throbber
Filed on behalf of: Patent Owner, Finchimica S.p.A.
`
`Paper __
`
`Date filed: August 31 2016
`
`By: E. Anthony Figg, Lead Counsel
`R. Danny Huntington, Back-up Counsel
`Sharon E. Crane, Ph.D., Back-up Counsel
`Seth E. Cockrum, Ph.D., Back-up Counsel
`Derek F. Dahlgren, Back-up Counsel
`ROTHWELL, FIGG, ERNST & MANBECK, P.C.
`607 14th Street, N.W., Suite 800
`Washington, DC 20005
`Phone: 202-783-6040
`Facsimile: 202-783-6031
`Emails: efigg@rothwellfigg.com
`dhuntington@rothwellfigg.com
`scrane(mrothwellfigg.com
`scockrum@rothwellfigg.com
`ddahlgren@rothwellfigg.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ADAMA MAKHTESHIM LTD.,
`Petitioner,
`
`V.
`
`FINCHIMICA S.P.A.,
`Patent Owner.
`
`Case IPR2016-00577
`Patent 8,304,559 B2
`
`DECLARATION OF DENNIS P. CURRAN, PH.D.
`
`FINCHIMICA EXHIBIT 2026
`ADAMA MAKHTESHIM v. FINCH/MICA
`CASE IPR2016-00577
`
`

`
`The undersigned, Dennis P. Curran, Ph.D., does hereby declare and state that:
`
`
`1.
`
`I make the following declaration based on my knowledge and belief.
`
`Qualifications
`
`2.
`
`I received my B.S. in Chemistry in 1975 from Boston College. My
`
`Ph.D. was granted from the University of Rochester in 1979 where I worked under
`
`Professor Andrew S. Kende. After a two year postdoctoral stay with Professor
`
`Barry M. Trost at the University of Wisconsin, I joined the faculty of the
`
`Chemistry Department at the University of Pittsburgh in 1981.
`
`3.
`
`I now hold the ranks of Distinguished Service Professor and Bayer
`
`Professor of Chemistry. I have received an Honorary Doctorate from the
`
`University of Paris (2010), and I am Fellow of the American Chemical Society
`
`(2009) and the American Association for the Advancement of Sciences (2001).
`
`4.
`
`Among other awards, I have received the American Chemical Society
`
`Ernest Guenther Award in the Chemistry of Natural Products (2014); the Chaire
`
`d’excellence, Agence National de la Recherche (ANR), France (2009–2010); the
`
`American Chemical Society Award for Creative Work in Fluorine Chemistry
`
`(2008); the University of Pittsburgh Innovator Award (2007); the Harry and Carol
`
`Mosher Award, Santa Clara Valley Section, American Chemical Society (2007);
`
`the Blaise Pascal International Research Chair, Préfecture de la Région D’Ile-de-
`
`France Paris (2007-2008); the Pittsburgh Award, Pittsburgh Section, American
`
`
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`1
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`

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`Chemical Society (2006); the Morley Medal, Cleveland Section, American
`
`Chemical Society (2006); the Pittsburgh Magazine Innovators Award (2003); the
`
`American Chemical Society Award for Creativity in Organic Synthesis (2000); the
`
`American Chemical Society Cope Scholar Award (1988); the Chancellor's
`
`Distinguished Research Award, University of Pittsburgh (1999); and the Janssen
`
`Prize for Creativity in Organic Synthesis (1998). I have coauthored about 475
`
`papers on research in the area of organic synthesis, and I am listed as a co-inventor
`
`on 40 U.S. patents, many of which have international counterparts. A copy of my
`
`curriculum vitae is submitted herewith as Exhibit 2020.
`
`Understanding of this Proceeding
`
`5.
`
`I have been retained in this matter by Rothwell, Figg, Ernst &
`
`Manbeck, P.C. of Washington, D.C. (“RFEM”), the attorneys representing party
`
`Pastorio in this proceeding, and am being compensated at my standard consulting
`
`fee of $575 per hour.
`
`6.
`
`I do not have any financial interest in either of the real parties in
`
`interest and neither my compensation nor my opinions depend on the outcome of
`
`this proceeding.
`
`7.
`
`I have been informed this proceeding is an Inter Partes Review before
`
`the Patent Trial and Appeal Board of the United States Patent and Trademark
`
`Office (“the Board”). I have been informed that an Inter Partes Review is a
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`
`
`2
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`

`
`proceeding before the Board to review the patentability of one or more issued
`
`claims in a United States patent on grounds that the subject matter claimed was
`
`anticipated by or rendered obvious in view of the prior art.
`
`8.
`
`I have been informed that Adama Makhteshim Ltd., (“Adama” or
`
`“Petitioner”) filed a Petition requesting Inter Partes Review (“the Petition”) of
`
`U.S. Patent No. 8,304,559 issued to Andrea Pastorio and Paolo Betti (“the ʼ559
`
`patent”) (Ex. 1001) and assigned to Finchimica, S.p.A. (“Finchimica”). I have
`
`reviewed the Petition, and understand that it alleges that claims 1-12 of the ’559
`
`patent are unpatentable in view of multiple combinations of various prior art
`
`references. I further understand the claims 13-15 of the ʼ559 patent have been
`
`statutorily disclaimed.
`
`9.
`
`I have further been informed that the Board ordered Inter Partes
`
`review of the ʼ559 patent in a decision dated May 24, 2016 (“the Board’s
`
`decision”) (Paper 7). I have reviewed the Board’s decision to order Inter Partes
`
`review, and understand the Board did not institute on all of the unpatentability
`
`grounds that Adama asserted in the Petition.
`
`10. Because the Board did not institute on all grounds, I understand that
`
`the only ground at issue in this proceeding is Ground 1, i.e., whether claims 1 – 12
`
`of the ʼ559 patent are unpatentable as obvious over EP 0295117 (“EP ʼ117”) in
`
`view of WO 2007/122440 (“WO ʼ440”) and further in view of CN 101250158
`
`
`
`3
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`

`
`(“CN ʼ158”). (Paper 7, p. 17). I have set forth my understanding of the legal
`
`concept of obviousness below.
`Legal Standards
`
`11.
`
`I have been informed that to demonstrate obviousness requires
`
`consideration of (1) the scope and content of the prior art, (2) the differences
`
`between the prior art and the claims at issue, and (3) the level of ordinary skill in
`
`the art, and (4) objective evidence of nonobviousness.
`
`12.
`
`I have also been informed that in an obviousness analysis, it is
`
`necessary to identify a reason that a person of ordinary skill in the art would have
`
`combined the teachings of prior art references to achieve the claimed invention. I
`
`have been informed that obviousness cannot be based on hindsight selection of
`
`elements of the claimed invention from among the disclosures of the prior art as a
`
`whole. I am also informed that a prior art reference may teach away from a
`
`particular combination when the prior art reference criticizes, discredits, or
`
`otherwise disparages investigation into the claimed invention.
`
`13.
`
`In forming my opinions, I considered the level of ordinary skill in the
`
`art and the scope and content of the prior art in the time frame around July 7, 2010,
`
`the claimed priority date of the Pastorio ʼ559 patent. One of ordinary skill in the
`
`art relevant to ʼ559 patent would have a bachelor’s or master’s degree in chemistry
`
`or a related discipline and have several years of experience in synthetic organic
`
`
`
`4
`
`

`
`chemistry. Alternatively, such a person could have a Ph.D. in organic chemistry,
`
`and 1-2 years of experience in synthetic organic chemistry.
`
`14.
`
`I have reviewed the definition of a person of ordinary skill in the art
`
`that is set forth in the Declaration of Gordon W. Gribble, Ph.D. (Ex. 1010, ¶14). I
`
`do not believe there are any substantive differences between the definition that Dr.
`
`Gribble has proposed, and my definition.
`
`Invention of the ʼ559 Patent Claims
`
`15. The ʼ559 patent discloses an improved process for synthesizing the
`
`compound having the general formula (I):
`
`(Ex. 1001, 1:23-40). When R1 and R2 are chlorine, the compound is known as
`
`
`
`fipronil.
`
`16. The process disclosed in the ʼ559 patent involves the oxidation of the
`
`compound having the general formula (II):
`
`
`
`5
`
`

`
`
`
`(Ex. 1001, 1:42060). When R1 and R2 are chlorine, the compound is known as the
`
`fipronil precursor.
`
`The ʼ559 Patent Expressly Criticizes the Prior Art Processes
`
`17. As background for the claimed invention, the ʼ559 patent discusses a
`
`number of previous processes for synthesizing the compound having the general
`
`formula (I). For example, it discusses EP 02951171 (“EP ʼ117”), which utilized a
`
`3-chlorobenzoic acid derivative in the synthesis. (Ex. 1001, 1:61-62). The ʼ559
`
`patent explains that the EP ʼ117 method had “evident disadvantages” in terms of
`
`yield and costs, including the “impossibility” of re-using the oxidizing agent. (Ex.
`
`1001, 1: 63-65). For this reason, the ʼ559 patent inventors described the method
`
`disclosed in EP ʼ117 as “unsatisfactory.” (Ex. 1001, 1:61-2:4; Ex. 2021, 70:12-
`
`72:3).
`
`
`1
`The EP ʼ117 reference discussed in the ʼ559 patent is the same EP ʼ117
`reference relied upon in Ground 1 of the Petition.
`6
`
`
`
`

`
`18. The ʼ559 patent also discusses another method that was proposed in
`
`WO 01/030760 (“WO ʼ760”; Ex. 2022). WO ʼ760 was filed on behalf of Aventis
`
`Cropscience S.A. (Ex. 2022, p. 1). According to the ʼ559 patent, the WO ʼ760
`
`application discloses a synthesis method in which the oxidation is conducted in the
`
`presence of trifluoroperacetic acid (“TFPA”) obtained from trifluoroacetic acid
`
`(“TFA”) in the presence of hydrogen peroxide and boric acid. (Ex. 1001, 1:66-
`
`2:3). The Pastorio ʼ559 patent identifies drawbacks or disadvantages of the
`
`method of WO ʼ760 and further describes that method as “unsatisfactory.” These
`
`drawbacks and disadvantages include the fact that (1) TFA is extremely expensive,
`
`(2) it releases hydrogen fluoride which attacks vitreous coatings of industrial
`
`equipment even at ambient conditions, and (3) a corrosion inhibitor would not
`
`protect equipment needed for recovery of the TFA. (Ex. 1001, 2:4-20).
`
`19. The Pastorio ʼ559 patent next discusses the WO ʼ440 reference.2 (Ex.
`
`1004). The ʼ559 patent states that WO ʼ440 overcomes the drawbacks of WO
`
`ʼ760. (Ex. 1001, 2:21-22). According to the ʼ559 patent, WO ʼ440 overcomes
`
`these drawbacks by using trichloroperacetic acid (“TCPA”) instead of TFPA. (Ex.
`
`1001, 2:23-24). The ʼ559 patent states that WO ʼ440 reports the TCPA is the
`
`effective oxidizing species and is formed in situ by the reaction of an oxidizing
`
`agent with trichloroacetic acid (“TCA”). (Ex. 1001, 2:25-27).
`
`2
`The WO ʼ440 reference discussed in the ʼ559 patent is the same WO ʼ440
`reference relied upon in Ground 1 of the Petition.
`7
`
`
`
`

`
`20.
`
`In addition to serving as the precursor for TCPA, WO ʼ440 explains
`
`that TCA also acts as a reaction solvent. (Ex. 1001, 2:28-29). Because TCA is a
`
`solid at the temperature at which the synthesis takes place, WO ʼ440 discloses that
`
`melting point depressant is required. (Ex. 1001, 2:30-35). The Pastorio ʼ559
`
`patent reports that, according to WO ʼ440, dichloroacetic acid (“DCA”) and
`
`monochloroacetic acid (“MCA”) are suitable for this purpose and reports that a
`
`mixture of 70-80% TCA and 30-20% DCA was suitable where the “sole purpose”
`
`of the DCA is to depress TCA’s melting point. (Ex. 1001, 2:36-42) (emphasis
`
`added).
`
`21. The ʼ559 patent concludes, however, that the WO ʼ440 process has its
`
`own drawbacks. (Ex. 1001, 2:43-44). These drawbacks include having to operate
`
`in a temperature range that favors formation of the sulfone over-oxidation product.
`
`Formation of that product consumes the desired fipronil product, which results in a
`
`decreased yield of fipronil. (Ex. 1001, 2:43-54). Another drawback is that the WO
`
`ʼ440 process requires the use of an additional solvent that acts as a melting point
`
`depressant for the TCA. (Ex. 1001: 2:55-63). Because of these drawbacks, the
`
`Pastorio inventors set out to develop a new method for the production of fipronil
`
`that avoided the problems with the prior art processes.
`
`8
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`
`
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`

`
`The ʼ559 Patent Considers the Use of DCA as the Reaction Medium to
`be Novel and Inventive
`
`22.
`
`In view of the disadvantages that the ʼ559 patent identified with the
`
`prior processes, it provides a new process that employs a low-cost, non-corrosive,
`
`efficient reagent that was not discovered by any of the prior researchers.
`
`According to the ʼ559 patent “[t]he present invention therefore sets out to provide a
`
`new method for the preparation of the compound having the general formula (I)
`
`using an economically advantageous oxidation method convenient to implement in
`
`industrial applications.” (Ex. 1001, 3: 4-8). The ʼ559 patent states that this
`
`objective is achieved by oxidizing the compound having the general formula (I) in
`
`the presence of dichloroacetic acid and an oxidizing agent. (Ex. 1001, 3:44 - 4:4).
`
`As a result of that process, the chemical species responsible for the oxidation,
`
`dichloroperacetic acid, is formed by oxidation of DCA by the oxidizing agent, e.g.,
`
`hydrogen peroxide. (Ex. 1001, 4:26-31). The ʼ559 patent provides that the
`
`oxidation “is conducted in the absence of trichloroacetic acid and/or
`
`trichloroperacetic acid, so that the process of the present invention does not require
`
`prior solubilization of the oxidant.” (Ex. 1001, 4:39-42). Accordingly, the ʼ559
`
`Patent explains that “[t]he present invention therefore allows to operate in the
`
`absence of solvents at the same temperature and to achieve excellent selectivity
`
`similar to the ones achieved with trifluoroperacetic acid but without having to use
`
`an extremely expensive solvent such as TFA . . . .” (Ex. 1001, 5:29-33).
`
`
`
`9
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`

`
`23. The ʼ559 patent goes on to state:
`
`Innovatively, the method of the present invention is conducted in the
`presence of an oxidising agent and of dichloroacetic acid making a
`plurality of operations superfluous, for example dissolution, otherwise
`essential in the known methods.
`
`Advantageously, the method of the present invention allows to
`achieve higher yields compared to the methods of the prior art, in that
`the reaction takes place with improved selectivity thereby preventing
`the consumption of useful product in parasite reactions.
`
`Advantageously, the method of the present invention, once the excess
`of unconverted reagent (II) has been easily recovered, makes
`subsequent purification of the compound having the general formula
`(I) superfluous, which as well as being burdensome in itself is
`economically disadvantageous.
`
`Advantageously, the use of the oxidising agent of the present
`invention does not require the use of solvents for the reaction, making
`the entire process much simpler and economically advantageous in
`industrial applications.
`
`In fact, according to a further advantageous aspect, the cost of such
`oxidant is lower than the cost of the oxidants traditionally used.
`
`Advantageously, the function performed by the DCA in the method of
`the present invention enables economies in terms of costs of the
`reagents, and simplification of the plant for implementing the
`teaching.
`
`Advantageously, the process of the present invention makes the use of
`corrosion inhibitors superfluous and allows to drastically increase the
`useful life of the equipment used.
`
`It was, in fact, observation of the premature corrosion of the plants
`which urged the authors of the present invention to look for an oxidant
`agent alternative to the oxidants traditionally used.
`
`As a result, the aforesaid advantage is twofold in that it derives both
`
`
`
`10
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`

`
`from the non-use of a corrosion inhibitor and from the increased
`useful life of the equipment.
`
`(Ex. 1001, 8:4-44)
`
`24. The ʼ559 patent also describes three examples for the production of
`
`fipronil. Each of these examples describes the use of DCA as the solvent for the
`
`oxidation reaction of the fipronil sulfide precursor. (Ex. 1001, 6:58-8:3).
`
`Claim Construction
`
`25.
`
`I have reviewed Dr. Gribble’s declaration, and understand that he has
`
`offered certain opinions regarding the scope of the ʼ559 patent claims. I disagree
`
`with Dr. Gribble’s opinions to the extent they are contradicted by the disclosures of
`
`the ʼ559 patent as they would be understood by one of ordinary skill in the art.
`
`The Claims Require DCA to Be Present in More than a Trivial
`Amount
`
`26.
`
`I understand that Dr. Gribble has offered his opinion that the ʼ559
`
`patent claims require DCA to be present “in at least some amount” but does not
`
`require DCA to be “present in any specified amount.” (Ex. 1010, ¶24). I disagree
`
`with Dr. Gribble if his intent is to allege that the DCA need be present in only
`
`trivial amounts. A person of ordinary skill would recognize from the ’559 patent
`
`that the use of DCA in the oxidation process is the essential feature of the novel
`
`process. As described above, the ʼ559 patent repeatedly emphasizes the use of
`
`
`
`11
`
`

`
`DCA as the reaction medium. Because DCA is the central feature of the invention,
`
`relegating it to a trivial component would nullify the whole point of the invention.
`
`The ʼ559 Patent Claims Exclude m-CPBA, TFA, and TFPA
`
`27.
`
`I understand that Dr. Gribble contends that a person of ordinary skill
`
`would have been motivated by the WO ’440 reference to substitute DCA for the
`
`reaction solvent, DCM, in the EP ’117 m-CPBA process, and the resulting process
`
`would be covered by the claims of the ’559 patent. Thus, a critical aspect of Dr.
`
`Gribble’s obviousness position is his opinion that the use of DCA in combination
`
`with m-CPBA is encompassed by the claims of the Pastorio ʼ559 patent. (Ex.
`
`1010, ¶¶31-32). I disagree with Dr. Gribble and submit that his hindsight efforts to
`
`modify the EP ’117 process ignore important facts, as well as the express teachings
`
`of the ’559 patent. A person of skill in the art would understand that the Pastorio
`
`ʼ559 patent clearly and unambiguously disavowed the use of m-CPBA. For
`
`example, the ʼ559 patent explains that the method using m-CPBA has “evident
`
`disadvantages.” (Ex. 1001, 1:61-65). As Dr. Gribble has acknowledged, the ʼ559
`
`patent also explains that both the EP ’117 process using m-CPBA as well as the
`
`WO ’760 process using trifluoroperacetic acid are “unsatisfactory.” (Ex. 1001,
`
`1:61-2:4; Ex. 2021, 70:12-72:3). In my opinion, a person of skill in the art would
`
`not have understood the ʼ559 patent claims to include the use of reagents, such as
`
`m-CPBA, that it specifically criticizes and characterizes as “unsatisfactory.”
`
`
`
`12
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`

`
`28. Similarly, Dr. Gribble has stated that the claims of the ʼ559 patent
`
`encompass the use of TFA and TFPA. (Ex. 1010, ¶33). Again, I disagree. A
`
`person of skill in the art would understand that the ʼ559 patent clearly and
`
`unambiguously teaches that the invention utilizes DCA without TFA. For
`
`example, the Pastorio ʼ559 patent states that the method using TFA is
`
`“unsatisfactory.” (Ex. 1001, 2:4-20). It also explains why the method is
`
`“unsatisfactory” by describing the drawbacks of using TFA in some detail. (Id.).
`
`In my opinion, a person of skill in the art would not have understood Pastorio’s
`
`invention to include the reagents, such as TFA and TFPA, that it specifically
`
`criticizes.
`
`29. Notably, Dr. Gribble does not address the ʼ559 patent’s criticism of
`
`the use of m-CPBA, TFA, or TFPA. Instead, he cites to a single sentence toward
`
`the end of the ʼ559 patent that states “one embodiment envisages that the peroxides
`
`illustrated earlier may be replaced or used in conjunction with a peracid and/or a
`
`persulphate.” (Ex. 1010, ¶32 citing Ex. 1001, 8:59-61). It is my opinion that a
`
`person of ordinary skill in the art would not have read that sentence as nullifying
`
`the ʼ559 patent’s earlier express criticism of the m-CPBA or TFA/TFPA methods.
`
`Thus, although the ʼ559 patent may not exclude the use of certain peracids and/or
`
`persulphates as oxidizing agents, a person of ordinary skill would have understood
`
`
`
`13
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`

`
`that the use of those peracids that it specifically characterizes as “unsatisfactory,”
`
`i.e., m-CPBA, TFPA, and TCPA, were disavowed.
`
`30. Dr. Gribble’s obviousness theory relies on EP ʼ117, and its use of m-
`
`CPBA as an oxidation agent. However, for the reasons discussed above, a person
`
`of ordinary skill in the art would have understood the ʼ559 patent claims exclude
`
`the use of m-CPBA.3 Thus, a person of ordinary skill in the art would not have
`
`looked to the process described in EP ʼ117, and would certainly not have thought
`
`to use the disavowed oxidizing agent that is described in that reference.
`
`Accordingly, a person of ordinary skill in the art would not have arrived at the
`
`combination of references that Dr. Gribble proposes, i.e., EP ʼ117 in view of WO
`
`ʼ440.
`
`The Process for Producing Fipronil Described in EP ʼ117 is
`Criticized and Distinguished in the ʼ559 Patent
`31. EP ʼ117 was first published on December 14, 1988. (Ex. 1002, p. 1).
`
`The reference discloses various methods for producing fipronil, including by
`
`oxidation of the sulfide precursor. (Ex. 1002, p. 11). EP ʼ117 discloses that the
`
`oxidants suitable for oxidizing the fipronil precursor are hydrogen peroxide, TFPA,
`
`or m-CPBA. (Id.). EP ʼ117 states the preferred oxidant is m-CPBA. (Id.). The
`
`EP ʼ117 method also requires the use of a solvent, such as dichloromethane,
`
`chloroform, or trifluoroacetic acid. A person of ordinary skill would have
`
`3
`The ʼ559 patent claims also exclude TFA and TFPA for the same reasons.
`14
`
`
`
`

`
`understood from EP ʼ117 that if m-CPBA was used as the oxidant, then the solvent
`
`would have been either dichloromethane or chloroform. However, if TFPA was
`
`the desired oxidizing agent, then TFA would have been used as the solvent along
`
`with hydrogen peroxide as an oxidizing agent to produce TFPA in situ.
`
`32. EP ʼ117 contains an example in which the sulfide precursor is
`
`oxidized with m-CPBA in DCM. (Ex. 1002, p. 15). In that example, 10 g of the
`
`sulfide precursor was dissolved in 100 mL of DCM. (Id.). 4.5 g of m-CPBA was
`
`then added to this solution, and the reaction was stirred overnight. (Id.). An
`
`additional 1.6 g of m-CPBA was then added. (Id.). The reaction proceeded over
`
`the course of two days, and produced 6 grams of fipronil, which is a yield of
`
`approximately 60%.
`
`33. Example 1 of EP ʼ117 uses a large excess of DCM – as is typical of
`
`reaction solvents – to dissolve small amounts of the oxidant m-CPBA and the
`
`fipronil sulfide precursor. Given the relative amounts, a person of ordinary skill in
`
`the art would have understood that the DCM was acting as a conventional solvent
`
`for the oxidant m-CPBA, which EP ʼ117 identifies as the role of DCM. (Ex. 1002,
`
`11:22-23). There is no suggestion or instruction that the m-CPBA would dissolve
`
`if DCM were used in minor amounts, or that a suitable process could be achieved
`
`by depressing the melting point of m-CPBA.
`
`
`
`15
`
`

`
`34. m-CPBA is the oxidant in the EP ʼ117 process. It is not the solvent.
`
`m-CPBA is a peracid and is a commonly used oxidizing agent (at least in
`
`laboratory scale methods), and is commercially available. It is sold as a solid that
`
`contains m-chlorobenzoic acid (“m-CBA”) and water. (Ex. 1020). The melting
`
`point of m-CPBA is 92-94°C. (Ex. 1020). A person of ordinary skill would not
`
`have expected that a small amount of DCM or DCA would reduce to the melting
`
`point of m-CPBA to 10°C - 20°C.
`
`WO ʼ440 Teaches that TCA is Critical to Overcoming the Flaws in
`the Prior Art Methods
`TCA Is an Essential Component of the WO ʼ440 Process
`
`35. WO ʼ440 explains that “[t]he known commercial process for the
`
`manufacture of [fipronil] uses corrosive and expensive chemicals such as trifluoro
`
`acetic acid.” (Ex. 1004, 1:15-17). Thus, WO ʼ440 reference sets out to describe
`
`what it characterizes as an improved process for manufacturing fipronil that does
`
`not utilize “the corrosive and expensive solvent trifluoroacetic acid.” (Ex. 1004,
`
`1:23-26). WO ʼ440’s improved process requires the use of trichloroacetic acid
`
`(“TCA”) as the solvent for the reaction, and an oxidizing agent. Use of these
`
`agents makes the new process of WO ʼ440 “simple and economical.” (Ex. 1004,
`
`6:18-19). In particular, WO ʼ440 explains that TCA “is commercially available at
`
`about one tenth the cost of [TFA] and is devoid of the corrosion problems arising
`
`due to HF.” (Ex. 1004, 7:11-14).
`
`
`
`16
`
`

`
`36. WO ʼ440 explains that the “process of the present invention involves
`
`the preparation of [fipronil] by a process comprising the step of oxidizing [the
`
`fipronil precursor].” (Ex. 1004, 6:23-25). Every embodiment of the oxidation step
`
`in WO ʼ440 requires the use of TCA. Indeed, WO ʼ440 is explicit that the
`
`“oxidation is carried out in a medium comprising at least one oxidizing agent and
`
`trichloroacetic acid, and/or the reaction product(s) of the at least one oxidizing
`
`agent and trichloroacetic acid, and at least one melting point depressant.” (Ex.
`
`1004, 6:26-7:4). WO ʼ440 also states that “our search for a substitute for TFA led
`
`to the present invention of using trichloroacetic acid.” (Ex. 1004, 6:20-21). WO
`
`ʼ440 includes two examples of the oxidation step both of which utilize TCA in the
`
`reaction medium. Thus, a person of ordinary skill in the art would have
`
`understood that every reaction disclosed by WO ʼ440 requires the use of TCA.
`
`37.
`
` From these disclosures, a person of ordinary skill would have
`
`understood that the invention disclosed in WO ʼ440 was an improved process for
`
`the production of fipronil that utilizes TCA as the reaction solvent. WO ʼ440
`
`comments that TCA “has not been reported as a medium.” (Ex. 1004, 5:19-20). It
`
`also states that the “present invention relates to an improved process of oxidation
`
`of [fipronil precursor] using an oxidizing agent…in a medium comprising [TCA]
`
`as a substitute for the hitherto used expensive and corrosive [TFA] solvent.” (Ex.
`
`1004, 2:11-16).
`
`
`
`17
`
`

`
`38. Based on these statements, a person of ordinary skill in the art would
`
`have understood that the WO ʼ440 authors were searching for an alternative
`
`process for the oxidation of the fipronil precursor that avoided the use of TFA,
`
`which was considered corrosive and expensive. The solution was to use TCA,
`
`which was previously considered unacceptable because it is a solid at the desired
`
`reaction temperature. The WO ʼ440 authors solved this problem by addition small
`
`amounts of a melting point depressant to reduce the melting point of TCA to below
`
`20°C, which is the desired reaction temperature because at that temperature the
`
`formation of the sulfone over-oxidation product is reduced. It is clear the WO ʼ440
`
`authors believed the use of TCA as a solvent to be novel and inventive.
`
`Accordingly, a person of ordinary skill in the art would not have understood WO
`
`ʼ440 to teach the oxidation to produce fipronil could be conducted in the absence
`
`of TCA.
`
`WO ʼ440 Teaches that DCA and DCM Are Included Only as Melting
`Point Depressants
`
`39. As discussed above, the WO ʼ440 reference is clear that the invention
`
`it describes is the replacement of TFA with TCA as the reaction solvent. (E.g., Ex.
`
`1004, 2:11-16). WO ʼ440 repeatedly discusses the advantages of TCA, and both
`
`examples in WO ʼ440 use TCA. However, the WO ʼ440 inventors recognized that
`
`it was important to conduct the reaction at a low temperature (e.g., below 20°C),
`
`and that TCA is a solid at those temperatures
`
`
`
`18
`
`

`
`40. Because TCA is solid under the desired reaction conditions, WO
`
`ʼ440’s process employs a melting point depressant to reduce the melting point of
`
`TCA to a temperature below the that temperature. WO ʼ440 describes several
`
`preferred melting point depressants such as “dichloroacetic acid (“DCA”),
`
`monochloroacetic acid, methylene dichloride, ethylene dichloride,
`
`monochlorobenzene or a haloalkane, or a mixture thereof.” (Ex. 1004, 7:8-11).
`
`WO ʼ440 makes clear that the use of a melting point depressant is only to allow the
`
`use of TCA as a solvent at the temperatures employed in the WO ʼ440 process.
`
`(See e.g., Ex. 1004, 9:19-21 (“…the purpose of [DCA’s] addition is only to
`
`sufficiently depress the melting of trichloro acetic acid…”).
`
`41. WO ʼ440 also provides guidance on the amount of the melting point
`
`depressant to use. For example, WO ʼ440 explains that the “composition of the
`
`mixture is chosen so as to depress the melting point of reaction medium
`
`sufficiently…” (Ex. 1004, 9:14-17). WO ʼ440 explains that in the case of DCA,
`
`“20-30% by weight content of dichloroacetic acid in the trichloroacetic acid is
`
`generally sufficient” to depress the melting point of TCA to the point that the
`
`reaction can take place. (Ex. 1004, 9:17-23). The examples of WO ʼ440 each
`
`utilize an amount of melting point depressant within the 20 – 30% range. More
`
`
`
`19
`
`

`
`specifically, Example 1 uses about 29% DCA and Example 2 uses about 21%
`
`DCM.4
`
`42. A person of ordinary skill in the art would have understood that the
`
`amount of DCA and DCM used in WO ʼ440 is consistent with their stated purpose
`
`as melting point depressants. More specifically, the amount of DCA and DCM
`
`used in WO ʼ440 is a minor proportion of the amount of TCA. Thus, although the
`
`melting point depressant may be included in the final reaction medium, a person of
`
`ordinary skill would have not considered the melting point depressant to be the
`
`desired solvent for the fipronil precursor. Rather, a person of ordinary skill would
`
`have understood that TCA is, as the Gharda WO ’440 inventors describe, the
`
`desired solvent or medium for the reaction, and the melting point depressants are
`
`employed only to facilitate the use of TCA as a solvent.
`
`WO ʼ440 Describes DCA as a “Poor Medium” for Oxidation
`
`43. The WO ʼ440 inventors clearly considered their invention to be the
`
`use of TCA as the solvent and the primary component of the reaction medium.
`
`But, because TCA requires the addition of a melting point depressant to reduce the
`
`melting point to a temperature below the desired reaction temperature, the WO
`
`reference identifies several suitable melting point depressants, including DCA.
`
`
`4
`The weight percentages of DCM or DCA used in Examples 1 and 2 of WO
`ʼ440 can be calculated using the density for TCA (1.62 g/cm3) (Ex. 2016), DCA
`(1.56 g/cm3) (Ex. 2018), and DCM (1.33 g/cm3) (Ex. 2017).
`20
`
`
`
`

`
`However, WO ʼ440 could not be clearer that DCA is added to the reaction mixture
`
`only to depress the melting point of TCA. (Ex. 1004, 9:17-21).
`
`44. Nonetheless, Dr. Gribble asserts that WO ʼ440 “discloses that DCA is
`
`itself a medium for the oxidation reaction of the sulfide precursor that produces
`
`Fipronil…” (Ex. 1010, ¶49). Dr. Gribble’s opinion depends entirely on a distorted
`
`reading of the reference. Specifically, Dr. Gribble refers to a single sentence
`
`(emphasized below) within a larger paragraph that explains how much TCA to use
`
`in a reaction:
`
`The quantity of trichloro acetic acid used should generally be
`sufficient to dissolve the substrate and allow the slurry of the reaction
`mass to be stirred properly. Preferably 1.0 lt to 2.0 lt of trichloro
`acetic acid is used per mole of the compound of formula-II. The
`composition of the mixture is chosen so as to depress the melting
`point of the reaction medium sufficiently, usually to less than 10° C.
`For example, the preferred melting point depressant dichloro
`acetic acid is a poor medium for oxidation and the purpose of its
`addition is only to sufficiently depress the melting point of
`trichloro acetic acid to facilitate ease of processing. 20-30% by
`weight content of dichloro acetic acid in the trichloro acetic acid is
`generally sufficient to achieve this objective. It is preferred to depress
`the melting point of the trichloro acetic acid to below 10° C.
`
`(Ex. 1004, 9:10-25).
`
`45. Dr. Gribble asserts that a person of ordinary skill would have
`
`understood from the WO ʼ440 reference, including the above-reproduced
`
`paragraph, that in describing DCA as a “poor medium for oxidation,” it
`
`nevertheless discloses the use of DCA as an oxidation medium for converting the
`
`
`
`21
`
`

`
`compound of general formula II (the fipronil precursor) to the compound of
`
`general formula I (fipronil). I disagree with Dr. Gribble’s opinion. A person of
`
`ordinary skill would have understood this sentence as a clear direction not to use
`
`DCA as the reaction medium.
`
`46. As an initial matter, a person of ordinary skill in the art would have
`
`understood that this paragraph is simply explaining how the oxida

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