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
`________________
`
`DECLARATION OF DR. CORY J. BERKLAND
`
`ALKERMES EXH. 2014
`Luye v. Alkermes
`IPR2016-01096
`
`
`
`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
`________________
`
`DECLARATION OF DR. CORY J. BERKLAND
`
`ALKERMES EXH. 2014
`Luye v. Alkermes
`IPR2016-01096
`
`
`
`I, Cory J. Berkland, Ph.D., declare as follows:
`
`I.
`
`Qualifications
`
`1.
`
`I offer this declaration at the request of counsel for Alkermes Pharma
`
`Ireland Limited and Alkermes Controlled Therapeutics, Inc. (collectively, “Patent
`
`Owners”), and in response to the declaration submitted by Dr. Patrick P. DeLuca
`
`(Exh. 1002).
`
`2.
`
`I am currently appointed as the Solon E. Summerfield Distinguished
`
`Professor in the Department of Pharmaceutical Chemistry and the Department of
`
`Chemical and Petroleum Engineering at the University of Kansas. I received a
`
`B.S. in Chemical Engineering from Iowa State University in December 1998, and
`
`an M.S. in Chemical Engineering from the University of Illinois in May 2001. I
`
`received a Ph.D. in Chemical and Biomolecular Engineering from the University
`
`of Illinois in May 2003. From 2004 to 2009, I was an Assistant Professor in the
`
`Department of Chemical and Petroleum Engineering and the Department of
`
`Pharmaceutical Chemistry at The University of Kansas. I was promoted to
`
`Associate Professor in 2009 and since 2012, I have been a Professor in these two
`
`departments with tenure.
`
`3. My areas of expertise include parenteral injectable drug formulations using
`
`particulates and powders, microencapsulation of pharmaceuticals, and controlled-
`
`release drug delivery. Through collaborations with industrial and academic
`
`1
`
`
`
`partners, and close relationships with other experts in controlled release, I have
`
`developed considerable expertise in the formulation and characterization of
`
`polysaccharide-based injection vehicles, such as those that use
`
`carboxymethylcellulose (“CMC”), and microparticles.
`
`4. The primary focus of my research has been the design and analysis of drug
`
`delivery approaches for improving the performance of therapeutic agents. I have
`
`worked on particles and aspects of pharmaceutical formulation and delivery,
`
`including injectable nanoparticle formulations, since 1997. Among other areas, I
`
`have conducted research aimed to formulate polysaccharide-based injection
`
`vehicles and designing controlled release microparticles.
`
`5. My research group at the University of Kansas currently works on
`
`formulation approaches designed to modify drug dissolution kinetics and to control
`
`drug release rates. My work has encompassed designing appropriate injection
`
`vehicles for parenteral injectables, developing nanoparticle formulations, and
`
`formulating polymers for delivering small molecules, proteins, and DNA. I have
`
`expertise in analyzing the performance of such formulations and in applying
`
`mathematical models to elucidate the underlying phenomena controlling the
`
`injectability and dissolution rate of such drugs. I have also designed and taught
`
`classes on drug delivery that focus primarily on drug transport in pharmaceutical
`
`formulations and through different biological barriers in the human body.
`
`2
`
`
`
`6.
`
`I have been a member of various professional organizations, including the
`
`American Institute of Chemical Engineers, the American Chemical Society, the
`
`American Association of Pharmaceutical Scientists, and the Controlled Release
`
`Society. I am a Fellow of the American Institute of Medical and Biological
`
`Engineering, and have received honors and awards from various national and
`
`international organizations, including the Leading Light Award from the
`
`University of Kansas, the Nagai Foundation Distinguished Lectureship, and the
`
`Controlled Release Society Young Investigator Award. Other awards and honors I
`
`have received are listed in my CV (Exh. 2015).
`
`7.
`
`I have sat on the editorial boards or advisory boards of scientific journals
`
`including Therapeutic Delivery, the Journal of Pharmaceutical Sciences, and the
`
`Journal of Pharmaceutical Innovation.
`
`8.
`
`I have published on such topics as drug delivery, parenteral injectable
`
`nanoparticle formulation, surface modification, and biomaterials. I have published
`
`approximately 150 articles in peer-reviewed journals, three book chapters, and
`
`have been named as a co-inventor on more than 50 U.S. patents or applications.
`
`9.
`
`I have served as a consultant for drug formulation and delivery for
`
`companies in the United States and internationally. I have been involved in the
`
`design and development of numerous pharmaceutical formulations, both in my
`
`capacity at the University of Kansas and as a company founder. For instance, I am
`
`3
`
`
`
`a co-founder of four companies: Orbis Biosciences, Inc., Savara Pharmaceuticals,
`
`Inc., Orion BioScience, Inc., and Bond Biosciences, Inc. I am the acting Chief
`
`Scientific Officer at Orbis Biosciences. Orbis develops controlled-release delivery
`
`systems, including parenteral injectable microsphere formulations. I was also a
`
`Member of the Scientific Advisory Board and the former Chief Technology
`
`Officer for Savara Pharmaceuticals, Inc. in Austin, Texas. Savara specializes in
`
`the development of pulmonary drug products. I am also the Chairperson of the
`
`Board of Directors of Orion BioScience, Inc., which develops injectable therapies
`
`for autoimmune diseases.
`
`II.
`
`Scope of Assignment and Approach
`
`10. I have been retained as an expert on behalf of Patent Owners to provide
`
`information and opinions to the Patent Trial and Appeal Board (“the Board”) to
`
`assist in its analysis of the patentability of certain claims of U.S. Patent No.
`
`6,667,061 (“the ’061 patent”) (Exh. 1001) under inter partes review (“IPR”).
`
`Specifically, counsel for Patent Owners asked me to provide opinions regarding
`
`the applicability of various prior art references to claims 1-13 and 17-23 of the
`
`’061 patent, in view of my knowledge of and experience with injectable
`
`formulations. These references include those raised by Petitioners, Luye Pharma
`
`Group, Limited, Shandong Luye Pharmaceutical Co., Limited, and Nanjing Luye
`
`Pharmaceutical Co., Limited (collectively, “Petitioners”).
`
`4
`
`
`
`11. I have been informed by counsel and I understand that the analysis of
`
`whether a patent is obvious is performed from the perspective of a person of
`
`ordinary skill in the art (“POSA”) at the time of the patented invention. I
`
`understand the relevant timeframe for the patented invention of the claims of the
`
`’061 patent is before May 25, 2000. I further understand that Petitioners and their
`
`declarant, Dr. Patrick DeLuca, use this date as well. (Exh. 1002 at ¶ 8.)
`
`12. I am being compensated for my time spent in connection with this matter
`
`at a rate of $500 per hour. My compensation does not depend on the outcome of
`
`this proceeding or the conclusions in this declaration.
`
`III. Applicable Standards and Controlling Principles
`
`A. Burden of Proof
`
`13. I have been informed by counsel and I understand that, after institution of
`
`an inter partes review, Petitioners bear the ultimate burden of proving the claims at
`
`issue are unpatentable by a preponderance of the evidence. I further understand
`
`that this means Petitioners must show that it is more likely than not that the
`
`challenged claims are obvious over the cited prior art.
`
`B. Obviousness
`
`14. I have been informed by counsel and I understand that nonobviousness is a
`
`requirement for patentability. Specifically, I understand nonobviousness means
`
`that the subject matter of the claimed invention in a patent, taken as a whole and
`
`5
`
`
`
`considered in light of the prior art references, would not have been obvious to a
`
`POSA at the time of the claimed invention.
`
`15. I have been informed by counsel and I understand that in an obviousness
`
`analysis, the patent challenger cannot rely on the hindsight of today’s knowledge,
`
`and that obviousness must be determined from the perspective of a POSA at the
`
`time of the claimed invention. For this reason, the party challenging the patent for
`
`obviousness may not use the patent as a blueprint or template to pick and choose
`
`references within the prior art, or portions thereof, to rely on in an obviousness
`
`analysis.
`
`16. I have been informed by counsel and I understand that a determination of
`
`obviousness requires analyzing the scope and content of the prior art, the level of
`
`ordinary skill in the relevant art, and the differences between the claims-at-issue
`
`and the prior art. I also have been informed by counsel, and I understand, that a
`
`claimed invention is not obvious unless it is shown that a person of ordinary skill
`
`would have had reason to combine the teachings of the prior art references to
`
`obtain the claimed invention, and would have had a reasonable expectation of
`
`success in achieving the claimed result.
`
`17. I have been informed by counsel and I understand that demonstrating that
`
`each element of a challenged claim was independently known in the art is
`
`insufficient. Rather, the challenging party must show that a POSA had an apparent
`
`6
`
`
`
`reason to combine elements in the claimed manner, and that there was a reasonable
`
`expectation that the combination would be successful.
`
`18. I have been informed by counsel and I understand that other evidence,
`
`referred to generally as “objective indicia,” may indicate the nonobviousness of an
`
`invention, such as unexpected results, and commercial success where there is a
`
`causal relationship or “nexus” between the claimed invention and its commercial
`
`embodiment.
`
`C. Inherency
`
`19. I have been informed by counsel and I understand that when a claim
`
`limitation is not expressly stated in the prior art, the claim limitation may be
`
`inherent. To rely on inherency, I have been informed by counsel and I understand
`
`that a patent challenger must show that the claim limitation at issue must be
`
`necessarily present in the prior art disclosure, or that the claim limitation is the
`
`natural and inevitable result of the combination of elements explicitly disclosed by
`
`the prior art. I have been informed by counsel and I understand that a finding of
`
`inherency cannot be based on mere probabilities or possibilities.
`
`D. Person of Ordinary Skill in the Art
`
`20. I have been informed by counsel and I understand that the person of
`
`ordinary skill in the art is a hypothetical person who is presumed to be familiar
`
`with the relevant scientific field and its literature at the time of the invention. This
`
`7
`
`
`
`hypothetical person is also a person of ordinary creativity capable of understanding
`
`the scientific principles applicable to the pertinent field.
`
`21. It is my opinion that the POSA in the field of the ’061 patent would have a
`
`bachelor’s degree in one of the following fields: pharmaceutical formulation,
`
`chemistry, polymer science, or a related field, and one or two years of industry
`
`training or experience in those field(s).
`
`22. Based on my training and experience, I believe I am a person of greater
`
`than ordinary skill in the relevant art, which permits me to give an opinion about
`
`the qualifications of one of ordinary skill at the time of the invention as well as
`
`interpret the prior art from the perspective of a POSA.
`
`23. I note that Dr. DeLuca’s opinion of a POSA as set forth in his declaration
`
`(Exh. 1002 at ¶ 12) is as follows:
`
`[A] person of ordinary skill in the art (a “POSA”) as to the
`patent at issue in this case would have at least a bachelor’s
`degree and a number of years of industry training or experience
`in one or more the following fields: pharmaceutical
`formulation, chemistry, pharmaceutical science, polymer
`chemistry, pharmaceutics, pharmaceutical technology,
`pharmacokinetics, and/or pharmacology. A POSA would draw
`on the pharmaceutical science literature, general textbooks,
`research articles and abstracts, and other sources of information
`in the field of pharmaceutical formulation and polymer
`microparticle science.
`
`8
`
`
`
`24. In my opinion, Dr. DeLuca’s proposed definition of a POSA is vague and
`
`imprecise and likely underestimates the skills a POSA would possess. Regardless,
`
`my opinions stated in this declaration would be the same if rendered from the
`
`perspective of a POSA as described by Dr. DeLuca.
`
`E. Claim Construction
`
`25. I have been informed by counsel and I understand that in an IPR
`
`proceeding, patent claim terms are given their broadest reasonable construction in
`
`light of the specification of the patent in which they appear. I have also been
`
`informed and understand that patent claim terms are generally given their ordinary
`
`and customary meaning as would be understood by a POSA in the context of the
`
`entire patent’s disclosure.
`
`26. Accordingly, I have interpreted the claim terms of the ’061 patent as
`
`having their broadest reasonable construction in light of the specification of the
`
`patent.
`
`IV.
`
`Summary of Opinions
`
`27. In this declaration, I conclude that claims 1-13 and 17-23 of the ’061 patent
`
`(Exh. 1001) are not rendered obvious by any combination of prior art presented by
`
`Petitioners, at least because:
`
` the cited art does not disclose the viscosity limitation present in all
`
`challenged claims of the ’061 patent;
`
`9
`
`
`
` the viscosity limitation is not inherent in the cited art; and
`
` a POSA would not have combined the pieces of art cited by
`
`Petitioners in a way that would arrive at the invention of the ’061
`
`patent.
`
`V.
`
`The Technology of the ’061 Patent
`
`28. The ’061 patent relates to “injectable suspensions having improved
`
`injectability, and to methods for the preparation of such injectable suspensions.”
`
`(Exh. 1001 at 1:10-15.)
`
`29. Injectable suspensions are multiphase, heterogeneous systems comprising
`
`an insoluble solid phase dispersed in a liquid phase. (Exh. 2001, DeLuca &
`
`Boylan, at 212; see also Exh. 1001 at 1:26-31.) They are considered one of the
`
`“most difficult parenteral forms to prepare.” (Exh. 2001, DeLuca & Boylan at
`
`212; see also Exh. 1001 at 1:19-25; Exh. 2016, DeLuca Tr. at 81:17-84:19.) This
`
`is because “[t]o be effective and pharmaceutically acceptable, injectable
`
`suspensions should preferably be: sterile; stable; resuspendable; syringeable;
`
`injectable; isotonic; and nonirritating.” (Exh. 1001 at 1:19-22; see also Exh. 2016,
`
`DeLuca Tr. at 81:17-84:19, 93:23-95:18.) For example, an injectable suspension
`
`should be “easy to suspend and inject” throughout its shelf life. (Exh. 2001,
`
`DeLuca & Boylan at 212; see also Exh. 1001 at 1:39-2:13; Exh. 2016, DeLuca Tr.
`
`at 88:22-89:2, 103:23-104:9.) Likewise, “[u]niform distribution of the drug is
`
`10
`
`
`
`required to ensure that an adequate dose is administered to the patient.” (Exh.
`
`2001, DeLuca & Boylan at 212; Exh. 2016, DeLuca Tr. at 83:10-16, 88:3-21.)
`
`30. The ’061 patent notes that an injectable solution should be syringeable and
`
`injectable (Exh. 1001 at 1:19-22), and outlines the difference between the two
`
`characteristics:
`
`Syringeability describes the ability of an injectable
`suspension to pass easily through a hypodermic needle
`on transfer from a vial prior to injection. It includes
`characteristics such as ease of withdrawal, clogging and
`foaming tendencies, and accuracy of dose
`measurements…. Injectability refers to the performance
`of the suspension during injection. Injectability includes
`factors such as pressure or force required for injection,
`evenness of flow, aspiration qualities, and freedom from
`clogging.
`
`(Exh. 1001 at 1:53-64.)
`
`31. In the ’061 patent, the solid phase of the injectable suspensions comprises
`
`microspheres, which are present at higher concentrations than solids in other types
`
`of injectable suspensions. (Exh. 1001 at 2:41-44.) Microspheres also typically
`
`have a larger particle size than that recommended for intramuscular or
`
`subcutaneous injections. (Id. at 2:45-49.) These differences make it even more
`
`difficult to successfully inject suspensions containing microspheres because
`
`11
`
`
`
`particle characteristics directly influence syringeability and injectability. (Exh.
`
`2001, DeLuca & Boylan at 214-215; Exh. 1001 at 2:49-54; Exh. 2016, DeLuca Tr.
`
`at 96:15-97:1.)
`
`32. The liquid phase of the injectable suspensions of the ’061 patent comprises
`
`the injection vehicle with a viscosity that improves injectability. (Exh. 1001 at
`
`4:57-62.) As of the time of the invention, it was believed that viscosity of the
`
`injection vehicle should be kept low in order to overcome injectability problems.
`
`(Id. at 2:26-54, 4:60-62; see also Exh. 1014 at 287, 299.) Dr. DeLuca also
`
`confirmed this thinking:
`
`In the injectables, you try to keep the viscosity as low as
`possible or low enough to be injected. Because the more
`materials you add to the parenteral, then you're going to
`increase the viscosity, because of more viscous that then
`you do -- you get to a point where it becomes difficult to
`push the plunger and get the -- the suspension through
`the needle.
`
`(Exh. 2016, DeLuca Tr. at 96:15-97:1.)
`
`33. In contrast to that conventional wisdom and common practice, the ’061
`
`patent describes improving injectability “by increasing the viscosity of the fluid
`
`phase of an injectable suspension.” (Exh. 1001 at 4:57-63.) All challenged claims
`
`of the ’061 patent require a viscosity of the fluid phase of the suspension “greater
`
`than about 20 cp and less than about 600 cp at 20ºC.” (Id. at claim 1.)
`12
`
`
`
`34. Viscosity of an injection vehicle can be impacted by a number of factors
`
`including the ingredients that make up the injection vehicle, sterilization, and the
`
`manner in which the injection vehicle is made. (Exh. 1002 at ¶ 9; see below
`
`paragraphs 63-65, 67-69, 71-73; see also below paragraphs 51, 125.) Because
`
`viscosity is, for instance, temperature dependent, the ’061 patent specifies that the
`
`claimed range corresponds to measurement at 20ºC.
`
`35. With respect to the particular ingredients or method of making the
`
`injection vehicle, the ’061 patent includes examples and descriptions of possible
`
`embodiments of the invention. (See, e.g., Exh. 1001 at 3:10-17.) However, the
`
`claims are more flexible. While some require particular components or specific
`
`ingredients, the crux of the invention is increasing “viscosity of the fluid phase of
`
`the suspension to the desired level for improved injectability.” (Exh. 1001 at
`
`Abstract.)
`
`36. The ’061 patent teaches that one manner of achieving that desired viscosity
`
`may involve the use of a viscosity enhancing agent. (See e.g., Exh. 1001 at
`
`abstract, 3:39-42; 12:1-2; 13:4-5.) One viscosity enhancing agent suitable for use
`
`in the invention, and relevant to the asserted grounds in the Petition, is CMC.
`
`(Exh. 1001 at 12:14-16.)
`
`37. CMC is a water-soluble derivative of biologically degradable natural
`
`polysaccharide cellulose, with various natural sources like wood pulp and cotton
`
`13
`
`
`
`linters. (Exh. 2034, Aqualon Brochure at 7; see also Exh. 2035, Yang 2007 at
`
`409.) It is widely used in pharmaceutical formulations including injectable
`
`suspensions. (Exh. 1008 at 78.)
`
`38. CMC can form both physical and chemical interactions with itself which
`
`increase viscosity. In solution, CMC can undergo “polymer chain entanglement.”
`
`(Exh. 2031, DeLuca 1996 at 291; see also Exh. 2042, Benchabane 2008 at 1180
`
`(“CMC solutions exhibit concentration-dependent viscoelastic properties.”).) The
`
`intermolecular structure of a CMC solution, and hence its viscosity, can vary
`
`depending on polymer concentration and other physical factors:
`
`In aqueous solution it represents a complex rheological
`system, since it forms aggregates and associations, and
`hence higher level structures. At higher polymer
`concentrations, extended Na CMC chains start to overlap
`and undergo the coiling process, which causes formation
`of the network structure in the concentrated regime.
`With higher polymer concentration the polymer-polymer
`interactions (entanglements) become the main factor
`influencing the rheology of the Na CMC solution.
`
`(Exh. 2037, Florjancic 2002 at 106.) This is a physical entanglement of the linear
`
`CMC molecule with other CMC molecules as they exist in solution. (Exh. 2016,
`
`DeLuca Tr. at 182:5-183:6.) These entanglements occur at certain critical
`
`concentrations, which are determined by the molecular weight and grade of the
`
`14
`
`
`
`CMC. (Exh. 2016, DeLuca Tr. at 110:24-111:4). Increasing the concentration of
`
`CMC would increase the polymer chain entanglement, and increase the viscosity
`
`of the overall solution due to large increases in the resistance to flow. (See Exh.
`
`2031, DeLuca 1996 at 291.) The reverse is also true. (See id.)
`
`39. Additionally, CMC can exhibit inter- and intra-molecular interactions that
`
`affect viscosity. CMC can hydrogen bond because of hydroxyl and carboxyl
`
`groups protruding from the polymer. When a CMC chain is fully extended, it
`
`resembles a flat ribbon with hydroxyl groups protruding laterally. (See Exh. 1022
`
`at 304-305.) The flat ribbon exposes CMC’s hydrophobic surface, which consists
`
`mostly of hydrogen atoms linked to carbon. (See id. at Fig. 7.) Thus, CMC in the
`
`proper configuration can also participate in hydrophobic interactions. CMC is also
`
`known to interact through ionic or ‘electrostatic’ bonding. (See id.) The more of
`
`these interactions occurring between molecules, the more viscous the solution
`
`becomes. On the other hand, fewer interactions means that the solution is less
`
`viscous.
`
`40. Typically, CMC is divided into grades and then repeatedly subdivided
`
`based on parameters like viscosity, molecular weights, degrees of substitution,
`
`degrees of polymerization, particle sizes, and other parameters. (Exh. 2034,
`
`Aqualon Brochure at 6; Exh. 1022 at 288, 305.) Many of these parameters impact
`
`the ultimate viscosity of a CMC solution. The selection of a particular grade and
`
`15
`
`
`
`type of CMC is generally guided by these parameters in view of the desired
`
`characteristics of the end product. (Exh. 1008 at 79-80.)
`
`41. As of the time of the invention, there was a wide variety of commercially
`
`available grades and types of CMC that would yield a broad range of possible
`
`viscosities for CMC solutions, even at fixed concentrations. (Exh. 1008 at 79; see
`
`also Exh. 2016, DeLuca Tr. at 121:24-123:1.) For instance, the 1994 Handbook of
`
`Pharmaceutical Excipients’ entry on CMC states that “aqueous 1% w/v solutions
`
`[of CMC] with viscosities of 5-4000 mPas (5-4000 cP) may be obtained.” (Exh.
`
`1008 at 79, emphasis added.) Similarly, Dow Chemical indicates that its “broad
`
`selection of CMC grades” allows “viscosity ranges from 10 mPa’s [cp] to 100,000
`
`mPa’s [cp] as a two percent solution.” (Exh. 2036, Dow CMC.) Furthermore, the
`
`Aqualon brochure for CMC from 1999 identified a range of viscosities for
`
`solutions containing some of its available CMC products from 5 cp to 10,000 cp at
`
`25ºC as a one percent solution. (Exh. 2034, Aqualon Brochure at 15.) Moreover,
`
`Aqualon noted that “[s]ome even lower viscosity types are available.” (Exh. 2034,
`
`Aqualon Brochure at 6 (emphasis added).)
`
`42. Because it is the viscosity that matters to the invention and not generally
`
`the particular components making up the injection vehicle or microspheres, the
`
`patent makes clear that the invention is “not limited to the use of CMC as the
`
`viscosity enhancing agent.” (Exh. 1001 at 12:17-19.)
`
`16
`
`
`
`VI. Petitioners’ Ground 1 Challenge
`
`43. I understand that the Board instituted IPR of claims 1-13, 22 and 23 under
`
`Petitioners’ Ground 1 challenge. I further understand that in Ground 1, Petitioners
`
`challenge claims 1-13, 22 and 23 as obvious under 35 U.S.C. § 103 over Johnson
`
`in view of Kino. I have reviewed Petitioners’ Ground 1 challenge and the
`
`materials they rely on, including the DeLuca Declaration. I have also reviewed the
`
`Board’s Institution Decision. I do not agree with the Board’s preliminary findings
`
`or the Petitioners’ assertions that any claims of the ’061 patent are obvious over the
`
`cited art.
`
`A. Johnson does not teach or disclose the claimed viscosity
`limitation present in all claims of the ’061 patent
`
`44. Claim 1, the sole independent claim of the ’061 patent, recites:
`
`1.
`
`A composition suitable for injection through a needle into a host,
`comprising:
`microparticles comprising a polymeric binder; and
`
`an injection vehicle, wherein said microparticles are
`suspended in said injection vehicle at a
`concentration of greater than about 30 mg/ml to
`form a suspension, wherein a fluid phase of said
`suspension has a viscosity greater than about 20 cp
`and less than about 600 cp at 20º C., wherein the
`viscosity of said fluid phase of said suspension
`provides injectability of the composition through a
`
`17
`
`
`
`needle ranging in diameter from 18-22 gauge.
`(Exh. 1001 at claim 1.)
`
`45. All other claims of the ’061 patent depend from claim 1. Thus, each claim
`
`requires that the fluid phase of a suspension has a viscosity greater than about 20
`
`cp and less than about 600 cp at 20°C. (Exh. 1001 at claims 1-23.)
`
`46. I understand that, although Petitioners have asserted only obviousness
`
`grounds to challenge the ’061 patent, they are relying solely on Johnson in their
`
`Ground 1 challenge of claim 1.
`
`47. I further understand that Petitioners and their declarant, Dr. DeLuca also
`
`relies solely on Johnson in his analysis of claim 1 (and claims 2-3). (Exh. 2016,
`
`DeLuca Tr. at 222:14-17.) Dr. DeLuca, in his declaration, admits that “Johnson is
`
`silent as to viscosity and temperature at which the viscosity is taken.” (Exh. 1002
`
`at ¶ 60.) Nevertheless, Petitioners and Dr. DeLuca argue that “a POSA would
`
`reasonably expect the injection vehicle of Johnson – having 3% CMC – to have a
`
`viscosity greater than 27cp at 20°C and certainly within the claimed range of 20-
`
`600cp at 20°C.” (Id.) As explained below, I do not agree that the Johnson
`
`injection vehicle would necessarily have a viscosity within the claimed range. In
`
`addition, I have reviewed the declaration of Dr. Stevin Gehrke, in which he
`
`18
`
`
`
`describes making the Johnson vehicle using commercially available CMCs1 and
`
`measuring their viscosities at 20°C. (Exh. 2059, Gehrke Decl., ¶ 5-11.) Dr.
`
`Gehrke’s tests, which I discuss in paragraphs 48-50 below, confirm that the
`
`Johnson vehicle can have a viscosity that falls outside the claimed range.
`
`Therefore, I do not agree that any of the claims of the ’061 patent are obvious
`
`under Petitioners’ Ground 1 challenge. Specifically, it is clear that the claimed
`
`viscosity would not be inherent to the cited references and it would not have been
`
`obvious to modify the cited references to attempt to achieve the claimed viscosity.
`
`i. At least one reasonable interpretation of the Johnson
`vehicle yields a viscosity below the claimed range.
`
`48. Dr. Gehrke describes making the Johnson vehicle with two different types
`
`of low viscosity CMC: 7ULC and 7ELC1 from Ashland. (Exh. 2059, Gehrke
`
`Decl.)
`
`49. Dr. Gehrke describes using standard methods and protocols for measuring
`
`viscosity consistent with those described in the ’061 patent and as would have been
`
`known by a POSA. (Id. at ¶ 5-11.)
`
`1 Dr. Gehrke’s declaration notes that he used CMC obtained from Ashland. (Exh.
`
`2059 ¶ 6.) Ashland acquired Hercules in 2008 (Exh. 2052, Ashland Press
`
`Release.) Hercules was the manufacturer of Aqualon-branded CMC which has
`
`been available since at least 1999. (Exh. 2034, Aqualon Brochure at Cover.)
`
`19
`
`
`
`50. As detailed in the chart below, each of these Ashland CMCs yielded a
`
`Johnson vehicle with a viscosity below 20 cp when measured at 20ºC and thus fall
`
`outside the range claimed in the ’061 patent. (Id. at ¶ 12.)
`
`TABLE A – JOHNSON VEHICLES (EXH. 2059, GEHRKE DECL.)
`Formulation
`Viscosity (cp) at 20ºC
`RPM
`3% Ashland 7ULC
`CMC, 0.9% NaCl, 1%
`polysorbate 20
`3% Ashland 7ELC1
`CMC, 0.9% NaCl,1%
`polysorbate 20
`
`200
`
`200
`
`6.03 cp
`
`9.41 cp
`
`ii. Johnson does not provide enough information to establish
`the viscosity of its injection vehicle would fall within the
`claimed range
`
`51. I understand that Petitioners rely on the injection vehicle of Johnson’s
`
`Example 7, which recites: “[t]he injection vehicle was an aqueous vehicle
`
`containing 3% w/v Carboxymethyl Cellulose (sodium salt), 1% v/v Tween 202
`
`(Polysorbate 20) and 0.9% sodium chloride.” (Exh. 1009 at 12:42-45; see also
`
`Exh. 1002 at ¶¶ 60-61; Exh. 2016, DeLuca Tr. at 226:9-18.) In my opinion, this
`
`generic description of an injection vehicle does not provide enough information to
`
`establish what its viscosity would be at 20°C, at least, because it does not teach or
`
`disclose:
`
`2 Tween® 20 is a commercial brand name for polysorbate 20. The two terms
`
`(Tween® 20 and polysorbate 20) are used interchangeably in this declaration.
`
`20
`
`
`
` what grade or type of CMC is being used;
`
` whether or how the CMC is sterilized;
`
` how the CMC is dissolved to form the solution;
`
` how the CMC solution is mixed;
`
` how or when the sodium chloride is added; and/or
`
` how or what the impact of 1% polysorbate 20 would be on viscosity.
`
`These are all important because “[t]he concentration, temperature, salt
`
`concentration, presence of surfactants, and other molecular structures have a
`
`considerable effect on the rheological properties of Na CMC.” (Exh. 2037,
`
`Florjancic 2002 at 106; see also Exh. 2044, Conceicao 2003 at 257 (“The
`
`rheological effects of adding CMC binder/thickening agents strongly depended on
`
`the amount added, molecular weight (MW), and the suspension preparation
`
`procedure.”).)
`
`52. Furthermore, as explained below, the uncertainty of these various factors,
`
`their impact on viscosity and the resultant wide range of possible viscosities that
`
`could be obtained in making the Johnson vehicle means that Johnson fails to
`
`disclose or teach a vehicle with a viscosity that necessarily falls within the claimed
`
`range. Additionally, Petitioners have provided no reason a POSA would have
`
`interpreted the Johnson vehicle only in a way so as to result in a formulation with a
`
`viscosity within the claimed range.
`
`21
`
`
`
`53. Johnson does not teach or disclose the specific type or grade of CMC in its
`
`vehicles. (Exh. 2016, DeLuca Tr. at 230:14-231:21.) As a naturally sourced
`
`excipient, CMC even within the same grade and type can have a wide range of
`
`variability in its physical and/or chemical properties. (Exh. 2016, DeLuca Tr. at
`
`176:2-24; Exh. 1022 at 288 (“[T]he viscosity data provided by raw material
`
`suppliers is useful in only a very general way. Such data can show, for example,
`
`that certain polymer grades yield more viscous solutions than other grades made by
`
`the same manufacturer. However, it is extremely difficult to compare data on
`
`different polymers supplied by different manufacturers. It is not uncommon to find
`
`that two polymers, the solutions of which have nearly the same quoted viscosity
`
`value, affect a disperse system in markedly different ways.”); see also Exh. 1022 at
`
`295 (“Another consideration is the degree of chemical uniformity. In general,
`
`synthetic polymers and modified natural polymers (such as cellulose and chitin
`
`derivatives) might be expected to have more reproducible characteristics than plant
`
`exudates, provided that suitable care is taken in raw material selection and
`
`manufacture. Certainly, the ability to procure pharmaceutical dispersion adjuvants
`
`with predictable, consistent rheological properties is an important factor in
`
`selection.”).)
`
`54. Dr. DeLuca noted that the grade and even lot number of the CMC needs to
`
`be specified. (Exh. 2016, DeLuca Tr. at 147:10-16; 176:2-24). In his 1996 paper,
`
`22
`
`
`
`he discussed the effect of CMC grades. (Exh. 2031, DeLuca 1996 at 290.)
`
`Specifically, Figure 2 shows that concentration has an increased effect for 7HF
`
`grade CMC compared to 7LF grade CMC (Exh. 2031, DeLuca 1996 at 293). He
`
`also stated that specifying the grade of CMC is important to allow a researcher to
`
`be able to make direct comparisons. (Exh. 2016, DeLuca Tr. at 176:16-24);
`
`otherwise, one would have to make assumptions.
`
`55. As discussed in paragraph 40 above, typically, CMC is divided into grades
`
`and then repeatedly subdivided based on a variety of parameters that can impact
`
`the ultimate viscosity of a CMC solution. In fact, as noted above in paragraph 41,
`
`as of the time of the invention, a POSA would have encountered a wide variety of
`
`commercially available grades and types of CMC that would yield a broad range of
`
`po
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
