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 Owner.
`____________
`
`Case IPR2016-01096
`Patent 6,667,061
`____________
`
`DECLARATION OF ROBSON F. STOREY, Ph.D.
`
`ALKERMES EXH. 2054
`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 Owner.
`____________
`
`Case IPR2016-01096
`Patent 6,667,061
`____________
`
`DECLARATION OF ROBSON F. STOREY, Ph.D.
`
`ALKERMES EXH. 2054
`Luye v. Alkermes
`IPR2016-01096
`
`
`
`I.
`
`Background and Qualifications
`
`1.
`
`I, Robson F. Storey, offer this declaration at the request of counsel for
`
`Alkermes Pharma Ireland Limited and Alkermes Controlled Therapeutics, Inc.
`
`(hereinafter, collectively “Alkermes”), and in response to the declaration submitted
`
`by Dr. Patrick P. DeLuca (Exh. 1002).
`
`2.
`
`I am a Professor of Polymer Science and Engineering in the School of
`
`Polymers and High-Performance Materials at The University of Southern
`
`Mississippi, where I have been employed since 1983. My research has focused on
`
`polymers and their properties, and especially upon biodegradable/biomedical
`
`polymers, including their applications in drug delivery systems.
`
`3.
`
`Prior to joining the faculty of The University of Southern Mississippi,
`
`from 1982-1983, I was a research chemist with American Cyanamid Company
`
`where
`
`my
`
`research
`
`focused
`
`on
`
`polymers,
`
`and
`
`especially
`
`biodegradable/biomedical/veterinary polymers. At American Cyanamid, I worked
`
`on the development of microparticle-based drug delivery systems using
`
`poly(lactic-co-glycolic acid), also known as PLGA.
`
`4.
`
`I received my Ph.D. in Polymer Science from the University of Akron,
`
`Akron, Ohio, in 1983. My Ph.D. thesis concerned synthesis and characterization
`
`of polyisobutylene polymers.
`
`2
`
`
`
`5.
`
`I have performed extensive research in the design, synthesis, and
`
`characterization of polymers, including biodegradable/biomedical polymers and
`
`their applications in drug delivery systems.
`
`I have published more than 160
`
`refereed journal articles on polymers,
`
`including biodegradable/biomedical
`
`polymers. I am a named inventor on more than 30 U.S. Patents, all directed toward
`
`polymers and their applications.
`
`6.
`
`I have supervised 41 Ph.D. students,
`
`including students whose
`
`doctoral research was directed to biodegradable/biomedical polymers.
`
`I have
`
`taught graduate courses regarding polymer synthesis and characterization.
`
`7.
`
`I have served as a referee and reviewer of journal articles concerning
`
`polymers,
`
`including biodegradable/biomedical polymers.
`
`I have been a co-
`
`organizer and paper editor of the Waterborne, High-Solids, and Powder Coatings
`
`Symposium, a specialized polymer symposium, since 1985 and currently serve as
`
`its chairman.
`
`8.
`
`I am knowledgeable regarding the level of skill of persons of ordinary
`
`skill in the art of polymers, including those engaged in the development of
`
`polymer-based drug delivery systems during and around the year 2000, when the
`
`provisional application for the U.S. Patent No. 6,667,061 (“the ’061 Patent”) was
`
`filed.
`
`3
`
`
`
`9.
`
`I am knowledgeable regarding the synthesis, properties, and
`
`applications of polymers, including biodegradable/biomedical polymers such as
`
`polylactide
`
`(“polylactic
`
`acid”),
`
`polyglycolide
`
`(“polyglycolic
`
`acid”),
`
`and
`
`poly(lactic-co-glycolic acid). I am also knowledgeable in the analytical tools used
`
`to study polymers, including, for example, size exclusion chromatography, light
`
`scattering, differential scanning calorimetry, and microscopy.
`
`10. A copy of my current curriculum vitae is provided at Appendix 1.
`
`11.
`
`12.
`
`I am being compensated at my standard rate of $500 per hr.
`
`I have reviewed the Petition, Paper 5, the decision of the Patent Trial
`
`and Appeal Board (“PTAB”) instituting inter partes review, Paper 13,
`
`the
`
`references at issue for trial, and the ’061 Patent, Exh. 1001. I have also reviewed
`
`the Declaration of Dr. Patrick P. DeLuca, Exh. 1002, the exhibits referenced in
`
`Appendix 2 to this Declaration, and Dr. DeLuca’s deposition transcript from
`
`February 22, 2017, Exh. 2016. I have formed my opinions in this matter based on
`
`my more than 30 years of experience and expertise with polymers and their
`
`applications in delivery systems as well as the materials that I have reviewed.
`
`II.
`
`Scope and Summary of Opinions
`
`13.
`
`I have been asked by counsel for Alkermes to (i) provide my views as
`
`to whether claims 20-21 of the ’061 Patent would have been obvious on the ground
`
`on which the PTAB has instituted trial, and (ii) address the comments provided by
`
`4
`
`
`
`Dr. DeLuca in his declaration in support of the Petition for inter partes review
`
`(“IPR”) for these claims. I was also asked for my views as to the microparticle and
`
`polymeric issues for the claims of the ’061 Patent at issue in ground 2 of the IPR.
`
`14.
`
`I understand that the PTAB rejected the Petition on the ground that
`
`claims 20-21 would have been obvious over Johnson (Exh. 1009) and Kino (Exh.
`
`1010), but instituted IPR on the ground that they would have been obvious over
`
`Gustafsson (Exh. 1011), Ramstack (Exh. 1005) and the Handbook (Exh. 1008). I
`
`understand that the PTAB also instituted IPR of claims 8-9, 12-13, and 22-23 in
`
`view of Gustafsson combined with Ramstack and instituted IPR of claims 1-3, 6-7,
`
`and 17-19 in view of Gustafsson.
`
`15.
`
`For the reasons set forth in detail below, it is my opinion that claims
`
`20-21 of the ’061 Patent would not have been obvious over the combination of
`
`Gustafsson, Ramstack, and the Handbook at the time of the invention. My analysis
`
`also applies to the other claims at issue in ground 2. As discussed below, there
`
`would not have been any reason to combine Gustafsson and Ramstack (with or
`
`without the Handbook) at the time of the invention as Petitioner contends for
`
`claims 8-9, 12-13, and 22-23.
`
`In addition, Gustafsson has no teaching of
`
`“microparticles” as required by the claims of the ’061 Patent and Gustafsson’s
`
`special coated microparticles teach away from the invention claimed in the ’061
`
`Patent.
`
`5
`
`
`
`16.
`
`In my opinion, a person of ordinary skill in the art (“POSA”) working
`
`to develop a microparticle-based injectable system for delivering risperidone
`
`would not have selected Gustafsson as a starting point for developing such a
`
`system because it is directed to active substances that are vastly different from
`
`risperidone, and is focused on solving a problem and providing a solution that are
`
`irrelevant to risperidone.
`
`Indeed, Gustafsson teaches away from the invention as
`
`claimed in the ’061 Patent:
`
`its coated microparticles do not meet the definition of
`
`microparticles in the ’061 Patent and are entirely different from them. Gustafsson
`
`also expressly teaches away from encapsulating active substances in a polymeric
`
`binder and in a PLGA polymer in particular.
`
`17.
`
`In my opinion, a POSA also would have had no reason to combine
`
`Gustafsson and Ramstack. These references teach completely different drug
`
`delivery systems. Gustafsson teaches a reservoir drug-delivery system while
`
`Ramstack discloses a matrix-based system. Gustafsson also expressly teaches
`
`away from: (i) using the matrix-type microparticles taught in Ramstack, and (ii)
`
`using PLGA as a polymeric binder or matrix. Ramstack, by contrast, teaches the
`
`dispersion of risperidone in a PLGA polymer, and describes PLGA as the preferred
`
`polymer for its microparticles.
`
`18.
`
`Petitioner’s expert, Dr. DeLuca, has offered no reason as to why a
`
`POSA would have combined Gustafsson and Ramstack, much less with a
`
`6
`
`
`
`reasonable expectation of success, and there is none. Dr. DeLuca opines that a
`
`POSA would have replaced the coated microparticle of Gustafsson with the
`
`microparticles taught
`
`in Ramstack. But
`
`that opinion has no support
`
`in the
`
`references. Gustafsson’s particular coated microparticle is the essence of
`
`Gustafsson’s invention and to replace it with a different microparticle, Ramstack’s
`
`PLGA-matrix microparticle—from which Gustafsson expressly teaches away—is
`
`at odds with the teachings of both Gustafsson and Ramstack. The Handbook
`
`similarly provides no basis for combining these references.
`
`19.
`
`The combination of Gustafsson and Ramstack in ground 2 is a product
`
`of picking and choosing unrelated elements from disparate references using the
`
`teaching of the ’061 Patent as a guide. In my opinion, there is no scientific basis
`
`for the combination given the disparate teachings.
`
`III. Obviousness Standards
`
`20.
`
`I have been advised by counsel on the legal standards to be applied in
`
`forming my opinion as to obviousness of claims of the ’061 Patent.
`
`21.
`
`I have been informed that the subject matter of a patent claim must be
`
`nonobvious in order for the claim to be patentable.
`
`It is my understanding that
`
`obviousness
`
`is established only when the Petitioner demonstrates, by a
`
`preponderance of the evidence, that the subject matter of the claim as a whole
`
`would have been obvious to a POSA at the time of the claimed invention.
`
`7
`
`
`
`22.
`
`I have also been informed that the obviousness analysis is performed
`
`from the perspective of a hypothetical POSA and relies on four considerations: (1)
`
`the scope and content of the prior art; (2) the differences between the prior art and
`
`the claims at issue; (3) the level of ordinary skill in the relevant art; and (4)
`
`objective indicia of nonobviousness.
`
`23.
`
`I also have been informed that a claimed invention is not obvious
`
`unless it is shown that a POSA would have had reason to select and 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.
`
`24.
`
`I have also been informed that it is important to guard against the use
`
`of hindsight in analyzing obviousness, such as using the patent at issue as a
`
`roadmap to pick and choose unrelated elements from disparate references in order
`
`to reconstruct the invention.
`
`25.
`
`In addition, I have been informed that, in considering obviousness, it
`
`is relevant whether the art includes references that "teach away" from the claimed
`
`invention.
`
`I have been informed that a reference teaches away from the claimed
`
`invention if a person of ordinary skill, reading the reference, would be discouraged
`
`from following a path which could lead to the claimed invention or would be led to
`
`follow a different path.
`
`8
`
`
`
`IV. The Person of Ordinary Skill In the Art
`
`26. According to Dr. DeLuca, a POSA would have at least a bachelor’s
`
`degree and a number of years of industry training or experience in one or more of
`
`the following fields: pharmaceutical
`
`formulation, chemistry, pharmaceutical
`
`science,
`
`polymer
`
`chemistry,
`
`pharmaceutics,
`
`pharmaceutical
`
`technology,
`
`pharmacokinetics, and/or pharmacology. (Exh. 1002 at ¶12).
`
`27.
`
`I disagree with Dr. DeLuca’s definition.
`
`In my opinion, a POSA
`
`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).
`
`28. Although Dr. DeLuca and I offer different definitions of a POSA, my
`
`conclusion is the same under either definition.
`
`V.
`
`The ’061 Patent and Claims
`
`29.
`
`The ’061 Patent relates to an injectable suspension having improved
`
`injectability.
`
`(Exh. 1001 at 1:12-15). The injectable suspension comprises
`
`microparticles suspended in an injection vehicle. Improved injectability means the
`
`suspension has good aspiration qualities, can be injected into a patient or a host
`
`without having to use excessive amounts of pressure or force, provides even flow
`
`characteristics, and is free from clogging. (Id. at 1:61-64).
`
`9
`
`
`
`30.
`
`The microparticles disclosed in the ’061 Patent contain active
`
`substances incorporated within a polymeric binder or matrix. The ’061 Patent
`
`expressly defines “microparticles” as “particles that contain an active agent or
`
`other substance dispersed or dissolved within a polymer that serves as a matrix or
`
`binder of the particle.” (Exh. 1001 at 5:14-18). The polymeric binder or matrix is
`
`preferably biodegradable and biocompatible.
`
`(Id. at 5:18-19). The ’061 Patent
`
`teaches that a copolymer of lactic acid and glycolic acid, known as poly(lactic-co-
`
`glycolic acid) or PLGA, is particularly suitable for use as a polymeric binder or
`
`matrix.1 (Id. at 14:10-32). The ’061 Patent uses PLGA as the polymer binder or
`
`matrix in all of the microparticles prepared in the patent (Id. at 17:11-19; 11:23-28
`
`(teaching placebo microparticles prepared using PLGA); 5:61-6:1 (citing U.S. Pat.
`
`No. 5,792,477, Exh. 2055)).
`
`31.
`
`The ’061 Patent teaches that particularly preferred active substances
`
`for delivery in its matrix-type microparticles include risperidone, its metabolite 9-
`
`hydroxyrisperidone, and pharmaceutically acceptable salts based on these actives,
`
`with risperidone being the most preferred. (Exh. 1001 at 14:64-15:7). Other than
`
`the placebo microparticles, which were designed to contain no active substances
`
`(id. at 11:23-28), all microparticles prepared in the examples of the ’061 Patent
`
`contained risperidone as the active substance.
`
`1 Poly(lactic-co-glycolic acid) is also known by other names including poly(d,l-
`lactic-co-glycolic acid) or poly(lactide-co-glycolide).
`
`10
`
`
`
`32. All the claims of the ’061 Patent require a composition suitable for
`
`injection that comprises “microparticles comprising a polymeric binder” and an
`
`“injection vehicle” with certain characteristics. Dependent claims 2-3, 6-9, and 12-
`
`13 have additional limitations related to the injection vehicle. Dependent claim 17
`
`requires that the microparticles comprise an active agent “encapsulated” within the
`
`polymeric binder. Claim 18 requires certain polymeric binders. Claim 19 requires
`
`PLGA having a molar ratio of lactide to glycolide in the range of from about 85:15
`
`to about 50:50 as the polymeric binder.
`
`33. Claim 20 is directed to a composition for delivering risperidone, its
`
`metabolite
`
`(9-hydroxyrisperidone),
`
`and
`
`pharmaceutically
`
`acceptable
`
`salts
`
`(collectively “risperidone”). Claim 20 depends from claim 17, which in turn
`
`depends from claim 1. I have been advised that claim 20 thereby incorporates all
`
`the limitations set forth in claims 1, 17, and 20. As a result, it requires, among
`
`other things, microparticles comprising a polymeric binder where risperidone is
`
`“encapsulated” within the polymeric binder.
`
`34. Claim 21 is similarly directed to a composition for delivering
`
`risperidone. Claim 21 depends from claim 19, which in turn depends from claim
`
`17. As a result, claim 21 incorporates all of the limitations recited above for claim
`
`20, and additionally requires that the polymeric binder encapsulating risperidone is
`
`11
`
`
`
`PLGA having a molar ratio of lactide to glycolide in the range of from about 85:15
`
`to about 50:50.
`
`35. Claims 22 and 23 depend from claim 1 and set forth limitations
`
`relating to the mass median diameter of the microparticles.
`
`VI. Overview of Ground 2 References
`
`36.
`
`The second ground for
`
`trial concerns Gustafsson (Exh. 1011),
`
`Ramstack (Exh. 1005), and the Handbook (Exh. 1008). In particular, for claims 20
`
`and 21, Petitioner’s expert, Dr. DeLuca, opined that “a POSA would expect to
`
`combine the risperidone microspheres of Ramstack and the injection vehicle of
`
`Gustafsson with a reasonable expectation of success.” (Exh. 1002 at ¶ 80).
`
`In
`
`instituting trial, the PTAB stated that “it would have been obvious to the ordinary
`
`artisan that the injection vehicle of Gustafsson could be used for Ramstack’s
`
`microparticles.” (Paper 13 at 30:12-15). Dr. DeLuca also opined that
`
`the
`
`“microparticles” limitation was met for claims 1-3, 6-9, 12-13, and 22-23 based on
`
`the teaching in Gustafsson but did not identify any polymeric binder. For claims
`
`17-19, Dr. DeLuca relies on the PLGA coating in Gustafsson as the polymeric
`
`binder. The same is true of the Petition. (Paper 5 at 45, 53).
`
`A.
`
`Gustafsson
`
`37. Gustafsson is directed to the development of an injectable sustained-
`
`release formulation for delivering “active substances sensitive to or instable in
`
`12
`
`
`
`organic solvents.” (Exh. 1011 at 6:35-7:2; see also DeLuca Tr. 238:22-239:4).
`
`These substances are complex biological molecules that include “proteins, peptides
`
`and polypeptides or other drugs or biologically active substances.” (Exh. 1011 at
`
`11:24-28).
`
`38.
`
`Proteins are particularly difficult to formulate in a controlled-release
`
`form due to conditions encountered in preparing the formulation. Gustafsson
`
`states:
`
`“[M]ost proteins are dependent on a well defined three-dimensional structure
`as
`to many of
`their properties,
`including biological activities and
`immunogenicity. Their three-dimensional structures can relatively easily be
`destroyed, for example by . . . exposure to organic solvents.”
`
`(Id. at 2:19-27).
`
`39. Gustafsson points to the difficulty in formulating proteins in a PLGA
`
`matrix in particular. Gustafsson warns:
`
`“[A] very serious drawback in connection with the use of PLGA . . . for
`sustained release of proteins is the requirement to utilize organic solvents to
`dissolve said PLGA, with the associated risk of compromising the stability
`of the protein.”
`
`“[T]he three-dimensional structures of most proteins are too sensitive to
`withstand the preparation procedures used and/or being stored in a PLGA-
`matrix.”
`
`(Id. at 2:27-32, 3:1-4 (emphasis added); see also DeLuca Tr. 241:9-24). As a
`
`result, Gustafsson explains that, despite significant effort, “no protein products
`
`13
`
`
`
`ha[d] appeared on the market based on PLGA technology.” (Exh. 1011 at 2:33-
`
`3:4).
`
`40. Gustafsson also notes the difficulties with PLGA-based systems for
`
`accurately controlling the release of the active substance:
`
`A parenterally administrable sustained release formulation should be able to
`control the release of the entrapped drug in an accurate way. In many of the
`systems based on PLGA the release of the active ingredient is largely
`dependent on the amount of drug substance incorporated into the
`microparticle, due to the formation of channels in the microparticles at
`higher drug loadings. This also contributes to a high initial burst at high
`drug loading.
`
`(Id. at 4:26-34).
`
`41.
`
`In response to these challenges, Gustafsson devised a specialized
`
`coated microparticle (or coated core particle) with a core-shell or reservoir-type
`
`structure. The active substances are first entrapped in “core particles [prepared]
`
`from a biodegradable material in an aq[u]eous medium that is essentially free from
`
`organic solvent.” (Id. at 7:3-27; 8:28-9:4). The core particle material is preferably
`
`“a starch or a chemically or physically modified starch.” (Id. at 7:34-35). After
`
`the core particles are dried, they are coated with a layer of polymer using an air
`
`suspension technique.
`
`(Id. at 9:10-14).
`
`In this procedure, the active substances
`
`trapped within the core particles do not come into contact with the organic solvent
`
`that is used to dissolve the polymer.
`
`(Id. at 7:11-27; see also DeLuca Tr. 238:8-
`
`14
`
`
`
`239:9, 241:25-242:4). As a result, their biological activities are preserved. (Exh.
`
`1011 at 9:33-10:4).
`
`42. While Gustafsson makes a general statement that “the invention is
`
`useful for all active substances which may be utilized in parenteral administration,”
`
`(id. at 6:33-35), the invention specifically provides a solution to the problem of
`
`sensitivity of active substances such as proteins to organic solvents used to
`
`dissolve PLGA or other water-insoluble polymers in producing a parenteral
`
`formulation.
`
`The invention in Gustafsson offers “a method of producing
`
`parenterally administrable sustained release formulations for sensitive substances,
`
`for instance proteins . . . that makes it possible to eliminate, or minimise, the
`
`exposure of the active ingredient to organic solvents.” (Id. 5:34-6:10).
`
`43.
`
`Indeed, all of Gustafsson’s examples use proteins, namely, bovine
`
`serum albumin (“BSA”) or insulin, as the active substance. (Exh. 1011 at 14:4-19:9;
`
`see also DeLuca Tr. 239:10-20). Gustafsson explains that
`
`the invention is
`
`exemplified by these substances because BSA “is the most extensively used model
`
`protein” for parenteral systems and “insulin is known to be a sensitive protein.”
`
`(Exh. 1011 at 14:4-11). Nowhere does Gustafsson mention risperidone, a small
`
`molecule that is insensitive to organic solvents used to dissolve water-insoluble
`
`polymers such as PLGA. The problem and solution provided by Gustafsson are
`
`for substances entirely different from risperidone, i.e., substances that are sensitive
`
`15
`
`
`
`to organic solvents and cannot be dissolved or dispersed in a PLGA polymeric
`
`binder or matrix.
`
`B.
`
`Ramstack
`
`44. Ramstack, by contrast, is drawn to “a method of encapsulating active
`
`agents to form controlled-release microparticles.” (Exh. 1005 at 1:14‒17).
`
`Ramstack teaches that the active substance is “dispersed or dissolved within a
`
`biodegradable polymer that serves as the matrix of the particle.” (Id. at 1:19-21,
`
`17:17-19) (emphasis added). The “biodegradable microparticles compris[e] a
`
`biodegradable polymeric binder and a biologically active agent.” (Id. at 8:5-7)
`
`(emphasis added).
`
`45. Ramstack teaches that the active agent in its microparticles may be
`
`risperidone. (Exh. 1005 at 8:21‒22; see also DeLuca Tr. 245:20-246:22).
`
`It
`
`devotes
`
`two examples
`
`(examples 2 and 3)
`
`to procedures
`
`for preparing
`
`microparticles encapsulating risperidone. (Exh. 1005 at 35:1-36:26; see also
`
`DeLuca Tr. 245:20-246:22).
`
`46. Ramstack also teaches that the “most preferred polymer for use in the
`
`practice of this invention is poly(dl-lactide-co-glycolide),” i.e., PLGA, wherein
`
`“the molar ratio of lactide to glycolide in such a copolymer be in the range of from
`
`about 85:15 to about 50:50.” (Exh. 1005 at 16:28‒31).
`
`16
`
`
`
`47. Ramstack is also directed to “a solvent system useful in a method of
`
`encapsulating active agents to form controlled-release microparticles.”
`
`(Id. at
`
`1:17-19). Particularly, “a blend of at least two substantially non-toxic solvents,
`
`free of halogenated hydrocarbons, is used to dissolve both the agent and the
`
`polymer.” (Id. at 8:25-27). Ramstack’s solvent system “is preferably a blend of at
`
`least two of the following: an ester, an alcohol, and a ketone.” (Id. at 15:9-10).
`
`Ramstack further states that “the most preferred” ester, alcohol and ketone are
`
`“ethyl acetate,” “benzyl alcohol,” and “methyl ethyl ketone,” respectively. (Id. at
`
`15:9-26). These are all organic solvents.
`
`48. Ramstack discloses that risperidone and the polymeric matrix material
`
`are both dissolved in a solution of organic solvents, stating:
`
`The organic phase includes the active agent as well as the wall forming
`polymer, i.e., the polymeric matrix material. The organic phase is prepared
`by dissolving or dispersing the active agent(s) in the organic solvent system
`of the present invention.
`
`(Id. at 20:6-9). Examples 2 and 3, which describe the preparation of risperidone-
`
`containing microparticles, are to the same effect. In each example, PLGA is first
`
`dissolved in a mixture of organic solvents (ethyl acetate and benzyl alcohol), and
`
`risperidone is subsequently dissolved in the polymer solution with organic solvents.
`
`(Id. at 35:6-12; 36:7-12).
`
`49. Ramstack examines the controlled release properties and biological
`
`effects of the risperidone-containing microparticles in an in vivo study using dogs
`
`17
`
`
`
`as the subjects.
`
`(Id. at 38-47). The release of risperidone was well controlled;
`
`Ramstack explains that after reaching peak plasma level of risperidone, “further
`
`release of risperidone . . . proceeded gradually and was long-lasting.” (Id. at 40:3-
`
`6). Ramstack monitored the biological effect of risperidone delivered via the
`
`microparticles by studying its anti-emetic (i.e., anti-vomiting) activity, and noted
`
`that the “anti-emetic activity lasted 35 to 42 days” for three formulations and “49
`
`days” for a fourth one, reflecting that the particles were long-acting. (Id. at 40:17-
`
`20). Ramstack does not identify any deficiency with its injectable risperidone
`
`containing PLGA-microparticles,
`
`the injection vehicle, or injectability of the
`
`suspension of microparticles. (Id. at 1:1-61:22; see also DeLuca Tr. 247:10-17.)
`
`C.
`
`The Handbook
`
`50. As its title suggests, the Handbook teaches various pharmaceutical
`
`excipients. (Exh. 1008). It does not address risperidone formulations.
`
`VII. Claims 20-21 Are Not Obvious Over Gustafsson in View of
`Ramstack and the Handbook
`
`51. With respect to claims 20-21, Dr. DeLuca has opined that a POSA
`
`would have “combine[d] the risperidone microspheres of Ramstack and the
`
`injection vehicle of Gustafsson with a reasonable expectation of success.” (Exh.
`
`1002 at ¶ 80). I disagree.
`
`52.
`
`In my opinion, a POSA would not have combined these teachings,
`
`because (A) a POSA would not have selected Gustafsson in developing an
`
`18
`
`
`
`injectable formulation for risperidone, (B) Gustafsson teaches away from the
`
`invention of the ’061 Patent, (C) Gustafsson teaches away from combination with
`
`Ramstack, and (D) a POSA would not have had a reason to combine these
`
`references.
`
`Indeed,
`
`replacing the invention of Gustafsson – its coated
`
`microparticles designed to avoid using a PLGA matrix – with the PLGA-matrix
`
`based microparticles of Ramstack is at odds with the references.
`
`A.
`
`A POSA Would Not Have Selected Gustafsson in
`Developing Microparticles for Delivering Risperidone
`
`53. A POSA would not have selected Gustafsson in developing
`
`microparticles for delivering risperidone for at
`
`least
`
`three reasons.
`
`First,
`
`Gustafsson is aimed at solving a different problem encountered during the
`
`formulation of sensitive actives that is not encountered with risperidone. Second, a
`
`POSA would have looked to references describing microparticles designed
`
`specifically for risperidone, not Gustafsson. Third, a POSA would be aware that
`
`risperidone is practically insoluble in water and thus would be discouraged from
`
`considering Gustafsson, whose principal embodiments and all examples involve
`
`protein active agents that are processed into core particles using water as the
`
`solvent.
`
`19
`
`
`
`1.
`
`Gustafsson Is Aimed at a Problem that Risperidone Does
`Not Have
`
`54. A POSA focused on developing a composition suitable for delivering
`
`microparticles containing risperidone by injection would first consult references
`
`directed to that subject matter, i.e., references with (i) microparticles that have
`
`been designed for delivering risperidone, or (ii) microparticles that have been
`
`designed for delivering molecules with similar physical and chemical properties as
`
`risperidone. As discussed in detail below, Gustafsson does not fit in either
`
`category.
`
`i.
`
`Gustafsson is directed to coated microparticles
`specially developed for actives that are sensitive
`to organic solvents
`
`55. As an initial matter, Gustafsson does not teach risperidone as an active
`
`for use in its microparticles. Although Gustafsson makes a general statement that
`
`“the invention is useful for all active substances which may be utilized in
`
`parenteral administration,” (Exh. 1011 at 6:33-35), Gustafsson teaches a
`
`formulation particularly adapted for delivering actives with particular properties
`
`that are not relevant to risperidone.
`
`56. As discussed above, Gustafsson explains that exposure to an organic
`
`solvent poses significant risks for complex biological molecules, such as “proteins,
`
`peptides and polypeptides or other drugs or biologically active substances which
`
`are sensitive to or instable in the presence of organic solvents.” (Id. at 11:24-28;
`
`20
`
`
`
`see also DeLuca Tr. 241:16-24). Gustafsson provides a solution – a specialized
`
`coated microparticle – for formulating such sensitive substances.
`
`(Exh. 1011 at
`
`6:35-7:10; DeLuca Tr. 238:8-239:9).
`
`ii.
`
`Sensitivity to organic solvents is not an issue for
`risperidone
`
`57. Risperidone is an active substance used for
`
`the treatment of
`
`schizophrenia.
`
`It has a chemical structure shown in the below diagram.
`
`It is a
`
`small molecule with a molecular weight of just 410.48 g/mol (equivalent to
`
`0.41048 kDa).
`
`Risperidone
`
`58. Unlike proteins,
`
`risperidone does not have a complex three-
`
`dimensional structure that is susceptible to being destroyed upon contact with an
`
`organic solvent.
`
`It
`
`is not sensitive to organic solvents used in formulating
`
`microparticles, such as those used to dissolve PLGA or other water-insoluble
`
`polymers. (DeLuca Tr. 49:25-50:2). Indeed, risperidone is practically insoluble in
`
`water and readily dissolves in organic solvents. (Id. at 49:22-24, 50:20-24). The
`
`prior art included references, such as Ramstack, that taught the use of organic
`
`21
`
`
`
`solvents to dissolve risperidone and PLGA, during the preparation of risperidone
`
`PLGA microparticles.
`
`2.
`
`Included Injectable Formulations for
`The Prior Art
`Delivering Risperidone
`
`59. Microparticles containing risperidone were part of the scope and
`
`content of the prior art in 2000. Ramstack and Kino (Exh. 1010) are two examples
`
`of such references.
`
`60. Ramstack devotes
`
`two examples
`
`to procedures
`
`for preparing
`
`microparticles encapsulating risperidone. (Exh. 1005 at 35:1-36:26). As discussed
`
`above, Ramstack does not
`
`teach any problem with its risperidone-containing
`
`microparticles. (DeLuca Tr. 247:10-17). To the contrary, it demonstrated the
`
`controlled release properties and biological effects of the risperidone-containing
`
`microparticles in an in vivo study. (Exh. 1005 at 38-47).
`
`61. Kino also teaches microparticles containing risperidone (Exh. 1010 at
`
`6:7-13), and does not disclose any problem with these microparticles. (DeLuca Tr.
`
`248:11-15).
`
`62. A POSA would not have had reason to select Gustafsson in
`
`developing an injectable risperidone formulation.
`
`Instead, a POSA tasked with
`
`developing an injectable risperidone formulation would have consulted references
`
`with pertinent teachings, such as Kino and Ramstack.
`
`22
`
`
`
`B.
`
`Gustafsson Teaches Away From the Invention of the ’061
`Patent
`
`63. Gustafsson teaches away from the invention claimed in the ’061
`
`Patent. Its polymer-coated microparticles, just as its starch-based core particles, do
`
`not meet the definition of microparticles in the ’061 Patent. Gustafsson also
`
`specifically teaches away from a PLGA polymeric matrix or binder.
`
`i.
`
`The Coated Microparticles Taught in Gustafsson Do Not
`Meet the Definition of the ’061 Patent
`
`64. Gustafsson’s coated microparticles do not have an active substance
`
`that is dissolved or dispersed in a polymer that serves as a matrix or polymeric
`
`binder of the particle. Gustafsson repeatedly explains that the polymer coats the
`
`microparticle and does not contain the active substance.
`
`Instead, the active
`
`substance is distributed in a reservoir, i.e., a drug-containing core made of natural
`
`or modified starch. (Exh. 1011 at 7:34-35; DeLuca Tr. 242:5-244:5). The polymer
`
`in Gustafsson is applied onto the surface of the core and forms a polymer shell or
`
`coating.
`
`(Exh. 1011
`
`at 9:10-14; DeLuca Tr. 239:5-9, 240:2-9). No active
`
`substance is distributed within the polymer outer shell or coating.
`
`65.
`
`I understand that the PTAB has stated that the coated microparticles
`
`of Gustafsson meet the definition in the ’061 Patent that “an active agent or other
`
`substance [is] dispersed or dissolved within a polymer that serves a matrix or
`
`binder of the particle.” (Paper 13 at 25). I disagree.
`
`23
`
`
`
`66.
`
`In particular, the PTAB stated that “the active is entrapped, that is,
`
`dispersed or dissolved in the polymer of the microparticle, before the microparticle
`
`is coated.” (Id. at 25-26, citing Exh. 1011 at 7:3-10). The cited section of
`
`Gustafsson states:
`
`“Briefly the invention is based on the idea on entrapping the active
`ingredient in microparticles without using any organic solvent, working up
`to the dry state and subsequently coating the
`the microparticles
`microparticles with a biodegradable polymer using an air suspension
`technique to remove, very rapidly, any organic solvent used for the polymer
`coating to avoid any substantial exposure of the active substance to organic
`solvent.”
`
`(Exh. 1011 at 7:3-10)
`
`(emphasis added).
`
`The passage uses
`
`the word
`
`“microparticles” to refer to core particles which contain the active substance
`
`entrapped in a starch core without the involvement of the “polymer.” (Id. at 7:34-
`
`35). The passage cited by the PTAB distinguishes between the core particles or
`
`“micr
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