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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
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`Moderna Therapeutics, Inc.
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`Petitioner
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`v.
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`Protiva Biotherapeutics, Inc.
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`Patent Owner
`___________
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`U.S. Patent No. 9,364,435
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`Issued: June 14, 2016
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`Named Inventor: Edward Yaworski, Kieu Lam,
`Lorne Palmer, Ian MacLachlan
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`Title: Lipid Formulations for Nucleic Acid Delivery
`___________
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`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,364,435
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`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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`Moderna Ex 1007-p. 1
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION .................................................................................. 1
`I.
`SUMMARY OF OPINIONS .................................................................. 1
`II.
`III. QUALIFICATION AND EXPERIENCE .............................................. 3
`IV. LEVEL OF ORDINARY SKILL IN THE ART .................................... 7
`V.
`LEGAL PRINCIPLES............................................................................ 8
`A.
`Claim Construction ...................................................................... 8
`B.
`Prior Art...................................................................................... 10
`C. Anticipation ................................................................................ 10
`D. Obviousness ............................................................................... 11
`VI. BACKGROUND .................................................................................. 15
`A.
`Lipid carrier particles for nucleic acid payloads ........................ 15
`B.
`The ’435 patent disclosure ......................................................... 21
`C.
`Claim construction ..................................................................... 28
`D.
`Prior art ....................................................................................... 28
`VII. THE CHALLENGED CLAIMS ARE INVALID ............................... 35
`A. Ground 1: Claims 1-20 are obvious in view of the Patent
`Owner’s Prior Disclosures ......................................................... 35
`B. Ground 2: Claims 1-20 are obvious in view of the ’196
`PCT in light of Lin and/or Ahmad ............................................. 50
`C. Ground 3: Claims 1-20 are anticipated by or obvious in
`view of the ’554 publication ...................................................... 53
`VIII. CONCLUSION .................................................................................... 66
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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
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`and drug delivery, primarily focusing on lipid and liposome technology.
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`2.
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`I have been engaged by Moderna Therapeutics, Inc. (“Moderna”)
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`as an expert in connection with matters raised in the Petition for Inter Partes
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`Review (“Petition”) of U.S. Patent No. 9,364,435 (the “’435 patent”) owned by
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`Protiva Biotherapeutics, Inc. (“Patent Owner”).
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`3.
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`This declaration is based on the information currently available to
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`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.
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`II. SUMMARY OF OPINIONS
`4.
`The ’435 patent is entitled “Lipid Formulations for Nucleic Acid
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`Delivery.” Ex. 1001. The ’435 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
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`nucleic acid payloads to a patient) comprising three lipid components (i.e.,
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`cationic lipid, non-cationic lipid and conjugated lipid), each of which fall
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`within a claimed proportion with regard to the total lipid in the particles. See,
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`e.g., id., cl. 1. The Petition challenges claims 1-20 of the ’435 patent.
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`5.
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`Petitioner’s Ground 1 challenges claims 1-20 of the ’435 patent as
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`obvious under 35 U.S.C. § 103 in view of Patent Owner’s prior disclosures in
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`PCT/CA2004/001051, Publication No. WO2005007196 A2 (“’196 PCT”), Ex.
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`1002, or U.S. Publication No. US2006/0134189 (“’189 publication”), Ex.
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`1003. Based on studying the petition and the exhibits cited in the petition as
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`well as other documents, it is my opinion that claims 1-20 of the ’435 patent
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`are obvious in view of the ’196 PCT or ’189 publication.
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`6.
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`Petitioner’s Ground 2 challenges claims 1-20 of the ’435 patent as
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`obvious in view of the Patent Owner’s prior disclosures in light of Lin (Ex.
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`1005) and/or Ahmad (Ex. 1006) under 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
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`my opinion that claims 1-20 of the ’435 patent are obvious in view of the
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`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 1-20 of the ’435 patent as
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`anticipated by the disclosures in U.S. Publication No. US2006/0240554 (“’554
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`publication”), Ex. 1004, under pre-AIA 35 U.S.C. § 102(b) or, in the
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`alternative, as obvious under 35 U.S.C. § 103 in view of the ’554 publication.
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`Based on studying the petition and the exhibits cited in the petition as well as
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`other documents, it is my opinion that claims 1-20 of the ’435 patent are
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`anticipated by the ’554 publication. In the alternative, it is my opinion that
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`claims 1-20 of the ’435 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
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`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.
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`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
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`LA, a diagnostic reagent comprised of Hexagonal (II) lipid that is a standard
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`practice for diagnosing lupus anticoagulant. The work leading to this product
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`was also 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
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`creation of Celator’s intellectual property platform and built the company from
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`a Canadian start up into an international pharmaceutical corporation with
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`research, manufacturing, clinical development, regulatory, commercial, and
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`legal functions. From 2005-2008, I was Chairman and CEO of its successor,
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`Celator Pharmaceuticals, Inc., a company using controlled-release liposomes to
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`deliver combinations of chemotherapeutic agents to tumors. Celator’s drug
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`Vxyeos was 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
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`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
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`reviewed 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
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`speak on these topics at major industry, financial, scientific and medical
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`symposia worldwide.
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`18.
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`I have also served on various government advisory committees.
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`For 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
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`of controlled release parenterals, served on the Committee of Science and the
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`Arts at the Franklin Institute in Philadelphia, and was a founding member on
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`the Scientific Advisory Board at Rider University. I have also advised the
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`Centre for Drug Research and Development in Vancouver, Canada on
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`liposomal delivery systems.
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`19.
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`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
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`and have held appointments in the Departments of Physics, Molecular Biology,
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`and Chemical Engineering.
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`20.
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`I am the Editor-in-Chief Emeritus of the Journal of Liposome
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`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.
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`I am an editor of Liposomes: Rational Design (Marcel Dekker,
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`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
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`delivery, and I have authored more than 90 scientific articles and reviews
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`principally related to nanotechnology, lipid supramolecular structure,
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`liposomes, and drug delivery including fusogenic liposomes and triggerable
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`lipid 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
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`of 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 ’435 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.
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`I am aware of information generally available to, and relied upon
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`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
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`standards).
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`28.
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`I reserve the right to supplement my opinions to address any
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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 ’435 patent should be interpreted
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`based on how it would be read by a person of ordinary skill in the art at the
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`time of the effective filing date of the application. It is my understanding that
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`factors such as the education level of those working in the field, the
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`sophistication of the technology, the type of problems encountered in the art,
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`the prior art solutions to those problems, and the speed at which innovations
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`are made may help establish the level of skill in the art.
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`30.
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`I am familiar with the technology at issue and the state of the art at
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`the earliest priority date of the ’435 patent.
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`31.
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`It is my opinion, based upon a review of the ’435 patent, its file
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`history, and my knowledge of the field of the art, a person of ordinary skill in
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`the art (“POSITA”) for the field of the ’435 patent would have specific
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`experience with lipid particle formation and use in the context of delivering
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`therapeutic payloads, and would have a Ph.D., an M.D., or a similar advanced
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`degree in an allied field (e.g., biophysics, microbiology, biochemistry) or an
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`equivalent combination of education and experience. This level of skill is
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`representative of the inventors on the ’435 patent and authors/inventors of prior
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`art cited herein. See Exs. 1001-1006.
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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.
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`Although I used this perspective, I do not believe that any of my opinions
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`would change if a slightly higher or lower level of skill were adopted.
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`V. LEGAL PRINCIPLES
`A. Claim Construction
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`33.
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`I am not a patent attorney and my opinions are limited to what I
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`believe a person of ordinary skill in the art would have understood, based on
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`the patent documents. I use the principles below, however, as a guide in
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`formulating my opinions.
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`34. My understanding is that a primary step in determining validity of
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`patent claims is to properly construe the claims to determine claim scope and
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`meaning.
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`35.
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`In an inter partes review proceeding, as I understand from
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`Moderna counsel, claims are to be given their broadest reasonable
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`interpretation (“BRI”) in light of the patent’s specification. 37 C.F.R.
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`§ 42.100(b). In other forums, such as in federal courts, different standards of
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`proof and claim interpretation are operative, which are not applied by the
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`patent office for inter partes review. Accordingly, I reserve the right to argue
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`for a different interpretation or construction of the challenged claims in other
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`proceedings, as appropriate.
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`36.
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`It is my understanding that in determining whether a patent claim
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`is anticipated or obvious in view of the prior art, the patent office must
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`construe the claim by giving the claim its broadest reasonable construction
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`with the specification. For the purposes of this review, I have construed each
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`claim term in accordance with its plain and ordinary meaning under the
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`required broadest reasonable construction.
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`B.
`37.
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`Prior Art
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`I understand that a patent or other publication must first qualify as
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`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
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`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
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`magazine or trade publication, qualifies as prior art to an asserted patent if the
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`date of publication is prior to the invention of the asserted patent.
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`38.
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`I understand that a U.S. or foreign patent also qualifies as prior art
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`to an asserted patent if the date of issuance of the patent is more than one year
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`before the filing date of the asserted patent. I further understand that a printed
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`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
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`one 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
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`patent if the application for that patent was filed in the United Stated before the
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`invention of the asserted patent.
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`40.
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`I understand that documents and materials that qualify as prior art
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`can be used to invalidate a patent claim via anticipation or obviousness.
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`C. Anticipation
`41.
`I understand that, once the claims of a patent have been properly
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`construed, the second step in determining anticipation of a patent claim
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`requires a comparison of the properly construed claim language to the prior art
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`on a limitation-by-limitation basis.
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`42.
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`I understand that a prior art reference “anticipates” an asserted
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`claim, and thus renders the claim invalid, if all elements of the claim are
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`disclosed in that prior art reference, either explicitly or inherently (i.e.,
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`necessarily present).
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`43.
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`I understand that anticipation in an inter partes review must be
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`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
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`invalid if the differences between the claimed subject matter and the prior art
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`are such that the subject matter as a whole would have been obvious at the time
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`the 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
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`the invention was made provides a reference point from which the prior art and
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`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
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`obvious.
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`46.
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`I also understand that an obviousness determination includes the
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`consideration of various factors such as (1) the scope and content of the prior
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`art, (2) the differences between the prior art and the asserted claims, (3) the
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`level of ordinary skill in the pertinent art, and (4) the existence of secondary
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`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
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`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
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`recognizes that market demand, rather than scientific literature, often drives
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`innovation, and that a motivation to combine references may be supplied by the
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`direction of the marketplace.
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`48.
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`I understand that if a technique has been used to improve one
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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.
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`I also understand that practical and common sense considerations
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`should guide a proper obviousness analysis, because familiar items may have
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`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
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`obviousness analysis therefore takes into account the inferences and creative
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`steps that a person of ordinary skill in the art would employ under the
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`circumstances.
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`50.
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`I understand that a particular combination may be proven obvious
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`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
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`the art has good reason to pursue the known options within his or her technical
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`grasp. The result is likely the product not of innovation but of ordinary skill in
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`the art and common sense.
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`51. The combination of familiar elements according to known
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`methods is likely to be obvious when it does no more than yield predictable
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`results. When a work is available in one field of endeavor, design incentives
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`and other market forces can prompt variations of it, either in the same field or a
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`different one. If a person of ordinary skill in the art can implement a
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`predictable variation, the patent claim is likely obvious.
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`52.
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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
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`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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`53.
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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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`54.
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`I understand that the disclosure of overlapping ranges in the prior
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`art establishes a prima facie case of obviousness under 35 U.S.C § 103, but that
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`a petitioner still has the burden of demonstrating invalidity by the
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`preponderance of the evidence.
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`55.
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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.
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`56.
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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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`57.
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`I understand that unexpected results can support a non-
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`obviousness determination but must show unexpected results for the entire
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`claimed range. This can be done by demonstrating that an embodiment has an
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`unexpected result and providing an adequate basis to support the conclusion
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`that other embodiments falling within the claim will behave in the same
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`manner.
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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
`
`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
`Lipid carrier particles for nucleic acid payloads
`60. Gene therapy—addressing disease at the level of the genetic
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`A.
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`cause, typically with nucleic acids—is an area of intensive medical research.
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`Therapeutic nucleic acids can be used for both gene delivery (e.g., mRNA) and
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`gene silencing (e.g., small interfering RNA (“siRNA”)). See Ex. 1008 (Gao),
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`E92; Ex. 1005 (Lin), 3307. Long before the ’435 patent, it was known that
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`systems comprised of combinations of different types of lipids with nucleic
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`acids could result in lipid-nucleic acid particles, an accepted delivery strategy
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`for nucleic acid therapeutics. See Ex. 1008 (Gao), E95.
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`61. The ’435 patent refers to such nucleic acid-lipid carrier particles
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`as “stable nucleic acid-lipid particles” or “SNALPs.” Ex. 1001, 5:62-6:2. The
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`’435 patent discloses three lipid components: a “cationic lipid,” a “non-
`
`cationic lipid,” and a “conjugated lipid.” Id., cl. 1 (components). These lipid
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`components were known to be basic building blocks of nucleic acid-lipid
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`particles long before the ’435 patent. See Ex. 1006 (Ahmad), 740, 746
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`(“[cationic lipids] for transfection typically consist of a mixture of cationic and
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`neutral (helper) lipid” and “strategies for optimization … could involve
`
`introducing PEG-lipids … to block … unspecific interactions”); Ex. 1008
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`(Gao), E95 (cationic lipid carrier particles “are often formulated with a
`
`noncharged phospholipid or cholesterol as a helper lipid … PEG-lipid
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`Moderna Ex 1007-p. 18
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`conjugates have been incorporated … to minimize interaction with blood
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`components ….”).
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`62. Cationic lipids have been used in the construction of nucleic acid-
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`lipid particles because they interact with the negative charges on nucleic acid
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`payloads facilitating the formation of such particles. See Ex. 1008 (Gao), E95.
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`Effective delivery of the nucleic acid (called the “transfection efficiency”) is
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`thought to require fusion between the particle [lipoplex] and a cell membrane.
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`See Ex. 1009 (Bennett), 48; Ex. 1008 (Gao), E95. Since cationic lipids can
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`also interact with negative charges on cell membranes, this has been believed
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`to promote, in some cases, the fusion event necessary for the effective delivery
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`of the nucleic acid. See Ex. 1006 (Ahmad), 745 (“[A]n overall positive
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`[cationic lipid]-DNA charge is required to promote initial electrostatic
`
`interactions with cell membranes.”).
`
`63. Moreover, it was known that non-cationic “helper” lipids, e.g.,
`
`certain phospholipids and/or cholesterols, could be combined with the cationic
`
`lipid to influence the ability of the particles to transfect cells. See Ex. 1008
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`(Gao), E95 (cationic lipids “are often formulated with a noncharged
`
`phospholipid or cholesterol as a helper lipid to form liposomes”); Ex. 1009
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`(Bennett), 47 (helper lipids used).
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`64. A “conjugated lipid” (e.g., a PEG-lipid) can be added to increase
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`in vivo circulation time by providing a neutral, hydrophilic coating to the
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`Moderna Ex 1007-p. 19
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`particle’s exterior. See Ex. 1008 (Gao), E97 (“PEG-lipid conjugates have been
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`incorporated into the lipoplexes to minimize the nonspecific interaction of
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`lipoplexes with blood components.”); Ex. 1010 (Heyes), 277 (“PEG-lipids both
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`stabilize the particle during the formulation process and shield the cationic bi-
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`layer, preventing rapid systemic clearance.”).
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`65.
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`“The structure of lipoplexes [was known to be] influenced by
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`multiple factors, including the charge ratio, the concentration of individual
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`lipids and DNA, the structure of the cationic lipid and the helper lipid, [and]
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`the physical aggregation state of the lipids ([e.g.,] multilamellar or unilamellar
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`liposomes, or micelles) ….” Ex. 1008 (Gao), E95. Transfection efficacy is
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`complex because “[a] large number of parameters [are] involved.” Ex. 1006
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`(Ahmad), 740. Different transfection mechanisms “may be facilitated by
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`alterations in liposome formulation….” Ex. 1009 (Bennet), 48.
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`66. The claims of the ’435 patent are not limited to a specific
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`combination of lipids and encompass broad ranges of lipids that have
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`dramatically varying structures likely resulting in drastically different
`
`activities. Effective proportions of lipid components for one set of lipid
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`species may not be effective for an alternative lipid species.
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`67. For example, it was well-established at the time of the ’435 patent
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`that “[t]he chemical structure of the cationic lipid ha[d] a major impact on the
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`transfection efficiency.” Ex. 1008 (Gao), E95. Indeed references incorporated
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`Moderna Ex 1007-p. 20
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`into the ’435 patent acknowledge that “alternative cationic lipids” to the one
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`tested would have “different [transfection] efficiencies.” See Ex. 1011 (’613
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`patent), 1:26-28 (“[A]lternative cationic lipids … work in essentially the same
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`manner but with different efficiencies.”).
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`68. Cationic lipid variables impacting transfection efficiency included
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`“the chemical structure of the cationic lipid [and] … the charge ratio between
`
`the cationic lipid and the DNA ….” Ex. 1008 (Gao), E95. These variables
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`could impact the proportion of cationic lipid that is most effective for a given
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`lipid component combination.
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`69. Hundreds of cationic lipids, both univalent and multivalent, were
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`known at the time of the ’435 patent, some with differing charges. Id., E95
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`(“[H]undreds of new cationic lipids have been developed … [that] differ by the
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`number of charges in their hydrophilic head group and by the detailed structure
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`of their hydrophobic moiety.”). Thus the charge density on the surface of a
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`nucleic acid-lipid particle, at a fixed cationic lipid proportion, can be
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`modulated by introducing cationic lipids of different valancies (i.e., using
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`cationic lipids with different charges). This would have been expected to
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`impact the ability of the particle to promote fusion events with target cell
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`membranes. See Ex. 1006 (Ahmad), 740. Both Ahmad and Lin identified
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`charge density as an important determinate of transfection efficacy in the
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`systems studied. Id., 744; Ex. 1005 (Lin), 3312.
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`Moderna Ex 1007-p. 21
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`70.
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`It was also well-known at the time of the ’435 patent that certain
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`lipid component combinations favor having a 50% or greater proportion of
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`cationic lipid. First, early researchers often chose a 50% proportion of cationic
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`lipid as a default in evaluating particle transfection efficiency. See, e.g., Ex.
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`1009 (Bennett), 49 (50% cationic lipid); Ex. 1012 (U.S. Patent 7,939,505)
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`(“’505 patent”), 44:61-65 (cationic lipid of “about 0.5% to about 70% (mol %)
`
`of the total amount of lipid”), 96:40-67 (Example 32 and Table 12)
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`(formulations with 50% cationic lipid), 99:34-101:45 (Examples 34-35 and
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`Tables 15-18) (same). Second, Researchers determined that, in some cases,
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`increasing the cationic lipid proportion above 50% increased transfection
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`efficiency. Ex. 1006 (Ahmad), 744; Ex. 1005 (Lin), 3312.
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`71. At the time of the ’435 patent the number of species of non-
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`cationic lipids that could be employed was large, and differences among such
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`lipids had been reported to impact the structure and perhaps the function of the
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`resulting nucleic acid-lipid particles. Ex. 1008 (Gao), E95 (transfection
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`efficiency varies with “the structure and proportion of the helper lipid in the
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