UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`U.S. Patent No. 9,404,127
`
`Issued: August 2, 2016
`
`Named Inventor: Ed Yaworski, Lloyd B. Jeffs, Lorne R. Palmer
`
`Title: Non-Liposomal Systems for Nucleic Acid Delivery
`___________
`
`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,404,127
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Moderna Ex 1007-p. 1
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`ARBUTUS - EXHIBIT 2030
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
`
`

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`TABLE OF CONTENTS
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`Page
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`I.(cid:3)
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`II.(cid:3)
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`INTRODUCTION .................................................................................. 1(cid:3)
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`SUMMARY OF OPINIONS .................................................................. 1(cid:3)
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`III.(cid:3) QUALIFICATION AND EXPERIENCE .............................................. 3(cid:3)
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`IV.(cid:3) LEVEL OF ORDINARY SKILL IN THE ART .................................... 8(cid:3)
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`V.(cid:3)
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`LEGAL PRINCIPLES............................................................................ 9(cid:3)
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`A.(cid:3)
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`B.(cid:3)
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`C.(cid:3)
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`Claim Construction ...................................................................... 9(cid:3)
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`Prior Art...................................................................................... 10(cid:3)
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`Anticipation ................................................................................ 11(cid:3)
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`D.(cid:3) Obviousness ............................................................................... 12(cid:3)
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`VI.(cid:3) BACKGROUND .................................................................................. 16(cid:3)
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`A.(cid:3)
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`B.(cid:3)
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`C.(cid:3)
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`D.(cid:3)
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`Lipid carrier particles for nucleic acid payloads ........................ 16(cid:3)
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`The ’127 patent disclosure ......................................................... 20(cid:3)
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`Claim Construction .................................................................... 23(cid:3)
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`Prior art ....................................................................................... 24(cid:3)
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`VII.(cid:3) THE CHALLENGED CLAIMS ARE INVALID ............................... 31(cid:3)
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`A.(cid:3) Ground 1: Claims 1-22 are anticipated by or obvious in
`view of the ’069 patent ............................................................... 31(cid:3)
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`B.(cid:3)
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`C.(cid:3)
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`Ground 2: Claims 1-22 are anticipated by or obvious in
`view of the ’817 PCT ................................................................. 47(cid:3)
`
`Ground 3: Claims 1-22 are anticipated by or obvious in
`view of the ’099 patent alone or in view of Koltover
`and/or Ewert ............................................................................... 49(cid:3)
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`D.(cid:3) Ground 4: claims 1-22 are obvious in view of the ’817
`PCT in light ofKoltover and/or Ewert ....................................... 64(cid:3)
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`VIII.(cid:3) CONCLUSION .................................................................................... 66(cid:3)
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`I, Dr. Andrew S. Janoff, PhD, declare as follows:
`I.
`INTRODUCTION
`1.
`My name is Andrew S. Janoff. I am a consultant in biotechnology
`
`and drug delivery, primarily focusing on lipid and liposome technology.
`
`2.
`
`I have been engaged by Moderna Therapeutics, Inc. (“Moderna”)
`
`as an expert in connection with matters raised in the Petition for Inter Partes
`
`Review (“Petition”) of U.S. Patent No. 9,404,127 (the “’127 patent”) owned by
`
`Protiva Biotherapeutics, Inc. (“Patent Owner”).
`
`3.
`
`This declaration is based on the information currently available to
`
`me. To the extent that additional information becomes available, I reserve the
`
`right to continue my investigation and study, which may include a review of
`
`documents and information that may be produced, as well as testimony from
`
`depositions that have not yet been taken.
`
`II.
`
`SUMMARY OF OPINIONS
`The ’127 patent is entitled “Non-Liposomal Systems for Nucleic
`
`4.
`
`Acid Delivery.” Ex. 1001. The ’127 patent is directed to a composition
`
`nucleic acid-lipid particles having a non-lamellar morphology used to deliver
`
`therapeutic nucleic acid payloads to a patient. See, e.g., id., cl. 1. The Petition
`
`challenges claims 1-22 of the ’127 patent.
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`5.
`
`Petitioner’s Ground 1 challenges claims 1-22 of the ’127 as
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`anticipated by the disclosures in U.S. Patent No. 8,058,069 (“’069 Patent”), Ex.
`
`1002, under pre-AIA 35 U.S.C. §§ 102(a) and § 102(e)(2) or, in the alternative,
`
`as obvious under 35 U.S.C. § 103 in view of the ’069 patent. Based on
`
`studying the petition and the exhibits cited in the petition as well as other
`
`documents, it is my opinion that claims 1-22 of the ’127 patent are anticipated
`
`by the ’069 Patent. In the alternative, it is my opinion that claims 1-22 of the
`
`’127 patent are obvious in view of the ’069 Patent.
`
`6.
`
`Petitioner’s Ground 2 challenges claims 1-22 of the ’127 patent as
`
`anticipated by the disclosures in the PCT/CA2008/002285, Publication No.
`
`WO 2009/082817 PCTA1 (“’817 PCT PCT”), Ex. 1003, under pre-AIA 35
`
`U.S.C. §§ 102(a) and 102(e)(1) or, in the alternative, as obvious under 35
`
`U.S.C. § 103 in view of the ’817 PCT. Based on studying the petition and the
`
`exhibits cited in the Petition as well as other documents, it is my opinion that
`
`claims 1-22 are anticipated by the ’817 PCT. In the alternative, it is my
`
`opinion that claims 1-22 of the ’127 patent are obvious in view of the ’817
`
`PCT.
`
`7.
`
`Petitioner’s Ground 3 challenges claims 1-22 of the ’127 patent as
`
`anticipated by U.S. Patent 7,514,099 (“’099 Patent”), Ex. 1004, under pre-AIA
`
`35 U.S.C. §§ 102(b) or, in the alternative, as obvious under 35 U.S.C. § 103 in
`
`view of the ’099 patent alone, or in combination with Koltover et al., An
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`Inverted Hexagonal Phase of Cationic Liposome-DNA Complexes Related to
`
`DNA Release and Delivery, 281 Science 78–81 (1998) (“Koltover”), Ex. 1005,
`
`and/or Ewert et al., Cationic Lipid-DNA Complexes for Non-Viral Gene
`
`Therapy: Relating Supramolecular Structures to Cellular Pathways, 5(1)
`
`Expert Opin Biol Ther. 33–53 (2005) (“Ewert”), Ex. 1006. Based on studying
`
`the Petition and the exhibits cited in the Petition as well as other documents, it
`
`is my opinion that claims 1-22 are anticipated by the ’099 patent. In the
`
`alternative, it is my opinion that claims 1-22 of the ’127 patent are obvious in
`
`view of the ’099 patent alone, or in combination with Koltover and/or Ewert.
`
`8.
`
`Petitioner’s Ground 4 challenges claims 1-22 of the ’127 patent as
`
`obvious in view of ’817 PCT, Ex. 1003, in light of Koltover, Ex. 1005, and/or
`
`Ewert, Ex. 1006 under 35 U.S.C. § 103. Based on studying the Petition and the
`
`exhibits cited in the Petition as well as other documents, it is my opinion that
`
`claims 1-22 are rendered obvious by the cited references.
`
`III. QUALIFICATION AND EXPERIENCE
`9.
`I am formally trained as a membrane biophysicist. I obtained my
`
`Ph.D. degree in Biophysics from Michigan State University in 1980. Before
`
`that, I received my MS in Biophysics from Michigan State University in 1977,
`
`and my BS in Biology from The American University in 1971. I received
`
`postdoctoral training in Pharmacology at the Harvard Medical School and the
`
`Massachusetts General Hospital.
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`10.
`
`I have played leadership roles in the discipline of pharmaceutical
`
`liposomology from its inception in 1981.
`
`11. After my post-doctoral work, I was recruited from Harvard by the
`
`industrialist, Jack Whitehead, and became the first senior founding scientist at
`
`the Liposome Company, Inc. I eventually became the Vice President of
`
`Research and Development at the Liposome Company. I led the team at the
`
`Liposome Company that discovered, formulated, and developed ABELCET, a
`
`novel lipid structure that is approved worldwide for systemic fungal infections.
`
`I first published the physical chemical characterization of this structure, along
`
`with an explanation of why it would yield a less toxic alternative to the
`
`traditional micelle formulation in the Proceedings of the National Academy of
`
`Sciences.
`
`12.
`
`I led the team at the Liposome Company that developed Staclot
`
`LA, a diagnostic reagent comprised of Hexagonal (II) lipid that is a standard
`
`practice for diagnosing lupus anticoagulant. The work leading to this product
`
`was also published in the Proceedings of the National Academy of Sciences.
`
`13.
`
`In addition I lead teams at the Liposome Company that formulated
`
`and characterized Myocet (Liposomal Doxorubicn Injection). This product is
`
`currently approved in Canada and the European Union and is used to treat
`
`metastatic breast cancer.
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`14.
`
`From 2001-2002, I was Chairman, and from 2002-2005, I was
`
`Chairman and CEO, of Celator Technologies, Inc. I was involved in the
`
`creation of Celator’s intellectual property platform and built the company from
`
`a Canadian start up into an international pharmaceutical corporation with
`
`research, manufacturing, clinical development, regulatory, commercial, and
`
`legal functions. From 2005-2008, I was Chairman and CEO of its successor,
`
`Celator Pharmaceuticals, Inc., a company using controlled-release liposomes to
`
`deliver combinations of chemotherapeutic agents to tumors. Celator’s drug
`
`Vxyeos was recently approved by the FDA for the treatment of leukemia.
`
`15.
`
`From 2009-2011, I was CEO of TranslationUP, which was a
`
`consortium of authorities from academic research, drug development, policy,
`
`finance, public relations, and law seeking to create a new model to more
`
`effectively advance government funded late-stage discovery concepts into
`
`clinical development.
`
`16.
`
`In my career, I have overseen the filing of eight INDs, two NDAs
`
`and one MAA in the areas of oncology, antiinfectives, and acute respiratory
`
`distress syndrome, all involving liposome or lipid-delivery systems.
`
`17.
`
`I have worked and published in the area of pulmonary surfactants
`
`involving treatment modalities in which lamellar lipid for instilling into
`
`neonate lungs was constructed to rearrange into the Hexagonal II architecture
`
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`at body temperature. An article that I published on this topic in Science was
`
`reviewed and highlighted in Lancet, a leading British Medical Journal.
`
`18.
`
`I have lectured and have conducted Grand Rounds in the areas of
`
`liposomes, lipid physical chemistry and drug delivery at many prestigious
`
`medical centers in the United States and Canada, and have been invited to
`
`speak on these topics at major industry, financial, scientific and medical
`
`symposia worldwide.
`
`19.
`
`I have also served on various government advisory committees.
`
`For example, I taught at the NATO Advanced Study Institute in Cape Sunion,
`
`Greece, participated in FDA symposia regarding the quality and performance
`
`of controlled release parenterals, served on the Committee of Science and the
`
`Arts at the Franklin Institute in Philadelphia, and was a founding member on
`
`the Scientific Advisory Board at Rider University. I have also advised the
`
`Centre for Drug Research and Development in Vancouver, Canada on
`
`liposomal delivery systems.
`
`20.
`
`I have served as an Adjunct Professor in the Department of
`
`Pathology, Anatomy and Cell Biology at Thomas Jefferson University Medical
`
`School. I have also been a visiting Research Scholar at Princeton University
`
`and have held appointments in the Departments of Physics, Molecular Biology,
`
`and Chemical Engineering.
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`21.
`
`I am the Editor-in-Chief Emeritus of the Journal of Liposome
`
`Research. I served on the editorial board of this Journal from 1994-1997, and
`
`was the Editor-in-Chief from 1997-2008.
`
`22.
`
`I am an editor of Liposomes: Rational Design (Marcel Dekker,
`
`New York, 1999), a volume of expert reviews in the field of liposomology.
`
`23.
`
`I hold over 75 U.S. patents in lipid nanotechnology and drug
`
`delivery, and I have authored more than 90 scientific articles and reviews
`
`principally related to nanotechnology, lipid supramolecular structure,
`
`liposomes, and drug delivery including fusogenic liposomes and triggerable
`
`lipid assemblies.
`
`24. My curriculum vitae is attached as Exhibit 1021.
`
`25.
`
`I am being compensated by Moderna for my time spent in
`
`developing this declaration at a rate of $750 per hour, and for any time spent
`
`testifying in connection with this declaration at a rate of $750 per hour. My
`
`compensation is not contingent upon the substance of my opinion, the content
`
`of this declaration or any testimony I may provide, or the outcome of the inter
`
`partes review or any other proceeding.
`
`26.
`
`I have no financial interest in Moderna.
`
`27. My opinion expressed in this declaration are based on the Petition
`
`and exhibits cited in the Petition, and other documents and materials identified
`
`in this declaration, including the ’127 patent (Ex. 1001) and its prosecution
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`history (Ex. 1022), the prior art references and materials discussed in this
`
`declaration, and any other references specifically identified in this declaration.
`
`28.
`
`I am aware of information generally available to, and relied upon
`
`by, persons of ordinary skill in the art at the relevant times, including technical
`
`dictionaries and technical reference materials (including, for example,
`
`textbooks, manuals, technical papers, articles, and relevant technical
`
`standards).
`
`29.
`
`I reserve the right to supplement my opinions to address any
`
`information obtained, or positions taken, based on any new information that
`
`comes to light throughout this proceeding.
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`30.
`It is my understanding that the ’127 patent should be interpreted
`
`based on how it would be read by a person of ordinary skill in the art at the
`
`time of the effective filing date of the application. It is my understanding that
`
`factors such as the education level of those working in the field, the
`
`sophistication of the technology, the type of problems encountered in the art,
`
`the prior art solutions to those problems, and the speed at which innovations
`
`are made may help establish the level of skill in the art.
`
`31.
`
`I am familiar with the technology at issue and the state of the art at
`
`the earliest priority date of the ’127 patent.
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`32.
`
`It is my opinion, based upon a review of the ’127 patent, its file
`
`history, and my knowledge of the field of the art, a person of ordinary skill in
`
`the art for the field of the ’127 patent would have specific experience with lipid
`
`particle formation and use in the context of delivering therapeutic payloads,
`
`and would have a Ph.D., an M.D., or a similar advanced degree in an allied
`
`field (e.g., biophysics, microbiology, biochemistry) or an equivalent
`
`combination of education and experience. This level of skill is representative
`
`of the inventors on the ’127 patent and authors/inventors of prior art cited
`
`herein. See Exs. 1002-1006.
`
`33.
`
`I have considered the issues discussed in the remainder of this
`
`declaration from the perspective of a person of ordinary skill in the art.
`
`Although I used this perspective, I do not believe that any of my opinions
`
`would change if a slightly higher or lower level of skill were adopted.
`
`V. LEGAL PRINCIPLES
`A.
`Claim Construction
`34.
`I am not a patent attorney and my opinions are limited to what I
`
`believe a person of ordinary skill in the art would have understood, based on
`
`the patent documents. I use the principles below, however, as a guide in
`
`formulating my opinions.
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`35. My understanding is that a primary step in determining validity of
`
`patent claims is to properly construe the claims to determine claim scope and
`
`meaning.
`
`36.
`
`In an inter partes review proceeding, as I understand from
`
`Moderna counsel, claims are to be given their broadest reasonable construction
`
`(“BRC”) in light of the patent’s specification. 37 C.F.R. § 42.100(b). In other
`
`forums, such as in federal courts, different standards of proof and claim
`
`interpretation are operative, which are not applied by the patent office for inter
`
`partes review. Accordingly, I reserve the right to argue for a different
`
`interpretation or construction of the challenged claims in other proceedings, as
`
`appropriate.
`
`37.
`
`It is my understanding that in determining whether a patent claim
`
`is anticipated or obvious in view of the prior art, the patent office must
`
`construe the claim by giving the claim its broadest reasonable construction
`
`with the specification. For the purposes of this review, I have construed each
`
`claim term in accordance with its plain and ordinary meaning under the
`
`required broadest reasonable construction.
`
`B.
`38.
`
`Prior Art
`I understand that a patent or other publication must first qualify as
`
`prior art before it can be used to invalidate a patent claim. I understand that a
`
`U.S. or foreign patent qualifies as prior art to an asserted patent if the date of
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`issuance of the patent is prior to the invention of the asserted patent. I further
`
`understand that a printed publication, such as an article published in a
`
`magazine or trade publication, qualifies as prior art to an asserted patent if the
`
`date of publication is prior to the invention of the asserted patent.
`
`39.
`
`I understand that a U.S. or foreign patent also qualifies as prior art
`
`to an asserted patent if the date of issuance of the patent is more than one year
`
`before the filing date of the asserted patent. I further understand that a printed
`
`publication, such as an article published in a magazine or trade publication,
`
`constitutes prior art to an asserted patent if the publication occurs more than
`
`one year before the filing date of the asserted patent.
`
`40.
`
`I understand that a U.S. patent qualifies as prior art to the asserted
`
`patent if the application for that patent was filed in the United Stated before the
`
`invention of the asserted patent.
`
`41.
`
`I understand that documents and materials that qualify as prior art
`
`can be used to invalidate a patent claim via anticipation or obviousness.
`
`C.
`42.
`
`Anticipation
`I understand that, once the claims of a patent have been properly
`
`construed, the second step in determining anticipation of a patent claim
`
`requires a comparison of the properly construed claim language to the prior art
`
`on a limitation-by-limitation basis.
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`43.
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`I understand that a prior art reference “anticipates” an asserted
`
`claim, and thus renders the claim invalid, if all elements of the claim are
`
`disclosed in that prior art reference, either explicitly or inherently (i.e.,
`
`necessarily present).
`
`44.
`
`I understand that an element may be anticipated by a prior art even
`
`if it is not explicitly mentioned by that reference if the claimed property is
`
`inherent in the disclosure. I understand that an inherent property is one that is
`
`necessarily present in the prior art’s disclosure and that adding a claim
`
`limitation to an inherent property to a previously known composition does not
`
`make the element patentable.
`
`45.
`
`I understand that anticipation in an inter partes review must be
`
`shown by a preponderance of the evidence.
`
`D.
`46.
`
`Obviousness
`I understand that even if a patent is not anticipated, it is still
`
`invalid if the differences between the claimed subject matter and the prior art
`
`are such that the subject matter as a whole would have been obvious at the time
`
`the invention was made to a person of ordinary skill in the pertinent art.
`
`47.
`
`I understand that a person of ordinary skill in the art at the time
`
`the invention was made provides a reference point from which the prior art and
`
`claimed invention should be viewed. This reference point prevents one from
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`using his or her own insight or hindsight in deciding whether a claim is
`
`obvious.
`
`48.
`
`I also understand that an obviousness determination includes the
`
`consideration of various factors such as (1) the scope and content of the prior
`
`art, (2) the differences between the prior art and the asserted claims, (3) the
`
`level of ordinary skill in the pertinent art, and (4) the existence of secondary
`
`considerations such as commercial success, long-felt but unresolved needs,
`
`failure of others, etc.
`
`49.
`
`I understand that an obviousness evaluation can be based on a
`
`combination of multiple prior art references. I understand that the prior art
`
`references themselves may provide a suggestion, motivation, or reason to
`
`combine, but other times the nexus linking two or more prior art references is
`
`simple common sense. I further understand that obviousness analysis
`
`recognizes that market demand, rather than scientific literature, often drives
`
`innovation, and that a motivation to combine references may be supplied by the
`
`direction of the marketplace.
`
`50.
`
`I understand that if a technique has been used to improve one
`
`device, and a person of ordinary skill in the art would recognize that it would
`
`improve similar devices in the same way, using the technique is obvious unless
`
`its actual application is beyond his or her skill.
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`51.
`
`I also understand that practical and common sense considerations
`
`should guide a proper obviousness analysis, because familiar items may have
`
`obvious uses beyond their primary purposes. I further understand that a person
`
`of ordinary skill in the art looking to overcome a problem will often be able to
`
`fit together the teachings of multiple publications. I understand that
`
`obviousness analysis therefore takes into account the inferences and creative
`
`steps that a person of ordinary skill in the art would employ under the
`
`circumstances.
`
`52.
`
`I understand that a particular combination may be proven obvious
`
`merely by showing that it was obvious to try the combination. For example,
`
`when there is a design need or market pressure to solve a problem and there are
`
`a finite number of identified, predictable solutions, a person of ordinary skill in
`
`the art has good reason to pursue the known options within his or her technical
`
`grasp. The result is likely the product not of innovation but of ordinary skill in
`
`the art and common sense.
`
`53.
`
`The combination of familiar elements according to known
`
`methods is likely to be obvious when it does no more than yield predictable
`
`results. When a work is available in one field of endeavor, design incentives
`
`and other market forces can prompt variations of it, either in the same field or a
`
`different one. If a person of ordinary skill in the art can implement a
`
`predictable variation, the patent claim is likely obvious.
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`54.
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`It is further my understanding that a proper obviousness analysis
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`focuses on what was known or obvious to a person of ordinary skill in the art,
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`not just the patentee. Accordingly, I understand that any need or problem
`
`addressed by the patent that was known in the field of endeavor at the time of
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`invention can provide a reason for combining the elements in the manner
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`claimed.
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`55.
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`I understand that a claim can be obvious in light of a single
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`reference, without the need to combine references, if the elements of the claim
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`that are not found explicitly or inherently in the reference can be supplied by
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`the common sense of one of skill in the art.
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`56.
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`I understand that secondary indicia of non-obviousness may
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`include (1) a long felt but unmet need in the prior art that was satisfied by the
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`invention of the patent; (2) commercial success of processes covered by the
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`patent; (3) unexpected results achieved by the invention; (4) praise of the
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`invention by others skilled in the art; (5) taking of licenses under the patent by
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`others; (6) deliberate copying of the invention; (7) failure of others to find a
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`solution to the long felt need; and (8) skepticism by experts.
`
`57.
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`I also understand that there must be a relationship between any
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`such secondary considerations and the invention. I further understand that
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`contemporaneous and independent invention by others is a secondary
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`consideration supporting an obviousness determination.
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`58.
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`In sum, my understanding is that prior art teachings are properly
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`combined where a person of ordinary skill in the art having the understanding
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`and knowledge reflected in the prior art and motivated by the general problem
`
`facing the inventor, would have been led to make the combination of elements
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`recited in the claims. Under this analysis, the prior art references themselves,
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`or any need or problem known in the field of endeavor at the time of the
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`invention, can provide a reason for combining the elements of multiple prior
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`art references in the claimed manner.
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`59.
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`I understand that obviousness in an inter partes review must be
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`shown by a preponderance of the evidence.
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`VI. BACKGROUND
`A.
`Lipid carrier particles for nucleic acid payloads
`Therapeutic nucleic acids can be used for both gene delivery (e.g.,
`60.
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`mRNA) and gene silencing (e.g., siRNA). Long before the ’127 patent, a
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`POSITA would have known that systems comprised of combinations of
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`different types of lipids with nucleic acids could result in lipid-nucleic acid
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`particles, an accepted delivery strategy for nucleic acid therapeutics. Examples
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`of such complexes are described in Exhibits 1002-1006. Ex. 1002 (’069
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`patent), cl. 1; Ex. 1003 (’817 PCT), [0001]; Ex. 1004 (’099 patent), 2:11-16;
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`Ex. 1005 (Koltover), 78; Ex. 1006 (Ewert), 33–34, 44.
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`61.
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`The ’127 patent refers to a version of these lipid carrier particles
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`as “stable nucleic acid-lipid particles” or “SNALPs.” Ex. 1001, 15:64-65. The
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`components of lipid-nucleic acid particles, e.g., SNALPs, were well-known in
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`the art prior to the ’127 patent.
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`62. Cationic lipids are useful in such particles because cationic lipids
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`can interact with the negative charge on nucleic acids facilitating formation of
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`lipid-nucleic acid complexes. Effective delivery of the nucleic acid payload in
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`such complexes is thought to require fusion between the complex and a cell
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`membrane. See Ex. 1008 (Hui 1996), 598. It is believed that cationic lipids
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`interact with negative charges on cell membranes thus promoting the fusion
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`event necessary for the effective delivery of the nucleic acid. See Ex. 1009
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`(Semple 2010), 172-175; Ex. 1010 (Heyes 2005), 277. Alternatively fusion
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`can be promoted by constructing nucleic acid cationic lipid complexes to
`
`transition from the common lamellar phase to non-lamellar phases at pH values
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`internal to cell. Non-cationic “helper” lipids, e.g., phospholipids and/or
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`cholesterols, can be combined with the cationic lipid to influence the ability of
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`the particles to fuse with the cell membrane. See Ex. 1010 (Heyes 2005), 277.
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`A “conjugated lipid” (e.g., a polyethylene glycol (“PEG”) lipid) can be added
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`to increase in vivo stability by “provid[ing] a neutral, hydropilic coating to the
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`particle’s exterior.” See Id., 277; see also Ex. 1006 (Ewert), 44.
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`63. A POSITA would have been aware that lipid-nucleic acid particles
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`can assume different three-dimensional structures. Particles comprised of a
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`lipid bilayer are said to be “lamellar.” Particles in which the lipids are
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`arranged in a non-bilayer morphology are said to be “non-lamellar.” The
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`ability of lipids to form lamellar and non-lamellar structures has been known in
`
`the field for decades.
`
`64.
`
`In the late 1990s, researchers determined specifically that cationic
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`lipid-nucleic acid complexes could assemble into different structures, including
`
`lamellar and non-lamellar (e.g., “inverse hexagonal”) architectures. See Ex.
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`1005 (Koltover), 78, Fig. 1 (lamellar and inverse hexagonal phases shown):
`
`See also Ex. 1006 (Ewert), 42-44 (non-lamellar structure).
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`65. Researchers pursued lipid-nucleic acid complexes that exhibited
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`an inverted hexagonal structure in vitro because such complexes were known
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`to readily fuse with cell membranes allowing effective transfection. See Ex.
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`1004 (’099 patent), 5:53-54, 5:57-60; Ex. 1010 (Heyes 2005), 277 (“Lipidic
`
`systems are most fusogenic when arranged in the reversed hexagonal phase
`
`….”). The cationic lipid used in the non-bilayer geometries disclosed in the
`
`’127 patent, DLin-DMA, was specifically known to have a propensity for
`
`promoting a non-lamellar structure. See Ex. 1010 (Heyes 2005), 282.
`
`66. Nucleic acid-lipid complexes assembled into the inverted
`
`hexagonal morphology were also known to be effective transfection systems
`
`well before the ’127 patent. For example, as early as 1998, complexes
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`comprised of a cationic lipid, the helper lipid DOPE and DNA were known to
`
`assemble into the inverted hexagonal geometry and fuse with model
`
`membranes. Ex. 1005 (Koltover), 78 (“[Cationic lipid]-DNA complexes
`
`containing DOPE … empirically known to transfect exhibit the [hexagonal
`
`geometry].”); Ex. 1006 (Ewert), 37 (transfection compositions of cationic lipid,
`
`helper lipid DOPC and DNA assemble into the inverse hexagonal geometry).
`
`67. A POSITA would have been aware that lipid-nucleic acid
`
`complexes can reconfigure from a lamellar to a non-lamellar geometry based
`
`upon variables such as the molecular geometries and proportions of the lipids
`
`selected and pH. Ex. 1004 (’099 patent), 6:10-15; Ex. 1005 (Koltover), 78; Ex.
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`1010 (Heyes 2005), 285. As an example, nucleic acid-lipid complexes can
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`exhibit a lamellar geometry at a pH 7.4 and rearrange to a non-lamellar
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`geometry at a pH of 5.5. Ex. 1004 (’099 patent), 33:36-54.
`
`68.
`
`It was known well before the priority date of the ’127 patent that
`
`lipid complexes might exist in a lamellar morphology, purely non-lamellar
`
`morphology, or as a combination of lamellar and non-lamellar morphologies.
`
`Ex. 1006 (Ewert), 42 (mixed morphologies and strictly non-lamellar
`
`morphology in cationic lipid-DNA complexes); Ex. 1005 (Koltover), Fig. 2
`
`(complexes transition from lamellar, to a mix of morphologies, to exclusively
`
`non-lamellar morphology depending on the concentration of helper lipid). The
`
`formulations in both Koltover and Ewert were designed to exhibit only non-
`
`lamellar morphologies.
`
`B.
`69.
`
`The ’127 patent disclosure
`The ’127 patent acknowledges that the following were known in
`
`the art prior to the ’127 filing date: (1) nucleic acid-lipid particles comprising a
`
`nucleic acid, cationic lipid, non-cationic lipid, and a conjugated lipid that
`
`inhibits aggregation of particles (Ex. 1001, 15:64-16:12 (SNALP component
`
`combinations known in the art)); (2) the methods of making the nucleic acid-
`
`lipid particles disclosed in the ’127 patent (id., 92:14-21 (list of known
`
`methods)), 104:14-31 (Stepwise Dilution Method known), 104:32-44 (Direct
`
`Dilution Method known); and (3) the methods of judging the three-dimensional
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`structure of the nucleic acid-lipid particles (id., 9:29-37 (cryo-TEM known in
`
`the art)). I agree that these were k