UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`ARKEMA INC. & ARKEMA FRANCE
`Petitioners
`
`
`
`
`
`v.
`
`HONEYWELL INTERNATIONAL, INC.
`Patent Owner
`______________________
`
`Case Nos. IPR2016-00643
`PGR2016-00011
`PGR2016-00012
`
`Patent No. 9,157,017
`______________________
`
`
`DECLARATION OF WILLIAM J. BROCK, PH.D., DABT, FELLOW ATS
`
`Arkema Exhibit 1004
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`Contents
`INTRODUCTION ........................................................................................... 4
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`I.
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`II. QUALIFICATIONS ........................................................................................ 4
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`III. PREVIOUS TESTIMONY AND COMPENSATION ................................... 7
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`IV. MATERIALS CONSIDERED ........................................................................ 8
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`V.
`
`SUMMARY OF OPINIONS ........................................................................... 8
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`VI. DEFINITION OF A PERSON OF ORDINARY SKILL IN THE ART ......10
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`VII. CLAIM CONSTRUCTION ..........................................................................11
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`A.
`
`B.
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`“low toxicity refrigerant suitable for use in automobile air
`conditioning” .......................................................................................12
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`“no substantial acute toxicity as measured by inhalation
`exposure to mice and rats” ..................................................................13
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`VIII. DETAILED STATEMENT OF OPINIONS .................................................14
`
`A.
`
`B.
`
`Toxicity Testing of Refrigerants .........................................................14
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`By 2002 A Person of Ordinary Skill in the Art Would Have
`Predicted a Low and No Substantial Acute Toxicity for
`HFO-1234yf ........................................................................................17
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`1.
`
`2.
`
`3.
`
`A person of ordinary skill in the art would have expected
`HFO-1234yf to have acute inhalation toxicity similar to
`the relatively non-toxic R-1243zf .............................................18
`
`Consideration of additional prior art toxicity information
`confirms that a person of ordinary skill in the art would
`have expected HFO-1234yf to have low (and no
`substantial) acute toxicity .........................................................21
`
`Reasonable predictions about the acute inhalation
`toxicity of R-1234yf and related compounds ...........................30
`
`IX. Honeywell’s Allegedly Unexpected Results Are Exactly What a
`Person of Ordinary Skill in the Art Would Have Expected ..........................38
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`X.
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`CONCLUSION ..............................................................................................39
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`I.
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`INTRODUCTION
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`1.
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`I, William J. Brock, Ph.D., DABT, FELLOW ATS, have been
`
`retained by Finnegan, Henderson, Farabow, Garrett, & Dunner, LLP (“Finnegan”)
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`on behalf of Arkema Inc. and Arkema France (collectively “Arkema”) as an expert
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`in toxicology, in general, and especially in the area of refrigerant compounds. My
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`qualifications in this area, as well as other areas, are established by my curriculum
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`vitae, which is attached as Appendix A.
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`II. QUALIFICATIONS
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`I have over 30 years of experience as a toxicologist in research and
`2.
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`development in the chemical, pharmaceutical, consumer product, food products,
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`and medical device industries. My curriculum vitae is attached as Appendix A.
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`3.
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`I received a B.S. in chemistry and biology from Geneva College in
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`1976, and received a Masters and Ph.D. in toxicology from the University of
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`Kentucky in 1980 and 1983, respectively. I continued at the University of
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`Kentucky as a post-doctoral fellow until June 1983.
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`4.
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`After receiving my Ph.D. and completing my post-doctoral
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`fellowship, I became employed by DuPont at Haskell Laboratory for Toxicology
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`and Industrial Medicine (now Haskell Laboratory for Health and Environmental
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`Sciences). As a toxicologist, I was responsible for the safety evaluation of
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`numerous substances including pharmaceuticals, food additives, agrochemicals,
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`and commodity chemicals; toxicity testing recommendations; toxicity study design
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`and monitoring; and representing DuPont on national and international toxicology
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`committees.
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`5.
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`During my tenure at DuPont’s Haskell laboratory, I supervised (as a
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`Study Director) the conduct of many toxicology studies that utilized the dog, rat,
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`mouse, rabbit, and other species routinely used for the safety evaluation of
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`substances. The duration of those studies consisted of single dose, subchronic (up
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`to 3 months) and chronic (up to 1 year) studies.
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`6.
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`In 1999, I became the Director for Scientific Affairs at Unilever. In
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`that position, I was responsible for the safety assessment of personal care products,
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`food ingredients, and drug products, primarily over-the-counter (OTC) drug
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`products.
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`7.
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`In 2002, I joined the international consulting firm, Environ. At
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`Environ, I began to develop a toxicological practice assisting clients with the
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`evaluation of substances, including commodity chemicals, medical device
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`ingredients, and food ingredients. In 2010, I joined Otsuka Pharmaceuticals as the
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`Associate Director of Toxicology in the department of Nonclinical Drug Safety
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`and became the Director of Toxicology in 2013. I resigned from Otsuka in August
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`2015.
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`8.
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`In 2004, I became an independent consultant at Brock Scientific
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`Consulting, LLC. The primary focus of my consulting practice is to assist clients
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`in the pharmaceutical industry. As an independent consultant, I continue to design
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`and oversee the conduct and reporting of toxicology studies that utilize multiple
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`species and multiple routes of administration on behalf of clients.
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`9.
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`I am certified in general toxicology by the American Board of
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`Toxicology (ABT) and recognized as a Fellow by the Academy of Toxicological
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`Sciences (ATS). I served on the Board of Directors and as President for both
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`certifying organizations.
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`10.
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`I served as a member and in a leadership capacity for several national
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`and international toxicology organizations including the Society of Toxicology;
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`American College of Toxicology; Drug Information Association; American
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`Chemistry Council; International Pharmaceutical Excipient Council Expert Review
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`Panel; American Society of Heating, Refrigerating and Air-Conditioning Engineers
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`Toxicology Standards Committees; and National Toxicology Program.
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`11.
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`I have been an invited speaker to the Committee on Toxicology,
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`National Research Council, International Pharmaceutical Excipient Council, the
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`government of China, and other professional organizations and universities to
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`provide lectures on various toxicological topics.
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`12.
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`I have an appointment as an adjunct associate professor at the
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`University of North Carolina, Chapel Hill in the Eshelman School of Pharmacy.
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`Also, I had previous adjunct appointments at West Chester University and the
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`University of Medicine and Dentistry of New Jersey.
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`13.
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`I have authored or co-authored seven book chapters on toxicology,
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`and have co-edited two books on toxicology and international pharmaceutical
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`regulations for nonclinical scientists. I have over forty peer-reviewed publications
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`and have presented or co-presented over approximately forty abstracts at
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`toxicology meetings.
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`14.
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`I am an Associate Editor for the International Journal of Toxicology,
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`serve on the editorial board for Toxicology and Industrial Health, and periodically
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`review submitted manuscripts for other peer-review toxicology journals including
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`Toxicological Sciences, Food and Chemical Toxicology, Current Eye Research,
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`Journal of Applied Toxicology, and other leading toxicology journals.
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`III. PREVIOUS TESTIMONY AND COMPENSATION
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`I was paid a consulting fee of $300 per hour for my time to research
`15.
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`and prepare this declaration. My compensation is not dependent in any way on the
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`outcome of the proceeding.
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`IV. MATERIALS CONSIDERED
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`In forming my opinions, I have had available the materials cited in
`16.
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`this report, Arkema’s petitions, as well as those listed in the attached Appendix B.
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`In addition to these materials, I may consider additional documents and
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`information in forming any supplemental opinions. To the extent I am provided
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`with additional documents or information, including any expert declarations in this
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`proceeding, I may offer further opinions.
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`V.
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`SUMMARY OF OPINIONS
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`17.
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`I have been asked by Finnegan on behalf of Arkema to consider U.S.
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`Patent No. 9,157,017 (Ex. 1001, “the ’017 patent”) and prior art1 related to it, and
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`to offer my opinions in the area of toxicity on the effect of that art on the claims of
`
`the ’017 patent.
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`18.
`
`In preparing this declaration, I have been educated generally on
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`relevant patent law issues, including the standards for obviousness.
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`19.
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`I understand that a patent claim is obvious if the differences between
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`the subject matter sought to be patented and the prior art are such that the subject
`
`matter as a whole would have been obvious at the time the invention was made to a
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`person having ordinary skill in the art to which the subject matter pertains.
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`1 I have been asked to assume, for the purposes of my evaluation, that documents
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`dated before October 25, 2002, are prior art to the ’017 patent.
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`20.
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`I have been informed that obviousness cannot be avoided simply by
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`showing some degree of unpredictability in the art so long as there was a
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`reasonable probability of success. I have also been informed that only a reasonable
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`expectation of success, not a guarantee, is needed.
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`21.
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`I have also been advised that certain factors known as “secondary
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`considerations” of non-obviousness must be considered if put forward by the
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`patentee. I understand that these include, but are not limited to, unexpected results,
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`failure by others, and skepticism by experts, commercial success, and long-felt but
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`unmet need.
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`22.
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`I have been informed that when unexpected results are used as
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`evidence of non-obviousness, the results must be shown to be unexpected
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`compared with the closest prior art. I have also been informed that evidence
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`presented to rebut a prima facie case of obviousness must be commensurate in
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`scope with the claims to which it pertains and that the court must consider what
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`properties would have been expected.
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`
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` With this understanding, it is my opinion that a person of ordinary 23.
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`skill in the art prior to October 2002 would have had a reasonable expectation that
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`R-1234yf would be low in toxicity with no substantial acute toxicity, and as a
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`result it would have been obvious to further develop R-1234yf for automotive air
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`conditioning (“AAC”) applications.2
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`24.
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`It is further my opinion that the allegedly unexpected toxicity
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`properties presented by Honeywell during the prosecution of the ’017 patent are
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`not, in fact, unexpected and are entirely predictable based on the analysis a person
`
`of skill in the art would have undertaken prior to October 2002.
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`VI. DEFINITION OF A PERSON OF ORDINARY SKILL IN THE ART
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`I understand that Dr. Brown, an expert in refrigerants and heat transfer
`25.
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`compositions, has opined that a person of ordinary skill in the relevant art—that is
`
`one who evaluates, designs, and develops new refrigerants for use as heat transfer
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`fluids—would generally possess a Ph.D. in Chemistry, Chemical Engineering,
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`Mechanical Engineering, Material Science, or in a related field or discipline and
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`would have at least 3 to 5 years of experience in the design, development, and/or
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`modeling of refrigerants, or alternatively such an individual would have a M.S.
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`degree in one of those fields with 5 to 10 years of experience in the refrigerant
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`industry. A person of ordinary skill in the art also would have experience with or
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`access to other individuals with knowledge and experience in the design,
`
`evaluation, and selection of lubricants as well as the toxicology of refrigerants. I
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`adopt this definition.
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`2 Throughout this declaration, I use R-1234yf and HFO-1234yf interchangeably.
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` As a toxicologist who has worked closely with persons of ordinary 26.
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`skill in the art as defined above, it is my opinion that such persons would have a
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`toxicologist available to him or her during the evaluation, design, and development
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`of refrigerants. It is my opinion that one of ordinary skill in the art in the field of
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`toxicology would possess a Ph.D. in toxicology or related sciences coupled with at
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`least 3 years of experience with toxicity testing and the evaluation of the results of
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`toxicity testing of hydrofluorocarbons. Alternatively, the person of ordinary skill
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`in the art may possess a M.S. in toxicology or related sciences coupled with at least
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`7 years of experience with toxicity testing and the evaluation of the results of
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`toxicity testing of hydrofluorocarbons.
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`VII. CLAIM CONSTRUCTION
`
` For the purposes of this proceeding, I have construed the claims as a 27.
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`person of ordinary skill in the art based on the claim language when read in view
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`of the specification. I understand that in post-grant proceedings the claims are
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`construed according to their broadest reasonable interpretation. The constructions
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`provided herein are based on that standard. I note, however, that my opinions in
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`this declaration do not change if broader or narrower constructions are adopted
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`during this proceeding.
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`A.
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`“low toxicity refrigerant suitable for use in automobile air
`conditioning”
`
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` Claims 1, 6, 12, and 19 states “low toxicity refrigerant suitable for use 28.
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`in automobile air conditioning.” (Ex. 1001 at Claims 1, 6, 12, 19.) The broadest
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`reasonable construction of this phrase, when read in light of the specification,
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`means “a refrigerant that has low acute toxicity as measured by inhalation
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`exposure to mice or rats.” This is consistent with the specification, which states
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`that “applicants believe that a relatively low toxicity level is associated with
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`compounds of Formula II, preferably wherein Y is CF3, wherein at least one R on
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`the unsaturated terminal carbon is H, and at least one of the remaining Rs is F.”
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`(Id. at 4:38-42.) This construction is also consistent with the specification’s only
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`other disclosure related to toxicity, specifically: “in highly preferred embodiments,
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`especially embodiments comprising the low toxicity compounds described above,
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`n is zero in which the unsaturated terminal carbon has not more than one F
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`substituent. Applicant has discovered that such compounds have a very low acute
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`toxicity level, as measured by inhalation exposure to mice and rats.” (Id. at 4:45-
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`50.) Reading that passage, a person of ordinary skill in the art would have
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`understood the reference to mice or rats refers to acute inhalation toxicity testing
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`with mice and rats as they are used almost exclusively for such testing, as often no
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`other animals are used.
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` As I have construed this phrase, it does not require a specific chronic 29.
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`toxicity level. Although Honeywell argued during prosecution that “in order to be
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`acceptable for use in conventional [AAC] at the time of the present invention, a
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`refrigerant must be Class A toxicity,” which takes into account both acute and
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`chronic toxicity data (Ex. 1050 at 11), there is nothing in the specification itself
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`that indicates Honeywell was even considering chronic toxicity at the time it
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`originally filed its applications. Thus, a person of ordinary skill in the art reading
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`the claims in view of the specification would not understand them to set any
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`particular standard with respect to chronic toxicity.
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`B.
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`“no substantial acute toxicity as measured by inhalation exposure
`to mice and rats”
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`30.
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` Dependent claims 4, 9, 16, and 20 recite the limitation “no substantial
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`acute toxicity as measured by inhalation exposure to mice and rats.” The
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`specification does not provide any indication what is meant by this phrase, nor
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`does the specification equate any particular LC50 to “no substantial acute toxicity.”
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`The phrase is also not uniquely defined in the toxicology art. As a result, under the
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`broadest reasonable interpretation, it is my opinion that the relative term “no
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`substantial” should be given its common and ordinary meaning.
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`31.
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`In this case, without conceding that the term is definite, this phrase
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`means “essentially no acute toxicity level as measured by inhalation exposure to
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`mice and rats.”
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`VIII. DETAILED STATEMENT OF OPINIONS
`A. Toxicity Testing of Refrigerants
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` As part of my analysis, I have considered the ’017 patent. I 32.
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`understand that the claims of the ’017 patent are directed to heat transfer
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`compositions (and their uses in AAC) “consisting essentially of: (i) at least about
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`50% by weight of a low toxicity refrigerant suitable for use in automobile air
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`conditioning systems, said refrigerant consisting essentially of 2,3,3,3-
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`tetrafluoropropene (HFO-1234yf); and (ii) lubricant consisting essentially of
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`polyalkylene glycol(s).” (E.g., Ex. 1001 at 18:37-43 (emphasis added).)
`
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`33.
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`In the evaluation of the toxicity profile of a material such as a gas,
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`volatile substance, or aerosol/particulate, determination of acute inhalation toxicity
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`is an important initial step. Beyond this, a further toxicity profile can include
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`various other toxicity tests, such as subchronic inhalation studies, mutagenicity
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`studies, and chronic exposure tests. With respect to the conduct of acute inhalation
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`studies, there are international guidelines published by governmental and non-
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`governmental organizations including the U.S. Environmental Protection Agency
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`(EPA) and the Organization for Economic Cooperation and Development (OECD),
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`e.g., EPA 870.1300 and OECD Test Guideline 403.
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`34.
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`In an acute inhalation toxicity study, different groups of experimental
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`animals, typically mice or rats, are exposed to the test substance for a defined
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`period of time in graduated concentrations to develop a dose-response relationship.
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`One concentration is most often examined per group of experimental animals.
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`Selection of the initial concentration is determined by consideration of data
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`available either for the particular substance or for structurally-related substances.
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`Controls are not usually used in acute inhalation toxicity studies. During and
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`following exposure, the animals are observed for toxicological effects and
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`mortality. Animals that die during the test are necropsied as soon as possible. The
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`abdominal and thoracic cavities in these dead animals are examined to identify any
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`possible target organ toxic effects. At the conclusion of the observation period,
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`usually 14 days, test animals that survive are humanely sacrificed and necropsied.
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` The exposure duration in an acute inhalation toxicity study is usually 35.
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`4 hours, although shorter or longer durations are used depending on the purpose of
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`the study.
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` The result of an acute inhalation toxicity study is the LC50 (median
`36.
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`lethal concentration). It is a statistically derived concentration of a substance that
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`would be expected to cause death in 50% of a population of experimental animals
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`exposed for a specified time. The LC50 value is expressed as weight of test
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`substance per standard volume of air (mg/L or mg/m3) or as parts per million
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`(ppm). The higher the LC50 value the less toxic the substance.
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` Another potential result from an acute inhalation toxicity study is the 37.
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`approximate lethal concentration (ALC). The ALC is the lowest concentration of
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`the test substance that results in a single mortality of the exposed animals. This is
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`a measured value. The ALC value is expressed as weight of test substance per
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`standard volume of air (mg/L or mg/m3) or as parts per million (ppm). This value
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`approximates the LC50 of a substance, although the ALC will be lower than the
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`LC50.
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` The data obtained from an acute inhalation toxicity study provides 38.
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`information on the potential human health hazards likely to arise from a single
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`exposure by inhalation.
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` Data from an acute inhalation toxicity study would be used to 39.
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`establish dose levels in subsequent acute and repeat dose toxicity studies.
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`40.
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`In addition, data from an acute inhalation study may serve as a basis
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`for classifying the toxicity of a compound, for example, “toxic” or “highly toxic.”
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`41.
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` OSHA defines “toxic” and “highly toxic” as follows (29 C.F.R. §
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`1910.1200 app. A (2002)) (Ex. 1077):
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`Toxic. A chemical falling within any of the following
`categories: . . .
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`(c) A chemical that has a median lethal concentration
`(LC50) in air of more than 200 parts per million but not
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`more than 2,000 parts per million by volume of gas or
`vapor, . . .
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`3. Highly toxic: A chemical falling within any of the
`following categories: . . .
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`(c) A chemical that has a median lethal concentration
`(LC50) in air of 200 parts per million by volume or less of
`gas or vapor.
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`
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` These definitions of “toxic” and “highly toxic” were incorporated into 42.
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`ASHRAE Standard 34 (Ex. 1154) by Addendum G to ASHRAE 34-2004.
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`B.
`
`By 2002 A Person of Ordinary Skill in the Art Would Have
`Predicted a Low and No Substantial Acute Toxicity for
`HFO-1234yf
`
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`43.
`
`In toxicology, one of the first steps in the evaluation of a substance
`
`with unknown toxicity, regardless of the end use of the substance, is to evaluate the
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`acute toxicity of the compound. Without any toxicity data for the compound, a
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`toxicologist assisting the skilled artisan would first consider the toxicity of
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`structurally-related halogenated compounds. Structurally-related compounds
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`include, for example, compounds with similar elements, similar numbers of atoms,
`
`and similar structures. A toxicologist would also consider any known structure-
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`toxicity relationships. By preparing a hierarchy of known acute toxicity values and
`
`evaluating the structures associated with those values, a toxicologist could often
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`predict, with a reasonable degree of scientific certainty, where the acute inhalation
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`toxicity of a compound would fall within that hierarchy.
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`
`
` Prior to 2002, the acute toxicity of many halogenated hydrocarbons 44.
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`was known. In addition, the art established clear correlations between the structure
`
`of a compound and its acute toxicity. For example, as will be discussed in detail
`
`below, it was well-known in 2002 that replacing a bromine or chlorine atom with a
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`fluorine atom in a compound would generally lead to relatively lower acute
`
`toxicity. (Ex. 1141, Clayton 1977 at 256; see also Ex. 1140, Clayton 1967 at 225-
`
`26.) In addition, by as early as the 1970s, researchers understood that adding
`
`electronegative fluorine atoms and trifluoromethyl groups adjacent to a double
`
`bond could render a compound more susceptible to nucleophilic attack, increasing
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`the acute toxicity. (E.g., Exs. 1140, Clayton 1967 at 225; 1141, Clayton 1977 at
`
`Table 1.)
`
`1.
`
`A person of ordinary skill in the art would have expected
`HFO-1234yf to have acute inhalation toxicity similar to the
`relatively non-toxic R-1243zf
`
`
`45.
`
`I have reviewed a Japanese Patent Application of Daikin, JP 4-
`
`110388, referred to as “Inagaki,” (Ex. 1012) which discloses a class of about 30
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`fluoroalkene refrigerants, and includes examples directed to five specific
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`refrigerants, as shown in the following table:
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`Example 1
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`R— l 2432f
`
`Example 2
`
`R-1234ze
`
`Example 3
`
`R- 1 243yc
`
`Example 4
`
`R—126lyf
`
`Example 5
`
`R—l234yf
`
`OR F3C-CF=CH2
`
`46. As a toxicologist, I consider these compounds to be structurally
`
`similar to one another. For example, each compound has three carbon atoms. All
`
`but one has three or four fluorine atoms, and all but one has either two or three
`
`hydrogens. Moreover, each has a double bond. Thus, at this basic level, a
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`toxicologist assisting a person of ordinary skill in the art to assess the acute toxicity
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`of R—l234yf would have considered the acute toxicity of at least these structurally
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`similar compounds, especially R—1243zf as its acute toxicity was known at the
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`time.
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`47.
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`In particular, prior to 2002 the acute inhalation toxicity for R-1243zf
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`was known to be low. For example, a 1975 patent states that “[t]rifluoropropene
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`(sic) is flammable, and acute studies indicate it to be relatively non-toxic.” (Ex.
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`1138, Butler at 2:35-36.) In a toxicity study report created in 1965 and submitted
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`to the EPA by Dow Corning in 1991, R-1243zf is specifically reported as having
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`an acute toxicity LC50 value of approximately 315,000 ppm. (Ex. 1139, Dow
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`Corning Report dated 1965, submitted to EPA in 1991.) Compared to the OSHA
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`classification for something having an LC50 value of between 200 ppm and 2,000
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`ppm, this value is significantly higher. Based on that and my experience in the
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`field, it is my opinion that an LC50 value of 315,000 ppm means that the compound
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`has no substantial acute toxicity as I have construed that term above.
`
`
`
` R-1234yf is structurally similar to R-1243zf, having only one 48.
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`additional fluorine atom. Based on this structural similarity, a toxicologist of
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`ordinary skill would have expected R-1234yf to have an acute inhalation toxicity
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`that is similar to that of R-1243zf. Thus, considering only the acute inhalation
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`toxicity of R-1243zf, a person of ordinary skill in the art, with the assistance of a
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`toxicologist, would have had a reasonable expectation that R-1234yf would
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`likewise “be relatively non-toxic,” that is, have “no substantial acute toxicity.”
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`2.
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`Consideration of additional prior art toxicity information
`confirms that a person of ordinary skill in the art would
`have expected HFO—1234yf to have low (and no substantial)
`acute toxicity
`
`a.
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`Fluorochemical compounds
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`49.
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`Consideration of additional fluorochemical compounds with known
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`acute toxicity Values, which a skilled toxicologist would likely have done, confirms
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`my opinion that a person of ordinary skill in the art prior to October 2002 would
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`have reasonably expected that R—1234yf would have low and no substantial acute
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`inhalation toxicity.
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`50.
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`In the 1960s and 1970s, Clayton and co-workers reported the acute
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`inhalation toxicities of haloalkanes and haloalkenes. (E.g., Exs. 1140, Clayton
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`1967; 1141, Clayton 1977.) For example, Table 1 of Clayton 1977, reproduced
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`below, reports acute inhalation toxicity Values for a series of fluoroalkenes:
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`Table I. Inhalation toxicity of several fluoroalkenes.“
`
`Acute toxicity for rats‘
`
`Structure
`
`1 CH.=CHF
`2 CF,=CH,
`
`3 CF,=CF,
`4 CF,CF=CF,
`5
`(cp,),c=cp,
`
`No. F
`atoms
`
`I
`2
`
`4
`6
`8
`
`ALC.
`ppm
`
`>800.000°
`I28,000
`>800.000=
`—
`—
`0.5. 0.76‘
`
`LC“
`ppm
`
`-
`—
`—
`40.000
`3.000
`—
`
`"Data of Clayton (5).
`"4-hr exposures except where noted.
`'80% CH,=CHF, 20% 0.; 12.5-hr exposure.
`‘80% CH,=CF., 20% 0,; I9-hr exposure.
`'0.5 ppm exposure was 6 hr; the 0.76 ppm exposure was 4 hr.
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` Although some of the values reported are ALC values instead of LC50
`51.
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`values, as mentioned above, an ALC value provides a reasonable estimate of the
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`LC50 value for a compound because the compound’s ALC value is almost always
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`lower than its LC50 value.
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`
`
` The data in Table 1 of Clayton 1977 teaches that inserting a fluorine 52.
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`atom on all carbons in a molecule will generally increase the acute inhalation
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`toxicity of the compound. For example, compound 1, which has only 1 fluorine
`
`atom per its 2 carbon atoms, has an ALC of greater than 800,000 ppm. In contrast,
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`the completely fluorinated compound 3 with 4 fluorine atoms per its 2 carbon
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`atoms has an LC50 value of 40,000 ppm. Although neither is toxic according to
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`OSHA’s classification of a toxic compound, the more fluorinated compound is
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`relatively more toxic than the less fluorinated compound. Stated differently,
`
`increasing the carbon-to-fluorine ratio generally leads to decreased acute inhalation
`
`toxicity. Specifically, looking at compound 3 in Table 1, there are two fluorine
`
`atoms on each carbon (C:F of 1:2). That compound possesses a higher acute
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`inhalation toxicity than either of compounds 1 (C:F of 2:1) or 2 (C:F of 1:1) that
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`include hydrogen atoms on at least one of the carbons.
`
`
`53.
`
`In addition, as noted by Clayton in 1967, “[t]he presence of a double
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`bond in the fluorocarbons creates a special chemical environment.” (Ex. 1140,
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`Clayton 1967 at 225.) In particular, “[t]he strong electronegative force of opposing
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`fluoroalkyl groups produces an area of low electron density between adjacent
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`carbons, making the site susceptible to nucleophilic attack.” (Id.) This means that
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`fluorine atoms tend to pull electron density away from typically electron-rich
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`double bonds. As a result of this shift in electron density, the double bond
`
`becomes a potential target for biological nucleophiles, such as –OH and nitrogen-
`
`containing groups, which may lead to higher acute toxicity.
`
`
`
` Accordingly, based on Clayton’s teaching regarding the effect of 54.
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`fluorine atoms on the susceptibility to nucleophilic attack of a double bond, a
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`person of ordinary skill before 2002 would have reasonably expected that a
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`compound with fewer fluorine atoms attached to a terminal, unsaturated carbon of
`
`a double bond would be less acutely toxic than a compound with one or two
`
`fluorine atoms attached to a terminal carbon of a double bond. The compounds in
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`Table 1 of Clayton 1977 demonstrate this very trend.
`
`
`
` This trend is further demonstrated by comparing the acute inhalation 55.
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`toxicity values of R-1243zf and R-1225zc, which were known prior to 2002. R-
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`1225zc possesses five fluorine atoms and has two fluorine atoms on the terminal
`
`unsaturated carbon. In contrast, R-1243zf possesses three fluorine atoms, as well
`
`as two hydrogen atoms on the terminal carbon of the double bond. The removal of
`
`those fluorine atoms decreased the acute inhalation toxicity of the compound by
`
`approximately 150-fold.
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`Acute Toxici of R-1243zf and R-1225zc
`
`R—l243zf
`
`R-1225zc
`
`(3,3,3—trifluoropropene)
`
`(1,1,3,3,3—pentafluoropropene)
`
`Formula
`
`CH2CHCF3
`
`CF3CH=CF;
`
`H
`
`HF
`
`F
`
`F
`
`Butler reports that R—1243zf is
`
`“relatively non-toxic.”
`
`(Ex. 1138, Butler at 2:29-39.)
`
`DuPont reported a 4—hr LC 50
`
`Value of < 2000 ppm
`
`Toxicity
`
`(Ex. 1148, DuPont Haskell
`
`Dow Corning (Ex. 1139)
`
`reported that the 4—hr LC5o value
`
`is 315,000 ppm
`
`Support Letter at A04 (2000))
`
`56. Honeywell’s later data relating to R—1225ye, the compound that
`
`results when one of the fluorine atoms attached to the terminal unsaturated carbon
`
`in compound 4 of Table 1 of Clayton 1977 is replaced with a hydrogen atom,
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`confirms this trend and demonstrates that the very low toxicity of R-1234yf is not
`
`unexpected. During prosecution of the ’017 patent, Honeywell submitted evidence
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`that R-1225ye has LC50 values of >250,000 ppm in rats, and from 100,000 ppm to
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`250,000 ppm in mice. (Ex. 1142, Rusch Decl. at ¶¶ 3-6). That is significantly
`
`higher (less toxic) than the LC50 value for compound 4 in the Clayton 1977 Table
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`1, which differs structurally in that it