydrogenase (GHD) protein conjugated to flavin adenine dinucleotide (FAD)
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`The claimed GHD protein exhibits FAD-conjugated GDH activity and can have
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`any amino acid sequence that is 90% similar to SEQ ID NO. 1. The claimed GDH
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`activity level for maltose must be 10 % or lower than for D-glucose.
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`25. SEQ ID NO. 1 in the ’071 Application is 593 amino acids long. As
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`many as ten percent of those 593 amino acids, which would be 59 of them, could
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`be substituted at random. There are 20 common proteinogenic amino acids.
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`Accordingly, any combination of one to fifty-nine of any of the 593 amino acids in
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`SEQ ID NO. 1 could be substituted with any of 19 other standard amino acids to
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`yield a protein that still falls within that language of claim 1 of the ‘125 Patent.
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`Claim 1 of the ‘125 Patent therefore could cover as many as about 2059 specific
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`different proteins (which is greater than 5x1076 proteins).
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`26. The ’071 Application in Table 1 reports that the required activity is
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`present for 9 different strains of GDH from Aspergillus oryzae and that seven of
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`those are SEQ ID NO: 1, while two of those strains (4203 and 30104) each differ
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`from SEQ ID NO: 1 by two amino acids. The ’071 Application therefore describes,
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`at best, three proteins with FAD-conjugated glucose dehydrogenase activity. The
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`sequences of those three proteins are 99.6% (591/593) identical to each other.
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`27. The differences among the more than 5.0x1076 proteins covered by the
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`’125 patent would have been wholly unpredictable to one of ordinary skill in the
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`art. After reviewing the specification of the ’071 Application and the ’125 patent,
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`it is my opinion that one of ordinary skill in the art would not have sufficient
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`direction for discerning which of the 5.0x1076 members of the genus would
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`perform similarly to SEQ ID NO. 1.
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`
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`B. Claims 1-10 do not meet the enablement requirement of 35 U.S.C. §112.
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`28. The disclosures of the ’071 application and the ’125 patent both fail to
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`teach those skilled in the art how to make and use the full scope of the claimed
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`invention without undue experimentation and do not provide enablement of the
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`enormous scope of the claimed range.
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`29. A POSA would have had no idea from the ’125 Patent disclosure
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`about how many variations to SEQ ID NO:1 could be tolerated while meeting the
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`functional limitation of FAD-conjugated glucose dehydrogenase activity. The only
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`way for a person of skill in the art to make and use the proteins covered by the
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`claims would be perform extensive experiments on many if not most of the more
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`than 5.0x1076 proteins potentially encompassed by the language of the claims.
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`30. Methods for isolating homologues and variants of a protein were
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`known in the art at the time of the invention, it was not routine to screen amongst
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`2059 possible variant combinations.
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`31. The total disclosure in the specification of the ’071 application and
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`’125 patent at best provide three exemplary polypeptides and the possible
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`requirement to include the six amino acid sequence AGVPWV. That information
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`provides only a starting point for discovering which of the more than 5.0x1076
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`proteins potentially covered perform the claimed function. A POSA would be
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`forced to synthesize or otherwise obtain a significant portion of the more than
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`5.0x1076 proteins in order to experimentally determine compatibility with the
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`remaining elements of claim 1 of the ’125 patent. The ’125 Patent does not
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`provide direction that could curtail the amount and nature of work involved in
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`discerning which proteins covered by the claims were functional and which ones
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`were not.
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`32. The function of the protein represented by SEQ ID NO: 1 and its
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`tolerability for any amino acid substitution, deletion, or insertion was not well
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`known to a POSA at the time of the invention. There have been many advances in
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`the field of proteomics in regards to protein structure estimation and functional
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`estimates. Most mathematical methods are highly accurate if the sequence is 10-20
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`amino acids long but as the sequence becomes longer, the accuracy drops off
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`rapidly. The Garnier-Osguthorpe-Robson (GOR) method is one of the best
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`predictors but can only predict secondary protein structure and folding at 50-65%
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`accurate. Without proper knowledge of how proteins fold and develop in their
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`structure, function is very difficult and limited by almost empirical data estimation.
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`Current methods have increased the accuracy up to 80% but require more
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`knowledge of the individual amino acids, their neighbors (the sequence) and
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`sometimes empirical data as well. See, Jean Garnier, Jean-Franqois Gibrat, and
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`Barry Robson “GOR Method for Predicting Protein Secondary Structure from
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`Amino Acid Sequence”. METHODS IN ENZYMOLOGY, VOL. 266. Academic
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`Press, Inc. NY, USA, 1996; Simossis VA, Heringa J. "Integrating protein
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`secondary structure prediction and multiple sequence alignment". Current Protein
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`& Peptide Science. 5 (4): 249–66. 2004. The ability to accurately predict the
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`response of a protein like that represented by SEQ ID NO: 1 without
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`experimentation at the time of the invention was not possible at the levels required
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`to analyze the more than 5.0x1076 covered proteins. The only way to make and use
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`all of the proteins covered by the claims of the ’125 Patent or to even understand
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`what proteins were covered would require significant experimentation.
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`33. The differences among the more than 5.0x1076 proteins covered by the
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`’125 patent would have been wholly unpredictable to one of ordinary skill in the
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`art. After reviewing the specification of the ’071 Application and the ’125 patent,
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`it is my opinion that one of ordinary skill in the art would not have sufficient
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`direction for discerning which of the 5.0x1076 members of the genus would
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`perform similarly to SEQ ID NO. 1.
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`C. Claims 1, 9, and 10 are anticipated under 35 U.S.C. § 102 or obvious
`under 35 U.S.C. § 103 in view of Tsuji.
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`34. SEQ ID No:4 of Tsuji is an amino acid sequence for the flavin-
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`binding glucose dehydrogenase derived from A. oryzae that shares 100% identity
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`with SEQ ID NO:1 of the ’125 patent. Tsuji, Sequence Listing, SEQ ID NO: 1.
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`D. Claims 1-10 are obvious under 35 U.S.C. § 103 in view of Machida and
`Omura or Senior.
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`35. The genome sequence of A. oryzae disclosed in Machida was
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`submitted to DDBJ under the accession numbers AP007150–AP007177. Machida,
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`pg.1161. AP007151.1 describes a strain of A. oryzae, and protein ID BAE55513.1
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`comprises an amino acid sequence 100% homologous to SEQ ID NO:1. Protein ID
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`BAE55513.1 was submitted to the database December 20, 2005.
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`36. Monitoring glucose for the management of diabetes has a long history
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`of over 1,000 years, but the modern electrochemical self-monitoring blood glucose
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`(SMBG) test has its origins in the work from the 1950’s to 1960’s of Clark and
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`Lyons (1962). Clark L.C., Jr., Lyons C. Electrode systems for continuous
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`monitoring in cardiovascular surgery. Ann. N. Y. Acad. Sci. 102:29–45. 1962.
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`They were the first to take an amperometric signal from an enzymatic reaction
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`using glucose oxidase and record a correlation between the current and glucose
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`concentration. Id. Electron mediators have been used to enhance the signal and
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`decrease the noise of the system as outlined by Cass and coworkers in 1984. Cass
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`A.E., Davis G., Francis G.D., Hill H.A., Aston W.J., Higgins I.J., Plotkin E.V.,
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`Scott L.D., Turner A.P. Ferrocene-mediated enzyme electrode for amperometric
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`determination of glucose. Anal. Chem. 56:667–671. 1984; Ferri, S. Kojima, K,
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`Sode, K. Review of Glucose Oxidases and Glucose Dehydrogenases: A Bird’s Eye
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`View of Glucose Sensing Enzymes. JDST 5, 5:1068-76, 2011 (relevant for its
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`review of the state of the art, with references, prior to the earliest possible priority
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`date of the ’125 Patent).
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`37. A POSA, aware of the sequence of FAD-conjugated GDH provided in
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`Machida and equipped with the disclosure of recombinant FAD-conjugated GDH-
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`based biosensors in Omura would have found it obvious to produce a biosensor
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`having an FAD-conjugated GDH comprising the amino acid sequence represented
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`by SEQ ID NO: 1 of the ’125 Patent.
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`38. Electrochemical biosensors as described in Omura and the elements
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`thereof recited in the claims of the ’125 Patent were well known a POSA at the
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`earliest priority date of the ’125 Patent. Aside from the test meter which converts
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`electrochemical current into a voltage that can be read by computers or a handheld
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`meter, the primary functional component in blood glucose testing is the test strip
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`itself. Most test strips are screen printed inks that are deposited onto a flat plastic
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`or other substrate (typically mylar) the inks are typically carbon mixed into a
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`polymer binder, solvent and other materials and patterned into a 2, 3 or even 4
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`electrode configuration. On top of the electrode system resides the chemicals
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`which typically have bioreagents (enzymes) such as glucose oxidase or glucose
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`dehydrogenases with a variety of co-factors (e.g., Pyrroloquinoline quinone or
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`PQQ, discovered in the 1970’s; Nicotine Adenine Dinucleotide Phosphate (NADP)
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`or, as in the case of the ’125 Patent, Flavin-Adenine-Dinucleotide (FAD) which
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`has been known to be a cofactor since the 1960’s). Other chemicals, such as
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`ferrocene or potassium ferri- or ferrocyanide have been used as electron mediators
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`as well since at least the 1980’s. See, Cass; Ferri; and Yoo E-H, Lee, S-Y. Glucose
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`Biosensors: An Overview of Use in Clinical Practice. Sensors 2010, 10, 4558-76.
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`2010 (relevant for its review of the state of the art, with references, prior to the
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`earliest possible priority date of the ’125 Patent).
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`39. A POSA would have been motivated to use the FAD-conjugated GDH
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`as discussed and sequenced in Machida in the FAD-conjugated GDH-based
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`biosensors described in Omura based on the desire to industrially produce a
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`coenzyme-binding glucose dehydrogenase in a commercial expression vector.
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`40. A POSA would have found further expectation of success in the
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`utility of such a biosensor using the FAD-conjugated GDH of A. oryzae from the
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`disclosure of Senior. Senior describes a glucose sensor using GDH from A. oryzae.
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`41. The biosensor taught by the obvious combination of Machida and
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`Omura would comprise a sequence identical to that of SEQ ID NO: 1 of the ’125
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`Patent and would, therefore necessarily possess the same relative enzymatic
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`activity toward maltose and glucose.
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`42. Senior discloses an A. oryzae FAD-conjugated GDH-based glucose
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`sensor and, as such, the glucose functionality of a sensor using that enzyme would
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`have been obvious to a POSA.
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`43. The use of a reaction layer with a hydrophilic polymer and an electron
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`acceptor was well known in the art before the earliest priority date of the ’125
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`Patent and was fully disclosed in Omura. Omura, at col. 1, lines 45-54; col. 18, line
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`53 – col. 19, line 3
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`44. The use of osmium, quinone, and ferricyan as electron acceptors in
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`biosensors, including glucose sensors, was known to those of ordinary skill in the
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`art before the earliest priority date of the ’125 Patent. Senior, p. 3, lines 16-22;
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`Omura, col. 19, lines 20-31.
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`45. The claimed electrode configuration of a working electrode, a counter
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`electrode, and a reference electrode on an insulating base plate are fundamental
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`principles in creating dehydrogenating-enzyme-based biosensors and was well
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`known in the art as evidenced by the structure of the sensor described in Omura.
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`Omura, col. 1, lines 45-54; col. 18, line 53 – col. 19, line 3.
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`46. Detection of oxidation current in dehydrogenating-enzyme-based
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`biosensors was well characterized in the art before the earliest priority date of the
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`’125 Patent. Senior, p. 3, lines 24-25; Omura, col. 18, line 53 – col. 19, line 3.
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`47. Glucose biosensors operable using a change in color intensity were
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`known in the art and described in both Omura and Senior. Senior, p. 3, lines 3-16;
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`Omura, col. 19, lines 3-4.
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`
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`E. Claims 2-8 are obvious under 35 U.S.C. § 103 in view of Tsuji and
`Omura.
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`48. A POSA, would be motivated to combine the FAD-conjugated GDH
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`of Tsuji with the glucose sensor structure described in Omura with the
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`understanding that an FAD-conjugated GDH having desirable relative glucose
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`reactivity characteristics such as the enzyme described in Tsuji and that the glucose
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`sensor of Omura was, “capable of accurately measuring a blood sugar level.”
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`Omura, Abstract. A POSA would have found it obvious and relatively simple to
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`swap a FAD-conjugated GDH from one species of Aspergillus (terreus) for the
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`same enzyme from another species of Aspergillus (oryzae) and expected successful
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`results.
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`F.
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`Claims 6 and 7 are obvious under 35 U.S.C. § 103 in view of Tsuji and
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`Senior
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`49. A POSA, desirous of determining glucose in fluids using a flavin-
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`dependent glucose dehydrogenase enzyme and a reducible compound would have
`
`been motivated to combine the recombinant FAD-conjugated GDH of Tsuji with
`
`the glucose sensor structure described in Senior. Senior, Abstract.
`
`50. Senior describes a glucose sensor that uses the isolated FAD-
`
`conjugated GDH from A. oryzae to produce changes in electro-magnetic radiation
`
`absorbance characteristics and/or electrical changes for glucose determination in a
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`fluid. Senior, Abstract; p. 4, lines 10-11. Tsuji provides a method for the large
`
`scale production of the same FAD-conjugated GDH from the same organism
`
`already used in Senior. Tsuji, ¶ [0085]. Accordingly, a POSA would have been
`
`motivated to combine Tsuji and Senior to increase production and availability of
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`the FAD-conjugated GDH through the use of recombinant E. coli and, at least
`
`because both references use the same enzyme from the same organism, a POSA
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`would have had a reasonable expectation of success in the combination.
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`51. Amperometric monitoring of the glucose oxidation reaction is
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`equivalent to the detection of an oxidation current as recited in claim 6.
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`
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`52.
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`I hereby declare that all statements made herein of my own
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`knowledge are true and that all statements made on information and belief are
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`believed to be true; that these statements were made with knowledge that willful
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`19
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`LifeScan Ex. 1008
`Page 19 of 20
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`Scanned by CamScanner
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`LifeScan Ex. 1008
`Page 20 of 20
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