throbber
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. 8,058,069
`
`Issued: November 15, 2011
`
`Named Inventors: Edward Yaworski, Kieu Lam, Lloyd Jeffs,
`Lorne Palmer, Ian MacLachlan
`
`Title: Lipid Formulations 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. 8,058,069
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION .................................................................................. 1
`I.
`SUMMARY OF OPINIONS .................................................................. 1
`II.
`III. QUALIFICATION AND EXPERIENCE .............................................. 3
`IV. LEVEL OF ORDINARY SKILL IN THE ART .................................... 8
`V.
`LEGAL PRINCIPLES............................................................................ 9
`A.
`Claim construction ....................................................................... 9
`B.
`Prior Art...................................................................................... 10
`C.
`Anticipation ................................................................................ 11
`D. Obviousness ............................................................................... 11
`VI. BACKGROUND .................................................................................. 16
`A.
`Lipid carrier particles for nucleic acid payloads ........................ 16
`B.
`The ’069 patent disclosure ......................................................... 23
`C.
`Claim Construction .................................................................... 30
`D.
`Prior art ....................................................................................... 30
`VII. THE CHALLENGED CLAIMS ARE INVALID ............................... 38
`A. Ground 1: Claims 1-22 are anticipated by or obvious in
`view of the Patent Owner’s Prior Disclosures ........................... 38
`Ground 2: Claims 1-22 are obvious in view of the Patent
`Owner’s Prior Disclosures in light of Lin and Ahmad .............. 54
`Ground 3 Claims 1-22 are anticipated by or obvious in
`view of the ’554 publication ...................................................... 57
`VIII. CONCLUSION .................................................................................... 71
`
`
`B.
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`E.
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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. 8,058,069 (the “’069 patent”) owned by
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`Protiva Biotherapeutics, Inc. (“Patent Owner”).
`
`3.
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`This declaration is based on the information currently available to
`
`me. To the extent that additional information becomes available, I reserve the
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`right to continue my investigation and study, which may include a review of
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`documents and information that may be produced, as well as testimony from
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`depositions that have not yet been taken.
`
`II. SUMMARY OF OPINIONS
`4.
`The ’069 patent is entitled “Lipid Formulations for Nucleic Acid
`
`Delivery.” Ex. 1001. The ’069 patent is directed to a composition of nucleic
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`acid-lipid particles (e.g., particles that can be used to deliver therapeutic nucleic
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`acid payloads) comprising four
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`lipid components (i.e., cationic
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`lipid,
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`phospholipid, cholesterol, and conjugated lipid), each of which fall within a
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`claimed proportion with regard to the total lipid in the particles. See, e.g., Ex.
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`1001, cl. 1. The petition challenges claims 1-22 of the ’069 patent.
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`5.
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`Petitioner’s Ground 1 challenges claims 1-22 of the ’069 patent as
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`anticipated by the Patent Owner’s prior disclosures in PCT/CA2004/001051,
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`Publication No. WO2005007196 A2 (“’196 PCT”), Ex. 1003, or U.S. Patent
`
`Publication No US2006/0134189 (“’189 publication”), Ex. 1004, under pre-AIA
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`35 U.S.C. § 102(b) or, in the alternative, as obvious under pre-AIA 35 U.S.C.
`
`§ 103 in view of Patent Owner’s prior disclosures. Based on studying the
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`petition and the exhibits cited in the petition as well as other documents, it is my
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`opinion that claims 1-22 of the ’069 patent are anticipated by the Patent Owner’s
`
`prior disclosures, including the ’196 PCT or the ’189 publication. In the
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`alternative, it is my opinion that claims 1-22 of the ’069 patent are obvious in
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`view of the Patent Owner’s prior disclosures.
`
`6.
`
`Petitioner’s Ground 2 challenges claims 1-22 of the ’069 patent as
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`obvious in view of the Patent Owner’s prior disclosures in light of Lin, Ex. 1006,
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`and Ahmad, Ex. 1007, under pre-AIA 35 U.S.C. § 103. Based on studying the
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`petition and the exhibits cited in the Petition as well as other documents, it is my
`
`opinion that claims 1-22 of the ’069 patent are obvious in view of the Patent
`
`Owner’s prior disclosures in light of Lin and/or Ahmad.
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`7.
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`Petitioner’s Ground 3 challenges claims 1-22 of the ’069 as
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`anticipated by the disclosures in U.S. Patent Publication No. 2006/0240554 A1
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`(“’554 publication”), Ex. 1005, under pre-AIA 35 U.S.C. §§ 102(b) or, in the
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`alternative, as obvious under pre-AIA 35 U.S.C. § 103 in view of the ’554
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`publication. Based on studying the petition and the exhibits cited in the petition
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`as well as other documents, it is my opinion that claims 1-22 of the ’069 patent
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`are anticipated by the ’554 publication. In the alternative, it is my opinion that
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`claims 1-22 of the ’069 patent are obvious in view of the ’554 publication.
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`III. QUALIFICATION AND EXPERIENCE
`8.
`I am formally trained as a membrane biophysicist. I obtained my
`
`Ph.D. degree in Biophysics from Michigan State University in 1980. Before
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`that, I received my MS in Biophysics from Michigan State University in 1977,
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`and my BS in Biology from The American University in 1971. I received
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`postdoctoral training in Pharmacology at the Harvard Medical School and in
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`Anesthesia at the Massachusetts General Hospital.
`
`9.
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`I have played leadership roles in the discipline of pharmaceutical
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`liposomology from its inception in 1981.
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`10. After my post-doctoral work, I was recruited from Harvard by the
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`industrialist, Jack Whitehead, and became the first senior founding scientist at
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`the Liposome Company, Inc. I eventually became the Vice President of
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`Research and Development at the Liposome Company. I led the team at the
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`Liposome Company that discovered, formulated, and developed ABELCET, a
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`novel lipid structure that is approved worldwide for systemic fungal infections.
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`I first published the physical chemical characterization of this structure, along
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`with an explanation of why it would yield a less toxic alternative to the
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`traditional micelle formulation in the Proceedings of the National Academy of
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`Sciences.
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`11.
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`I led the team at the Liposome Company that developed Staclot LA,
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`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
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`published in the Proceedings of the National Academy of Sciences.
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`12.
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`In addition I lead teams at the Liposome Company that formulated
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`and characterized Myocet (Liposomal Doxorubicn Injection). This product is
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`currently approved in Canada and the European Union and is used to treat
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`metastatic breast cancer.
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`13. From 2001-2002, I was Chairman, and from 2002-2005, I was
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`Chairman and CEO, of Celator Technologies, Inc. I was involved in the creation
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`of Celator’s intellectual property platform and built the company from a
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`Canadian start up into an international pharmaceutical corporation with research,
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`manufacturing, clinical development, regulatory, commercial, and legal
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`functions. From 2005-2008, I was Chairman and CEO of its successor, Celator
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`Pharmaceuticals, Inc., a company using controlled-release liposomes to deliver
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`combinations of chemotherapeutic agents to tumors. Celator’s drug Vxyeos was
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`recently approved by the FDA for the treatment of leukemia.
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`14. From 2009-2011, I was CEO of TranslationUP, which was a
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`consortium of authorities from academic research, drug development, policy,
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`finance, public relations, and law seeking to create a new model to more
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`effectively advance government funded late-stage discovery concepts into
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`clinical development.
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`15.
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`In my career, I have overseen the filing of eight INDs, two NDAs
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`and one MAA in the areas of oncology, antiinfectives, and acute respiratory
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`distress syndrome, all involving liposome or lipid-delivery systems.
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`16.
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`I have worked and published in the area of pulmonary surfactants
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`involving treatment modalities in which lamellar lipid for instilling into neonate
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`lungs was constructed to rearrange into the Hexagonal II architecture at body
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`temperature. An article that I published on this topic in Science was reviewed
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`and highlighted in Lancet, a leading British Medical Journal.
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`17.
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`I have lectured and have conducted Grand Rounds in the areas of
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`liposomes, lipid physical chemistry and drug delivery at many prestigious
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`medical centers in the United States and Canada, and have been invited to speak
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`on these topics at major industry, financial, scientific and medical symposia
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`worldwide.
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`I have also served on various government advisory committees. For
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`18.
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`example, I taught at the NATO Advanced Study Institute in Cape Sunion,
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`Greece, participated in FDA symposia regarding the quality and performance of
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`controlled release parenterals, served on the Committee of Science and the Arts
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`at the Franklin Institute in Philadelphia, and was a founding member on the
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`Scientific Advisory Board at Rider University. I have also advised the Centre
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`for Drug Research and Development in Vancouver, Canada on liposomal
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`delivery systems.
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`19.
`
`I have served as an Adjunct Professor in the Department of
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`Pathology, Anatomy and Cell Biology at Thomas Jefferson University Medical
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`School. I have also been a visiting Research Scholar at Princeton University and
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`have held appointments in the Departments of Physics, Molecular Biology, and
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`Chemical Engineering.
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`20.
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`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
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`was the Editor-in-Chief from 1997-2008.
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`21.
`
`I am an editor of Liposomes: Rational Design (Marcel Dekker, New
`
`York, 1999), a volume of expert reviews in the field of liposomology.
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`22.
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`I hold over 75 U.S. patents in lipid nanotechnology and drug
`
`delivery, and I have authored more than 90 scientific articles and reviews
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`principally related to nanotechnology, lipid supramolecular structure, liposomes,
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`and drug delivery including fusogenic liposomes and triggerable lipid
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`assemblies.
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`23. My curriculum vitae is attached as Exhibit 1018.
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`24.
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`I am being compensated by Moderna for my time spent in
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`developing this declaration at a rate of $750 per hour, and for any time spent
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`testifying in connection with this declaration at a rate of $750 per hour. My
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`compensation is not contingent upon the substance of my opinion, the content of
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`this declaration or any testimony I may provide, or the outcome of the inter
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`partes review or any other proceeding.
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`25.
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`I have no financial interest in Moderna.
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`26. My opinion expressed in this declaration are based on the Petition
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`and exhibits cited in the Petition, and other documents and materials identified
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`in this declaration, including the ’069 patent (Ex. 1001) and its prosecution
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`history (Ex. 1016), the prior art references and materials discussed in this
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`declaration, and any other references specifically identified in this declaration.
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`27.
`
`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
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`dictionaries and technical reference materials (including, for example,
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`textbooks, manuals, technical papers, articles, and relevant technical standards).
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`I reserve the right to supplement my opinions to address any
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`28.
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`information obtained, or positions taken, based on any new information that
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`comes to light throughout this proceeding.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
`29.
`It is my understanding that the ’069 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.
`
`30.
`
`I am familiar with the technology at issue and the state of the art at
`
`the earliest priority date of the ’069 patent.
`
`31.
`
`It is my opinion, based upon a review of the ’069 patent, its file
`
`history, and my knowledge of the field of the art, that a person of ordinary skill
`
`in the art for the field of the ’069 patent would have specific experience with
`
`lipid particle formation and use in the context of delivering therapeutic payloads,
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`and would have a Ph.D., an M.D., or a similar advanced degree in an allied field
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`(e.g., biophysics, microbiology, biochemistry) or an equivalent combination of
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`education and experience. This level of skill is representative of the
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`authors/inventors of prior art cited herein. See Exs. 1002-1006.
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`32.
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`I have considered the issues discussed in the remainder of this
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`declaration from the perspective of a person of ordinary skill in the art. Although
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`I used this perspective, I do not believe that any of my opinions would change if
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`a slightly higher or lower level of skill were adopted.
`
`V. LEGAL PRINCIPLES
`A. Claim construction
`33.
`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
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`patent documents. I use the principles below, however, as a guide in formulating
`
`my opinions.
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`34. My understanding is that a primary step in determining validity of
`
`patent claims is to properly construe the claims to determine claim scope and
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`meaning.
`
`35.
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`In an inter partes review proceeding, as I understand from Moderna
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`counsel, claims used to be given their broadest reasonable interpretation in light
`
`of the patent’s specification. 37 C.F.R. § 42.100(b). I understand that the current
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`claim construction standard in inter partes review proceedings is now governed
`
`by Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) and that the claims
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`are interpreted as one of ordinary skill in the art would understand the claim
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`terms at the time of the invention. I also understand that this analysis is focused
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`primarily on the intrinsic record.
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`36.
`
`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 under the Phillips standard. For the purposes of this review, I have
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`construed each claim term in accordance with its plain and ordinary meaning
`
`under the required Phillips standard.
`
`B.
`37.
`
`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
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`U.S. or foreign patent qualifies as prior art to an asserted patent if the date of
`
`issuance of the patent is prior to the invention of the asserted patent. I further
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`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.
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`38.
`
`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,
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`constitutes prior art to an asserted patent if the publication occurs more than one
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`year before the filing date of the asserted patent.
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`39.
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`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
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`invention of the asserted patent.
`
`40.
`
`I understand that documents and materials that qualify as prior art
`
`can be used to invalidate a patent claim via anticipation or obviousness.
`
`C. Anticipation
`41.
`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
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`limitation-by-limitation basis.
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`42.
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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.,
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`necessarily present).
`
`43.
`
`I understand that anticipation in an inter partes review must be
`
`shown by a preponderance of the evidence.
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`D. Obviousness
`44.
`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
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`that the subject matter as a whole would have been obvious at the time the
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`invention was made to a person of ordinary skill in the pertinent art.
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`45.
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`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
`
`using his or her own insight or hindsight in deciding whether a claim is obvious.
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`46.
`
`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
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`ordinary skill in the pertinent art, and (4) the existence of secondary
`
`considerations such as commercial success, long-felt but unresolved needs,
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`failure of others, etc.
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`47.
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`I understand that an obviousness evaluation can be based on a
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`combination of multiple prior art references. I understand that the prior art
`
`references themselves may provide a suggestion, motivation, or reason to
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`combine, but other times the nexus linking two or more prior art references is
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`simple common sense. I further understand that obviousness analysis recognizes
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`that market demand, rather than scientific literature, often drives innovation, and
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`that a motivation to combine references may be supplied by the direction of the
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`marketplace.
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`I understand that if a technique has been used to improve one
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`48.
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`device, and a person of ordinary skill in the art would recognize that it would
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`improve similar devices in the same way, using the technique is obvious unless
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`its actual application is beyond his or her skill.
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`49.
`
`I also understand that practical and common sense considerations
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`should guide a proper obviousness analysis, because familiar items may have
`
`obvious uses beyond their primary purposes. I further understand that a person
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`of ordinary skill in the art looking to overcome a problem will often be able to
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`fit together the teachings of multiple publications. I understand that obviousness
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`analysis therefore takes into account the inferences and creative steps that a
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`person of ordinary skill in the art would employ under the circumstances.
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`50.
`
`I understand that a particular combination may be proven obvious
`
`merely by showing that it was obvious to try the combination. For example,
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`when there is a design need or market pressure to solve a problem and there are
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`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.
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`51. The combination of familiar elements according to known methods
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`is likely to be obvious when it does no more than yield predictable results. When
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`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
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`a person of ordinary skill in the art can implement a predictable variation, the
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`patent claim is likely obvious.
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`52.
`
`It is further my understanding that a proper obviousness analysis
`
`focuses on what was known or obvious to a person of ordinary skill in the art,
`
`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
`
`invention can provide a reason for combining the elements in the manner
`
`claimed.
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`53.
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`I understand that a claim can be obvious in light of a single
`
`reference, without the need to combine references, if the elements of the claim
`
`that are not found explicitly or inherently in the reference can be supplied by the
`
`common sense of one of skill in the art.
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`54.
`
`I understand that the disclosure of overlapping ranges in the prior
`
`art establishes a prima facie case of obviousness under 35 U.S.C § 103, but that
`
`a petitioner still has the burden of demonstrating invalidity by the preponderance
`
`of the evidence.
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`55.
`
`I understand that secondary indicia of non-obviousness may include
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`(1) a long felt but unmet need in the prior art that was satisfied by the invention
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`of the patent; (2) commercial success of processes covered by the patent; (3)
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`unexpected results achieved by the invention; (4) praise of the invention by
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`others skilled in the art; (5) taking of licenses under the patent by others; (6)
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`deliberate copying of the invention; (7) failure of others to find a solution to the
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`long felt need; and (8) skepticism by experts.
`
`56.
`
`I also understand that there must be a relationship between any 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.
`
`57.
`
`I understand that unexpected results can support a nonobviousness
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`determination but must show unexpected results for the entire claimed range.
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`This can be done by demonstrating that an embodiment has an unexpected result
`
`and providing an adequate basis to support the conclusion that other
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`embodiments falling within the claim will behave in the same manner.
`
`58.
`
`In sum, my understanding is that prior art teachings are properly
`
`combined where a person of ordinary skill in the art having the understanding
`
`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, or
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`any need or problem known in the field of endeavor at the time of the invention,
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`can provide a reason for combining the elements of multiple prior art references
`
`in the claimed manner.
`
`59.
`
`I understand that obviousness in an inter partes review must be
`
`shown by a preponderance of the evidence.
`
`VI. BACKGROUND
`A. Lipid carrier particles for nucleic acid payloads
`60. Gene therapy—addressing disease at the level of the genetic cause,
`
`typically with nucleic acids—is an area of intensive medical research.
`
`Therapeutic nucleic acids can be used for both nucleic acid delivery and gene
`
`silencing (e.g., small interfering RNA (“siRNA”)). See Ex. 1009 (Gao), E92;
`
`Ex. 1006 (Lin), 3307. Long before the ’069 patent, it was known that systems
`
`comprised of combinations of different types of lipids with nucleic acids could
`
`result in lipid-nucleic acid particles, an accepted delivery strategy for nucleic
`
`acid therapeutics. See Ex. 1009 (Gao), E95.
`
`61. The ’069 patent specification describes nucleic acid-lipid carrier
`
`particles that the patentees refer to as “stable nucleic acid-lipid particles” or
`
`“SNALPs.” Ex. 1001, 5:51-58. The ’069 patent discloses four lipid
`
`components: a cationic lipid, two non-cationic lipids (a phospholipid and
`
`cholesterol), and a conjugated lipid (e.g., a polyethylene glycol (“PEG”) lipid).
`
`See, e.g., Ex. 1001, cl. 1 (components). These lipid components were known to
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`be basic building blocks of nucleic acid-lipid particles long before the ’069
`
`patent. See Ex. 1007 (Ahmad), 740, 746 (“[cationic lipids] for transfection
`
`typically consist of a mixture of cationic and neutral (helper) lipid” and
`
`“strategies for optimization … could involve introducing … PEG –lipids ….”);
`
`Ex. 1009 (Gao), E95, 97 (cationic lipid carrier particles “are often formulated
`
`with a noncharged phospholipid or cholesterol as a helper lipid … PEG-lipid
`
`conjugates have been incorporated … to minimize interaction with blood
`
`components ....”).
`
`62. Cationic lipids have been used in the construction of nucleic acid-
`
`lipid particles because they interact with the negative charge on nucleic acid
`
`payload facilitating formation of lipid-nucleic acid complexes. See Ex. 1009
`
`(Gao), E95. Effective delivery of the nucleic acid (called the “transfection
`
`efficiency”) is thought to require fusion between the lipid complex and a cell
`
`membrane. See Ex. 1010 (Bennett), 48; Ex. 1009 (Gao), E95; Ex. 1007
`
`(Ahmad), 746. Since cationic lipids can also interact with negative charges on
`
`cell membranes (under appropriate conditions, depending on the specific
`
`mixture of lipids in the carrier particle), this has been believed to promote, in
`
`some cases, the fusion event necessary for the effective delivery of the nucleic
`
`acid. See Ex. 1007 (Ahmad), 745(“[A]n overall positive [cationic lipid]-DNA
`
`charge is required to promote initial electrostatic interactions with cell
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`membranes.”).
`
`63. Moreover, it was known that non-cationic “helper” lipids, e.g.,
`
`certain phospholipids and/or cholesterols, can be combined with the cationic
`
`lipid to influence the ability of the particles to transfect cells. See Ex. 1009
`
`(Gao), E95 (cationic lipids “are often formulated with a noncharged
`
`phospholipid or cholesterol as a helper lipid to form liposomes. …. Lipoplexes
`
`form spontaneously when cationic liposomes are mixed with DNA. The
`
`structure of lipoplexes is influenced by multiple factors…. [including]…. the
`
`method of preparation. Lipoplexes come in various forms, including…lipid-
`
`coated DNA arranged in an hexagonal lattice, or partially condensed DNA
`
`surrounded by a lipid bilayer.”); Ex. 1010 (Bennett), 47 (use of helper lipids).
`
`64. A “conjugated lipid” (e.g., a PEG-lipid) can be added to increase in
`
`vivo circulation time by providing a neutral, hydrophilic coating to the particle’s
`
`exterior. See Ex. 1009 (Gao), E97 (“PEG-lipid conjugates have been
`
`incorporated into the lipoplexes to minimize the nonspecific interaction of
`
`lipoplexes with blood components.”); Ex. 1011 (Heyes), 277 (“PEG-lipids both
`
`stabilize the particle during the formulation process and shield the cationic bi-
`
`layer, preventing rapid systemic clearance.”).
`
`65.
`
`“The structure of lipoplexes is influenced by multiple factors,
`
`including the charge ratio, the concentration of individual lipids and DNA, the
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`structure of the cationic lipid and the helper lipid, [and] the physical aggregation
`
`state of the lipids ([e.g.,] multilamellar or unilamellar liposomes, or micelles)
`
`….” Ex. 1009 (Gao), E95. Transfection efficacy is complex because “[a] large
`
`number of parameters [are] involved.” Ex. 1007 (Ahmad), 740. Different
`
`transfection mechanisms “may be facilitated by alterations in liposome
`
`formulation ….” Ex. 1010 (Bennet), 48.
`
`66. The claims of the ’069 patent are not limited to a combination of
`
`specific lipids, formation protocols, or the type of nucleic acid payload and
`
`encompass broad ranges of lipids that have dramatically varying structures likely
`
`resulting in drastically different activities. Effective proportions of lipid
`
`components for one set of lipid species and payload may not be effective for
`
`alternative lipid species and payloads.
`
`67. For example, it was well-established at the time of the ’069 patent
`
`that “[t]he chemical structure of the cationic lipid ha[d] a major impact on the
`
`transfection efficiency.” Ex. 1009 (Gao), E95; Ex. 1011 (Heyes), 286.
`
`References incorporated into the ’069 patent acknowledge that “alternative
`
`cationic lipids” to the one tested would have “different [transfection]
`
`efficiencies.” See Ex. 1012 (’613 patent), 1:26-28 (“[A]lternative cationic lipids
`
`that work in essentially the same manner but with different efficiencies.”). I
`
`note, however, that many cationic lipids, including those disclosed in the ’069
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`patent do not necessarily work in the same manner. For example, some are pH
`
`dependent and others are not.
`
`68. Cationic lipid variables impacting transfection efficiency include
`
`“the chemical structure of the cationic lipid [and] … the charge ratio between
`
`the cationic lipid and the DNA ….” Ex. 1009 (Gao), E95. One example is
`
`whether the cationic lipid is comprised of a tertiary (e.g., ionizable) or quaternary
`
`(e.g., fixed positively charged) amine. Cationic lipids comprised of ionizable
`
`tertiary amines with pKas around 7 possess substantially neutral charges at
`
`physiological pH. Ex. 1011 (Heyes), 284. A POSITA would have known that
`
`these and other variables could impact the proportion of cationic lipid that is
`
`most effective for a given lipid component combination.
`
`69. Hundreds of cationic lipids both univalent and multivalent,
`
`ionizable or with fixed positive charges were known at the time of the ’069
`
`patent. Ex. 1009 (Gao), E95; Ex. 1011 (Heyes), 286 (“[H]undreds of new
`
`cationic lipids have been developed … [that] differ by the number of charges in
`
`their hydrophilic head group and by the detailed structure of their hydrophobic
`
`moiety.”). Thus the charge density on the surface of a nucleic acid-lipid particle,
`
`at a fixed cationic lipid proportion, can be modulated by introducing cationic
`
`lipids of different valancie

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