`Date Filed: July 24, 2017
`
`Filed On Behalf Of:
`
`Alkermes Pharma Ireland Limited and
`Alkermes Controlled Therapeutics, Inc.
`
`By:
`
`Scott K. Reed
`sreed@fchs.com
`212-218-2100
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`LUYE PHARMA GROUP LTD., LUYE PHARMA (USA) LTD., SHANDONG
`LUYE PHARMACEUTICAL CO., LTD., and NANJING LUYE
`PHARMACEUTICAL CO., LTD.,
`Petitioners,
`v.
`ALKERMES PHARMA IRELAND LTD and ALKERMES CONTROLLED
`THERAPEUTICS, INC.
`Patent Owners.
`________________
`
`Case IPR2016-01096
`U.S. Patent No. 6,667,061
`________________
`
`PATENT OWNERS’ MOTION FOR OBSERVATIONS ON CROSS-
`EXAMINATION OF PATRICK DELUCA, PH.D.
`
`
`
`I.
`
`The Viscosity Limitation is Not Inherent in Johnson or Gustafsson
`
`In Exh. 2081 at page 121, line 22 to page 124, line 5, Dr. DeLuca testified
`
`that “it’s possible” for a POSA to use a medium or high viscosity grade CMC in an
`
`injection vehicle. This is relevant to Petitioners’ assertions that the Johnson and
`
`Gustafsson vehicles would comprise only low viscosity CMC. (Reply at 11-13,
`
`18-19; Exh. 1024 at ¶¶ 54, 57-60, 65, 86-87.) This is relevant because it confirms
`
`that Petitioners should have accounted for all viscosity grades of CMCs to prove
`
`inherency.
`
`In Exh. 2081 at page 135, line 4 to page 137, line 4; see also Exh. 2073, Dr.
`
`DeLuca confirmed that “viscosity [of a CMC solution] doesn’t change between
`
`food grade, pharma grade and industrial grade.” This is relevant to Petitioners’
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`assertion that Patent Owners’ testing is flawed because it did not use
`
`pharmaceutical grade CMC. (Reply at 8, 10-13, 18-19; Exh. 1024 at 41-45, 57-58,
`
`86.) This is relevant because it contradicts Petitioners’ testing criticism and
`
`establishes that use of a non-pharmaceutical grade CMC does not impact viscosity.
`
`In Exh. 2081 at page 133, line 19 to page 135, line 3, see also Exhs. 2031,
`
`2073, Dr. DeLuca confirmed that “in looking for an appropriate vehicle for drug
`
`delivery,” he has used high and low viscosity, food grade CMCs. This is relevant
`
`to Petitioners’ assertions that the Johnson and Gustafsson vehicles would comprise
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`only low viscosity, pharmaceutical grade CMC. (Reply at 8, 10-13, 18-19; Exh.
`
`1
`
`
`
`1024 at ¶¶ 41-45, 54, 57-60, 65, 86-87.) This is relevant because it confirms that
`
`Petitioners should have accounted for all viscosity grades CMC to prove inherency
`
`and it contradicts Petitioners’ testing criticism.
`
`In Exh. 2081 at page 167, lines 21-25; see also id. at 158:4-167:20, 167:25-
`
`170:9; Exhs. 2074-2077, Dr. DeLuca confirmed that “Blanose 7UL® and 7EL®
`
`were commercially available as of the time of the invention.” This is relevant to
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`Petitioners’ assertion that Patent Owners’ testing is flawed because it did not use
`
`commercially available CMC. (Reply at 8-11, 13-14, 18; Exh. 1024 at ¶¶ 31-36,
`
`40-41, 43-45, 65, 86-87.) This is relevant because it contradicts Petitioners’ testing
`
`criticism and establishes that the tested CMCs were commercially available at the
`
`time of the invention.
`
`In Exh. 2081 at page 176, lines 18-25; see also id. at 170:14-176:17; Exhs.
`
`2039, 2078-2079, Dr. DeLuca confirmed the “use of an ultra low viscosity [non-
`
`pharmaceutical] grade CMC for a pharmaceutical application.” This is relevant to
`
`Petitioners’ assertions that Patent Owners’ testing is flawed because it did not use
`
`low viscosity pharmaceutical grade CMC. (Reply at 10-13, 18; Exh. 1024 at ¶¶
`
`41-45, 57-58, 86-87.) This is relevant because it contradicts Petitioners’ testing
`
`criticism and establishes that comparable CMCs to those tested are used in
`
`pharmaceutical applications.
`
`2
`
`
`
`In Exh. 2081 at page 208, lines 11-14; see also Exh. 2038, Dr. DeLuca
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`confirmed that Ashland classifies its “CMC 7UL® and 7EL® as low viscosity
`
`grade CMC.” This is relevant to Petitioners’ assertion that Patent Owners’ testing
`
`was flawed because it did not use low viscosity CMCs. (Reply at 8, 10-13, 18-19;
`
`Exh. 1024 at ¶¶ 54, 57-60, 65, 86-87.) This is relevant because it contradicts
`
`Petitioners’ testing criticism and establishes that 7UL and 7EL CMCs are
`
`considered low viscosity CMCs.
`
`In Exh. 2081 at page 166, lines 3-6; see also Exh. 2075, Dr. DeLuca
`
`confirmed that a third party “refers to Blanose 7ULC® as a low viscosity grade
`
`CMC.” This is relevant to Petitioners’ assertion that Patent Owners’ testing was
`
`flawed because it did not use low viscosity CMCs. (Reply at 8, 10-13, 18-19; Exh.
`
`1024 at ¶¶ 54, 57-60, 65, 86-87.) This is relevant because it contradicts
`
`Petitioners’ testing criticism and establishes that 7UL CMC is considered low
`
`viscosity CMC.
`
`In Exh. 2081 at page 48, line 18 to page 49, line 16, Dr. DeLuca confirmed
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`that Gustafsson does not “state the source of the CMC,” “say anything about
`
`pharmaceutical grade CMC,” “say anything about whether it’s a low viscosity
`
`CMC,” and “say anything about the commercial availability of the CMC.” This is
`
`relevant to Petitioners’ assertions that Gustafsson’s vehicle would inherently have
`
`a viscosity within the claimed range and that Patent Owners’ testing is flawed
`
`3
`
`
`
`because it did not use a particular subcategory of CMCs. (Reply at 8-11, 13-14,
`
`18-19; Exh. 1024 at ¶¶ 31-36, 40-45, 86-89.) This is relevant because it confirms
`
`the generic nature of Gustafsson’s disclosure and it undermines Petitioners’ claim
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`that a POSA would only use a particular subcategory.
`
`In Exh. 2081 at page 104, lines 4 to 16; see also id. at 76:5-8, 117:13-125:5,
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`Dr. DeLuca confirmed that Johnson Example 7 does not state low viscosity CMC
`
`and that Johnson “didn’t specify the supplier” of CMC. This is relevant to
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`Petitioners’ assertions that Johnson’s vehicle would inherently have a viscosity
`
`within the claimed range and that Patent Owners’ testing is flawed because it did
`
`not use a particular subcategory of CMCs. (Reply at 10-14, 16-17; Exh. 1024 at ¶¶
`
`31-36, 40-45, 56-60.) This is relevant because it confirms the generic nature of
`
`Johnson’s disclosure and it undermines Petitioners’ claim that a POSA would only
`
`use a particular subcategory of CMC.
`
`In Exh. 2081 at page 196, line 25 to page 197, line 8; see also id. at 184:17-
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`185:8, Dr. DeLuca confirmed that whether the CMC is added “before or after the
`
`sodium chloride” could impact viscosity. This is relevant to Petitioners’ assertions
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`that the Johnson and Gustafsson vehicles would inherently have viscosities within
`
`the claimed range. (Reply at 8-14, 16-19; Exh. 1024 at ¶¶ 31-36, 40-45, 56-60, 86-
`
`89.) This is relevant because it confirms that order of addition of ingredients can
`
`4
`
`
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`impact viscosity and supports that Petitioners should have accounted for this factor
`
`in proving inherency.
`
`In Exh. 2081 at page 58, line 15 to page 59, line 11, Dr. DeLuca confirmed
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`that a POSA “could use a different amount or type of CMC” in an injection vehicle
`
`depending on test model. This is relevant to Petitioners’ assertion that a POSA
`
`would understand the same CMC is used in all Johnson’s vehicles. (Reply at 11-
`
`12; Exh. 1024 at ¶ 54.) This is relevant because it undermines Petitioners’
`
`assertion and confirms that the amount and type of CMC used can change based on
`
`the particular model being studied.
`
`In Exh. 2081 at page 102, line 22 to page 103, line 13, Dr. DeLuca
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`confirmed that “CMC that comes from two different suppliers can have different
`
`characteristics” including “different viscosity ranges.” This is relevant to
`
`Petitioners’ assertions that the Johnson and Gustafsson vehicles would inherently
`
`have viscosities within the claimed range. (Reply at 8-14, 16-19; Exh. 1024 at ¶¶
`
`31-36, 40-45, 56-60, 86-89.) This is relevant because it confirms that the supplier
`
`of CMC can impact viscosity and supports that Petitioners should have accounted
`
`for this in proving inherency.
`
`In Exh. 2081 at page 235, line 13 to page 236, line 25, Dr. DeLuca
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`confirmed that polysorbates can “have hydrophobic interactions with water” and
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`“form hydrogen bonds in water;” and CMC can also “have hydrophobic interaction
`
`5
`
`
`
`with water” and “form hydrogen bonds with water” and “the addition of
`
`polysorbate in the aqueous solution with CMC can impact CMC directly or
`
`indirectly . . . through these interactions.” This is relevant to Petitioners’ assertions
`
`that polysorbates would have a minimal impact on viscosity and that the Johnson
`
`vehicle would inherently have a viscosity within the claimed range. (Reply at 16-
`
`17; Exh. 1024 at ¶¶ 67-68.) This is relevant because it confirms that polysorbates
`
`can impact viscosity and supports that Petitioners should have accounted for this in
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`relying on the Tracy Declaration to prove inherency.
`
`In Exh. 2081 at page 238, line 21 to 239, line 12, Dr. DeLuca confirmed that
`
`he “didn’t dispute” Dr. Berkland’s testimony “that the method of dissolution or
`
`mixing could impact viscosity” including “using different mixing methods and
`
`speeds.” This is relevant to Petitioners’ assertions that the Johnson and Gustafsson
`
`vehicles would inherently have viscosities within the claimed range. (Reply at 14-
`
`15; Exh. 1024 at ¶¶ 67-68.) This is relevant because it confirms that the method of
`
`dissolution and mixing can impact viscosity and supports that Petitioners should
`
`have accounted for this in proving inherency.
`
`In Exh. 2081 at page 150, line 14 to page 152, line 13, Dr. DeLuca
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`confirmed that he believed a viscosity would be inherent if it fell within a 10
`
`percent margin of error of the manufacturer’s specification. This is relevant to
`
`Petitioners’ assertions that the Johnson and Gustafsson vehicles would inherently
`
`6
`
`
`
`have viscosities within the claimed range. (Reply at 8-14, 16-19; Exh. 1024 at ¶¶
`
`31-36, 40-45, 56-60, 86-89.) This is relevant because it establishes the standard
`
`Dr. DeLuca applied in his inherency analysis.
`
`II.
`
`The Microparticle Limitation is Not Satisfied by Gustafsson
`
`In Exh. 2081 at page 233, line 16 to page 235, line 12, Dr. DeLuca
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`confirmed that the polymer of the microparticles of the ’061 patent must “serve[]
`
`as a matrix or binder” and that “the active agent has to be dispersed or dissolved
`
`within the polymer.” This is relevant to Petitioners’ assertions that the
`
`microparticle limitation is satisfied by any microparticle including by Gustafsson’s
`
`PLGA coating. (Reply at 6-8, 19-26; Exh. 1024 at ¶¶ 25-30, 90-97, 100, 104.)
`
`This is relevant because it contradicts Petitioners’ assertions and establishes that
`
`the microparticle limitation requires that the polymeric binder function as a matrix
`
`or binder of the active agent and the active agent be dispersed or dissolved in the
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`polymeric binder.
`
`In Exh. 2081 at page 221, lines 3 to page 222, line 12, Dr. DeLuca
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`confirmed that the active agents in Gustafsson “were not dispersed in the PLGA”
`
`and that the PLGA coating of the Gustafsson microparticles is “theoretically free”
`
`of any active. This is relevant to Petitioners’ assertion that the microparticle
`
`limitation is satisfied by Gustafsson’s PLGA coating. (Reply at 6-8 19-26; Exh.
`
`1024 at ¶¶ 25-30, 90-97, 100, 104.) This is relevant because it contradicts
`
`7
`
`
`
`Petitioners’ assertion and establishes the active is not dispersed or dissolved in the
`
`PLGA coating of Gustafsson’s microparticles.
`
`III. A POSA Would Not Have Combined the Cited Art
`
`In Exh. 2081 at page 211, line 23 to page 212, line 21, Dr. DeLuca
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`confirmed that he “did not see any reason why” a POSA would replace the BSA
`
`active in Gustafsson’s microparticles with Ramstack’s risperidone. This is relevant
`
`to Petitioners’ assertion that the combination of Gustafsson’s microparticles and
`
`Ramstack’s risperidone renders claism 20-21 obvious. (Reply at 23-26; Exh. 1024
`
`at ¶¶ 103-112.) This is relevant because it confirms there is no reason to combine.
`
`In Exh. 2081 at page 218, line 16 to page 219, line 20, Dr. DeLuca
`
`confirmed he did not identify any problems with Ramstack’s injection vehicle or
`
`microparticles. This is relevant to Petitioners’ assertion that a POSA would
`
`combine components of Ramstack with Gustafsson’s injection vehicle. (Reply at
`
`23-26; Exh. 1024 at ¶¶ 99-112.) This is relevant because it contradicts any
`
`motivation to replace or modify Ramstack’s microspheres or vehicle.
`
`In Exh. 2081 at page 227, line 22 to page 228, line 19, Dr. DeLuca
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`confirmed that Gustafsson does not identify that its injection vehicle improves on
`
`any other injection vehicle. This is relevant because it contradicts Petitioners’
`
`assertion that a POSA would be motivated to combine components of Ramstack
`
`with Gustafsson’s injection vehicle. (Reply at 23-26; Exh. 1024 at ¶¶ 99-112.)
`
`8
`
`
`
`In Exh. 2081 at page 229, lines 18-22, Dr. DeLuca confirmed that the
`
`injection vehicle of Ramstack, like the vehicle of Gustafsson, used CMC as a
`
`suspension aid. This is relevant to Petitioners’ assertion that a POSA would
`
`combine components of Ramstack with Gustafsson’s injection vehicle. (Reply at
`
`23-26; Exh. 1024 at ¶¶ 99-112.) This is relevant because it contradicts any
`
`motivation to make such a combination.
`
`In Exh. 2081 at page 214, line 20 to page 215, line 20, Dr. DeLuca
`
`confirmed that Ramstack teaches dissolving the risperidone and PLGA in organic
`
`solvents in making Ramstack’s microparticles. This testimony is relevant because
`
`it contradicts Petitioners’ assertion that Ramstack and Gustafsson would be
`
`combined. (Reply at 26; Ex. 1024 at ¶¶ 101, 105.).
`
`In Exh. at page 221, lines 11-19, Dr. DeLuca testified Gustafsson is focused
`
`on avoiding the problem caused by dispersing an active and PLGA in an organic
`
`solvent. This testimony is relevant because it contradicts Petitioners’ assertion that
`
`Ramstack and Gustafsson would be combined. (Reply at 26; Ex. 1024 at ¶¶ 101,
`
`105.)
`
`In Exh. 2081 at page 40, line 24 to page 41, line 20; see also id. at 33:24-
`
`37:3, Dr. DeLuca testified that “[i]t’s not necessary to really worry about
`
`[density]” when developing an injectable formulation of microparticles. This is
`
`relevant to Petitioners’ assertions that a POSA would increase density to stabilize
`
`9
`
`
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`the formulation or to reduce sedimentation. (Reply at 17; Exh. 1024 at ¶¶ 73-76.)
`
`This is relevant because it contradicts the asserted motivations to combine the
`
`teachings of Kino and Johnson to arrive at claims 4, 5, 10 and 11.
`
`IV. A POSA Would Not Alter Viscosity based on Suspendability
`
`In Exh. 2081 at page 11, line 11 to page 12, line 2, Dr. DeLuca testified that,
`
`in formulating an injectable suspension, a POSA “is going to be really concerned
`
`about syringeability/injectability.” This is relevant because it contradicts
`
`Petitioners’ assertion that suspendability would motivate a POSA to increase
`
`viscosity. (Reply at 4-6, 15, 17, 23, 27; Exh. 1024 at ¶¶ 14-24, 39, 71, 78-79, 116.)
`
`In Exh. 2081 at page 155, line 13 to page 156, line 3; see also id. at 22:24-
`
`23:5, Dr. DeLuca confirmed that “Kino didn’t have any suspendability issues using
`
`an injection vehicle with a viscosity of 1 cp” for its PLGA-based microspheres.
`
`This is relevant to Petitioners’ assertion that suspendability would motivate a
`
`POSA to increase viscosity. (Reply at 4-6, 15, 17, 23, 27; Exh. 1024 at ¶¶ 14-24,
`
`39, 71, 78-79, 116.) This is relevant because it contradicts Petitioners’ assertion
`
`that a POSA would increase viscosity.
`
`10
`
`
`
`July 24, 2017
`
`Respectfully submitted,
`
`/Scott Reed/
`Scott K. Reed (Reg. No. 32,433)
`FITZPATRICK, CELLA, HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel: (212) 218-2100
`
`Counsel for Patent Owners
`
`11
`
`
`
`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing PATENT OWNERS’ MOTION FOR
`
`OBSERVATIONS ON CROSS-EXAMINATION OF PATRICK DELUCA,
`
`PH.D. was served on July 24, 2017 by causing it to be sent by email to counsel for
`
`Petitioners, who have consented to electronic service, at the following email
`
`addresses:
`
`wmentlik.ipr@lernerdavid.com
`
`pkochanski@lernerdavid.com
`
`tvanbuskirk@lernerdavid.com
`
`nvaleyko@lernerdavid.com
`
`July 24, 2017
`
`Respectfully submitted,
`
`/Scott Reed/
`Scott K. Reed (Reg. No. 32,433)
`FITZPATRICK, CELLA, HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel: (212) 218-2100
`
`Counsel for Patent Owners
`
`12
`
`