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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2018-00739
`Patent No. 9,364,435
`_____________________________
`
`DECLARATION OF DAVID H. THOMPSON, PH. D.
`
`ARBUTUS - EXHIBIT 2004
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
`
`

`

`
`
`TABLE OF CONTENTS
`QUALIFICATIONS ........................................................................................ 1 
`I. 
`SCOPE OF WORK.......................................................................................... 2 
`II. 
`III.  LEGAL STANDARDS ................................................................................... 3 
`IV.  LEVEL OF ORDINARY SKILL IN THE ART ............................................. 6 
`V. 
`BACKGROUND ............................................................................................. 7 
`VI.  CLAIM CONSTRUCTION .......................................................................... 12 
`VII.  GROUND 1 – CLAIMS 1-20 ARE NOT OBVIOUS IN VIEW OF
`PATENT OWNER’S DISCLOSURES IN THE ’196 PCT AND ’189
`PUBLICATION ............................................................................................. 16 
`A. 
`Claim 1 ................................................................................................ 16 
`B. 
`Unexpected Results ............................................................................. 22 
`C. 
`Claims 2-20 ......................................................................................... 31 
`VIII.  GROUND 2 – CLAIMS 1-20 ARE NOT OBVIOUS IN VIEW OF
`PATENT OWNER’S PRIOR DISCLOSURES IN LIGHT OF LIN
`AND/OR AHMAD ........................................................................................ 38 
`IX.  GROUND 3 – CLAIMS 1-20 ARE NEITHER ANTICIPATED BY
`NOR OBVIOUS IN VIEW OF THE ’554 PUBLICATION ........................ 45 
`A. 
`Claim 1 ................................................................................................ 45 
`1. 
`Anticipation by L054 ................................................................ 45 
`2. 
`Anticipation by ranges .............................................................. 52 
`3. 
`Obvious over ranges ................................................................. 56 
`Claims 2-20 ......................................................................................... 58 
`B. 
`X.  OBJECTIVE INDICIA OF NONOBVIOUSNESS ...................................... 71 
`A. 
`Long-felt need ..................................................................................... 72 
`
`-i-
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`
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`B. 
`Skepticism ........................................................................................... 76 
`Unexpected Results ............................................................................. 77 
`C. 
`Commercial Success............................................................................ 83 
`D. 
`XI.  CONCLUDING STATEMENTS .................................................................. 84 
`
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`-ii-
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`
`I.
`
`I, David H. Thompson, declare as follows:
`
`QUALIFICATIONS
`1.
`I am a Professor of Chemistry at Purdue University and Director of
`
`the Medicinal Chemistry Group in the Purdue Center for Cancer Research. My
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`primary research interests include development of transiently-stable carrier
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`systems for drug and nucleic acid delivery.
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`2.
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`I received my Ph.D. in Organic Chemistry from Colorado State
`
`University in 1984. I also hold a Bachelor of the Arts in Biology and a Bachelor of
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`Science in Chemistry from the University of Missouri, Columbia.
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`3.
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`I have been a visiting professor at numerous institutions including,
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`Chulalongkorn University, Department of Pharmaceutics; Technical University of
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`Denmark, Department of Micro & Nanotechnology; Japan Advanced Institute of
`
`Science & Technology, Department of Biomaterials; Osaka University,
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`Department of Applied Chemistry; University of Florida, Department of
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`Pharmaceutics; and University of British Columbia, Department of Biochemistry.
`
`4.
`
`I am listed as a co-inventor on 7 United States patents. I have also
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`published more than 140 peer reviewed scientific papers.
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`5.
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`I have studied, taught, practiced, and conducted research involving the
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`formulation, use, characterization, and delivery of lipid particles. I have expertise
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`with the delivery of therapeutic agents using lipid particles.
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`1
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`

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`6.
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`A copy of my Curriculum Vitae, attached as EX2010, contains further
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`details on my education, experience, publications, and other qualifications to
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`render an expert opinion in this matter.
`
`II.
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`SCOPE OF WORK
`7.
`I understand that a petition was filed with the United States Patent and
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`Trademark Office for inter partes review of U.S. Patent No. 9,364,435 (“the ’435
`
`patent,” EX1001).
`
`8.
`
`I further understand that the Patent Trial and Appeal Board (“PTAB”
`
`or the “Board”) has decided to institute inter partes review of claims 1-20 of the
`
`’435 patent under 35 U.S.C. §§ 102 and 103 based on the disclosures of
`
`WO2005/007196 (“the ’196 PCT,” EX1002), US 2006/134189 (“the ’189 PCT,”
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`EX1003), Lin, et al, “Three-Dimensional Imaging of Lipid Gene-Carriers:
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`Membrane Charge Density Controls Universal Transfection Behavior in Lamellar
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`Cationic Liposome-DNA Complexes,” (“Lin,” EX1005), Ahmad, et al, “New
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`multivalent cationic lipids reveal bell curve for transfection efficiency versus
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`membrane charge density: lipid–DNA complexes for gene delivery,” (“Ahmad,”
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`EX1006), and US 2006/0240554 (“the ’554 publication,” EX1004).
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`9.
`
`I have been specifically asked to provide my expert opinions on the
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`patentability of the claims of the ’435 patent in view of the asserted grounds in the
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`petition. In connection with this analysis, I have reviewed the ’435 patent and the
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`-2-
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`prior art cited against the patentability of claims 1-20. I have also reviewed and
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`considered the petition, Dr. Janoff’s declaration and deposition transcript, and the
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`Board’s Decision on Institution of Inter Partes Review, and may cite these
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`documents in this declaration.
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`10.
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`I am being compensated at a rate of $600 per hour for my work in this
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`matter. I am also being reimbursed for reasonable and customary expenses
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`associated with my work in this investigation. My compensation is not contingent
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`on the outcome of this matter or the specifics of my testimony.
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`III. LEGAL STANDARDS
`11.
`I have been advised that a claimed invention is not patentable under
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`an anticipation theory (35 U.S.C. § 102) if all claim elements are found in a single
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`prior art reference. I further understand that anticipation is about prior invention
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`and therefore the single prior art reference must be found to disclose all elements
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`of the claimed invention arranged as in the claim. I also understand that picking,
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`choosing, and combining various embodiments disclosed within a single reference
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`is not proper under an anticipation theory.
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`12.
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`I understand that differences between the prior art reference and a
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`claimed invention, however slight, invoke the question of obviousness, not
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`anticipation.
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`-3-
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`13.
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`I have been advised that a claimed invention is not patentable under
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`35 U.S.C. § 103 if it is obvious. A patent claim is unpatentable if the claimed
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`invention would have been obvious to a person of ordinary skill in the field at the
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`time the claimed invention was made. This means that even if all of the
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`requirements of the claim cannot be found in a single prior art reference that would
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`anticipate the claim, a person of ordinary skill in the relevant field who knew about
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`all this prior art would have come up with the claimed invention.
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`14.
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`I have further been advised that the ultimate conclusion of whether a
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`claim is obvious should be based upon several factual determinations. That is, a
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`determination of obviousness requires inquiries into: (1) the level of ordinary skill
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`in the field; (2) the scope and content of the prior art; (3) what difference, if any,
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`existed between the claimed invention and the prior art; and (4) any objective
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`indicia of nonobviousness.
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`15.
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`I have been advised that, in determining the level of ordinary skill in
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`the field that someone would have had at the time the claimed invention was made,
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`I should consider: (1) the levels of education and experience of persons working in
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`the field; (2) the types of problems encountered in the field; and (3) the
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`sophistication of the technology.
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`16.
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`I have been advised that a patent claim composed of several elements
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`is not proved obvious merely by demonstrating that each of its elements was
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`-4-
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`independently known in the prior art. In evaluating whether such a claim would
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`have been obvious, I may consider whether there is a reason that would have
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`prompted a person of ordinary skill in the field to combine the elements or
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`concepts from the prior art in the same way as in the claimed invention.
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`17.
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`I have also been advised, however, that I must be careful not to
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`determine obviousness using the benefit of hindsight; many true inventions might
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`seem obvious after the fact. I should put myself in the position of a person of
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`ordinary skill in the field at the time the claimed invention was made and I should
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`not consider what is known today or what is learned from the teaching of the
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`patent.
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`18. Finally, I have been advised that any obviousness rationale for
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`modifying or combining prior art must include a showing that a person of ordinary
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`skill would have had a reasonable expectation of success.
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`19. With regard to objective indicia of nonobviousness, I have been
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`advised that any objective evidence may be considered as an indication that the
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`claimed invention would not have been obvious at the time the claimed invention
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`was made. I understand that the purpose of objective indicia is to prevent a
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`hindsight analysis of the obviousness of the claims.
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`-5-
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`20.
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`I have been advised that there are several factors that may be
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`considered as objective indicia. These factors include the long-felt need,
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`skepticism, unexpected results and commercial success of the invention.
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`21.
`
`I have been further advised that in order for objective indicia to be
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`significant, there must be a sufficient nexus between the claimed invention and the
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`evidence of objective indicia. I understand that this nexus serves to provide a link
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`between the merits of the claimed invention and the evidence of objective indicia
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`provided.
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`22.
`I have been advised that, in determining the level of ordinary skill in
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`the art that someone would have had at the time the claimed invention was made, I
`
`should consider: (1) the levels of education and experience of persons working in
`
`the field; (2) the types of problems encountered in the field; and (3) the
`
`sophistication of the technology. I have been advised that an invention must be
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`evaluated not through the eyes of the inventor, who may have been of exceptional
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`skill, but as by one of ordinary skill in the art.
`
`23.
`
`I understand that Dr. Janoff defined a person of ordinary skill as one
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`that “would have specific experience with lipid particle formation and use in the
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`context of delivering therapeutic payloads, and would have a Ph.D., an M.D., or
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`similar advanced degree in an allied field (e.g., biophysics, microbiology,
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`-6-
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`biochemistry) or an equivalent combination of education and experience.” EX1007
`
`¶31. I understand this was adopted by the Board. Paper 15 at 5-7.
`
`24.
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`In my opinion, the level of ordinary skill defined by Dr. Janoff and the
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`Board is inappropriate. With regard to the “specific experience,” Dr. Janoff states
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`that the “level of skill is representative of the inventors on the ʼ435 patent and
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`authors/inventors of prior art cited herein.” EX1007 ¶31. The inventors of the ʼ435
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`patent, however, are artisans of exceptional skill in the subject matter of the ʼ435
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`patent. Thus, in my view, Dr. Janoff has not simply applied a slightly higher level
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`of skill in the art in setting forth his opinions in his declaration, but has assumed a
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`much higher level of skill than that of a person of ordinary skill in the art.
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`V. BACKGROUND
`25. An objective of genetic therapy at the time, and to this day, is the
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`development of drugs — that is, nucleic acids — to treat systemic diseases such as
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`cancer, inflammation, virus infection, and cardiovascular disease. While genetic
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`therapy holds the promise of highly specific targeting of disease pathways, it was
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`known that this promise would only be realized through the development of
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`appropriate delivery vehicles. Delivery is critical because a therapeutic agent is
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`useless if it does not reach its target. This is particularly true with nucleic acids —
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`large, negatively charged molecules — that cannot simply be given to a patient
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`systemically (e.g., intravenously) and allowed to passively enter cells, as would be
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`-7-
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`the case with many small molecule drugs. Therapeutic nucleic acids require an
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`effective delivery vehicle, which historically has proved to present a considerable
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`technical obstacle. See, e.g., EX2016 (“You can write down the steps. You can
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`write down what you think will happen. But then you have to put it in a 50-
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`nanometer particle that’s safe and potent to deliver.”); EX2014 at 11 (“The major
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`hurdle right now is delivery, delivery, delivery,” says Sharp), (“Khvorova believes
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`that the medical benefits of RNAi will be huge if the delivery issues can be
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`resolved.”).
`
`26.
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` The first generation of nucleic acid delivery systems that were
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`developed included cationic liposome nucleic acid complexes (also known as
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`liposomes). See EX1002 ¶8 (defining “cationic liposome complex” as lipoplex);
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`EX2007, 2:27-28 (same). Lipoplexes were found to be unsuitable for many
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`applications, particularly systemic uses, due in large part to the toxic nature of the
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`cationic lipids. See, e.g., EX1008 at 5.
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`27. The toxicity of cationic lipids is observed both at the systemic level
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`and at the cellular level. Cationic lipids cause clustering of membrane
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`glycoproteins on cell surfaces, thereby disrupting normal cellular protein
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`trafficking and receptor recycling, and thus are cytotoxic to cells themselves.
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`Toxicity also occurs at the organ level, as these lipids are often not readily
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`biodegradable, such that they accumulate to cytotoxic concentrations in the liver
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`-8-
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`and spleen. Cationic lipids also have immunostimulatory capacity and have been
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`associated with immunogenic and inflammatory responses. The presence of
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`cationic lipids also results in these complexes being rapidly cleared from the body,
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`further limiting their therapeutic utility. Furthermore, it was understood that the
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`cationic lipid component can cause aggregation of lipid particles.
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`28. These technical obstacles of toxicity, immunogenicity, and
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`aggregation due to use of cationic lipids in a delivery vehicle for nucleic acids was
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`well known in 2008 and thus those in the field at the time sought to minimize the
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`cationic lipid component of a lipid delivery vehicle. This is evidenced in the
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`references cited in the petition.
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`29. For example, Ahmad teaches that the cationic lipid component should
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`be minimized to reduce cytotoxicity and metabolic effort associated with
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`elimination of cationic lipids.
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`Minimizing the amount of cationic lipid is desirable to reduce cost as
`well as potential toxic effects of the cationic lipid. In addition,
`achieving a given σM with fewer, more highly charged molecules
`should mean a smaller metabolic effort for the elimination of the
`lipids from the cell.
`EX1006 at 7.
`
`30. Gao discusses toxicity caused by the cationic lipid component.
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`Detailed toxicological studies … revealed that the cationic lipid
`contributes significantly to the toxicity observed. Similar toxic effects
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`-9-
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`are also noticeable in systemic gene delivery via the tail vein with
`other types of cationic lipids. Symptoms include acute pulmonary
`hypotension, induction of inflammatory cytokines, tissue infiltration
`of neutrophils in lungs, decrease in white cell counts, and in some
`cases tissue injury in liver and spleen. In humans, various degrees of
`adverse inflammatory reactions, including flulike symptoms with
`fever and airway inflammation, ….
`EX1008 at 5.
`
`31. Gao further discloses that the cationic lipid component caused
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`unwanted interactions with serum proteins, including complement.
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`Another factor related to the severity of transfection-related side
`effects is complement activation and adsorption of serum proteins
`onto their surface, which in turn act as opsonins to trigger the uptake
`of opsonized particles by macrophages and other immune cells.
`Various strategies have been considered to deal with the toxic
`responses.
`EX1008 at 5-6; see also Table 1.
`
`32. Gao also describes that the cationic lipid component of lipoplexes
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`caused unwanted interactions with non-target cells.
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`Once administered in vivo, lipoplexes tend to interact with negatively
`charged blood components and form large aggregates that could be
`absorbed onto the surface of circulating red blood cells, trapped in a
`thick mucus layer, or embolized in microvasculatures, preventing
`them from reaching the intended target cells in the distal location.
`EX1008 at 5.
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`-10-
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`33. Additionally, it was appreciated that the cationic lipid component of
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`lipoplexes caused aggregation of lipid particles. EX1008 at 9 (“[T]he polycations
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`in either lipoplexes or polyplexes have the intrinsic property of causing significant
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`aggregation in biological matrices full of negatively charged molecules ….”); see
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`also EX1004 ¶136.
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`34. Therefore, it was well established at the time of filing of the patent
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`that cationic lipids used in a delivery vehicle for nucleic acids were toxic,
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`immunogenic, and caused aggregation. As Dr. Zamore of Alnylam stated, “I
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`wouldn’t want anyone injecting cationic lipids into my bloodstream.” EX2011 at
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`42.
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`35. At the filing date of the patent, the aim of those working in the field
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`sought lipid particles that were substantially non-toxic and therefore suitable for
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`systemic applications. However, at that time, the development of nucleic acid-lipid
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`particles that were suitable for systemic applications had not been achieved.
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`Furthermore, it was widely understood at that time that in order to design nucleic
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`acid-lipid particles suitable for systemic use the amount of cationic lipid in the
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`formulation should be kept as low as possible, because of concerns over the known
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`toxic effects of cationic lipids.
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`-11-
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`VI. CLAIM CONSTRUCTION
`36. The petition materials provided an unreasonably broad construction of
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`“nucleic acid-lipid particle,” stating that it should be construed as “a composition
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`of lipids and a nucleic acid for delivering a nucleic acid to a target site on interest.”
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`Pet. 24.
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`37.
`
`I have been apprised that the Board, in its Institution Decision,
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`rejected the construction in the petition and offered a different one. That is, the
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`Board construed “nucleic acid-lipid particle” as “a particle that comprises a nucleic
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`acid and lipids, in which the nucleic acid may be encapsulated in the lipid portion
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`of the particle.” Paper 15 at 10-11 (citing EX1001, 11:14–22).
`
`38.
`
`In my opinion, both constructions of “nucleic acid-lipid particle” in
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`the petition materials and in the Institution Decision are incorrect and unreasonably
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`broad at least to the extent they encompass lipid particles lacking any encapsulated
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`nucleic acid. The petition materials and the Board focused on a different term —
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`i.e., the term “lipid particle” — and only incompletely address the corresponding
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`discussion in the ’435 patent specification. But the claimed term is not “lipid
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`particle,” the claimed term is “nucleic acid-lipid particle.”
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`39. A “nucleic acid-lipid particle” expressly includes a nucleic acid.
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`According to the ʼ435 patent, “nucleic acids, when present in the lipid particles of
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`the present invention, are resistant in aqueous solution to degradation with a
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`-12-
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`nuclease.” EX1001, 11:51-54. The ’435 patent describes nucleic acid
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`encapsulation in the lipid particle as conferring resistance to such enzymatic
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`degradation. EX1001, 11:20-22 (“[T]he active agent or therapeutic agent may be
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`encapsulated in the lipid, thereby protecting the agent from enzymatic
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`degradation.”); see also EX2007 4:15-19; 22:40-47; 23:1-3; 23:27-29; 26:35-37
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`(describing resistance to nuclease enzymatic degradation as indicating nucleic
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`encapsulation in the liposomes).
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`40. A “lipid particle” “may [include a nucleic acid] encapsulated in the
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`lipid portion of the particle, thereby protecting it from enzymatic degradation.”
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`EX1001, 11:14–22. A “nucleic acid-lipid particle,” however, does include a
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`nucleic acid encapsulated in the lipid portion of the particle, thereby protecting it
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`from enzymatic degradation. EX1001, 11:23-31, 11:51-54.
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`41.
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`I understand that, during cross-examination, Dr. Janoff testified
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`multiple times that the lipid particles as claimed are defined as SNALPs. See, e.g.,
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`EX2028, 118:18-119:4, 119:9-17, 120:5-6, 121:14-25. Dr. Janoff cited to a
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`provision of U.S. Patent No. 9,404,127 (“the ’127 patent,” EX2029) at 5:15-22 that
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`is identically recited in the ’435 patent. Compare EX2029, 5:15-22 with EX1001,
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`19:19-26.
`
`42. Dr. Janoff is correct in that the specification repeatedly identifies
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`SNALPs as the invention of the patent for delivering a nucleic acid payload. See
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`-13-
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`e.g., EX1001, 3:9-13 (“The present invention provides novel, serum-stable lipid
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`particles ….”), 47:23-24 (“[T]he lipid particles of the invention are serum-stable
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`nucleic acid-lipid particles (SNALP)…”), 3:32-37, 14:20-25.
`
`43.
`
`In my opinion, a fair and reasonable reading of the ’435 patent
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`specification supports Dr. Janoff’s position in that there is no meaningful
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`distinction between the ’435 patent specification’s descriptions of a “lipid particle”
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`containing a nucleic acid (i.e., a nucleic acid-lipid particle) and particle
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`characteristics that confer serum stability. Compare EX1001, 11:14-22, 11:51-54
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`(“[N]ucleic acids, when present in the lipid particles of the invention, are resistant
`
`in aqueous solution to degradation with a nuclease.”) with 13:32-37 (“‘Serum-
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`stable’ in relation to nucleic acid-lipid particles such as SNALP means that the
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`particle is not significantly degraded after exposure to a serum or nuclease assay
`
`that would significantly degrade free DNA or RNA”).
`
`44.
`
`In my opinion, a narrow focus on a linguistic difference between a
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`nucleic acid-lipid particle and the term “SNALP” is misguided and risks
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`overlooking pertinent disclosure and context provided in the ’435 patent. The ’435
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`patent specification states that “nucleic acids, when present in the lipid particles of
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`the invention, are resistant in aqueous solution to degradation with a nuclease.” Id.,
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`11:51-54. Such physical properties of the particles providing nuclease degradation
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`resistance, or encapsulation of the nucleic acid, are also as described in the ’435
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`-14-
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`patent specification as conferring the identified serum stability. Id., 13:32-37. This
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`is certainly true if the claimed particles are SNALP, as supported not only by the
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`specification of the ’435 but as affirmed by petitioner’s expert Dr. Janoff.
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`45.
`
`I disagree with the Board’s analysis presented at pages 9-10 of the
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`Institution Decision at least for the reasons explained above. As explained above,
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`there is no meaningful distinction between a nucleic acid-lipid particle and a
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`SNALP in the context of the ’435 patent. None of the provisions of the ’435 patent
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`specification identified by the Board indicate otherwise. Paper 15 at 9-10. The
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`Board’s discussion of whether particles are “limited to in vivo use,” is confusing
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`and loses sight of both the context of the ’435 patent specification and a reasonable
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`perspective of a person of ordinary skill in the art. For example, the Board cites to
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`an example of SNALP being tested for transfection activity in vitro as indicating
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`the same composition is not a SNALP. Paper 15 at 10 (citing Example 2 at 69:6–
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`70:52 (“Eg5 siRNA Formulated as 1:57 SNALP are Potent Inhibitors of Cell
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`Growth In Vitro”)). The composition in Example 2 is expressly described as “1:57
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`SNALP.” A person of ordinary skill in the art would understand that composition
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`can be both 1) formulated such that the nucleic acid is encapsulated in the lipid
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`particle, rendering the composition extremely useful for systemic applications; and
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`2) tested for in vitro transfection activity. It is not uncommon for compositions to
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`be assessed for in vitro transfection activity and then subject to testing in vivo.
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`-15-
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`46. Regardless of whether the Board construes “nucleic acid-lipid
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`particle” as a SNALP as indicated by Dr. Janoff; as a lipid particle with an
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`encapsulated nucleic acid (thereby protecting it from enzymatic degradation); or
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`under the broad construction presented in the Institution Decision, the petition
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`materials fail to establish the unpatentability of claims 1-20.
`
`VII. GROUND 1 – CLAIMS 1-20 ARE NOT OBVIOUS IN VIEW OF
`PATENT OWNER’S DISCLOSURES IN THE ’196 PCT AND ’189
`PUBLICATION
`47.
`It is my opinion that the petition fails to demonstrate that claims 1-20
`
`of the ’435 patent are obvious in view of the ’196 PCT and the ’189 publication.
`
`Since the petition materials provide no meaningful discussion of the ’189
`
`publication, the below arguments focus on lack of obviousness in view of the ’196
`
`PCT.
`
`48. Although I understand that it is not Patent Owner’s burden to prove, it
`
`is my opinion that claims 1-20 of the ’435 patent are not obvious.
`
`A. Claim 1
`49. First, the petition materials fail to address all the lipid components of
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`the claimed nucleic acid-lipid particle composition. Second, the petition materials
`
`fail to address the combination of the lipid components of the claimed nucleic acid-
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`lipid particle composition. Third, the petition materials fail to explain why a person
`
`of ordinary skill in the art would have wanted to combine the individual lipid
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`-16-
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`components disclosed in the ’196 PCT. Fourth, the petition materials fail to
`
`address that a skilled artisan would have had no reasonable expectation of success
`
`that the claimed nucleic acid-lipid particle composition would be well-tolerated
`
`and efficacious. Finally, much of the evidence of unexpected results within the
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`patent is disregarded, and what is considered is mischaracterized in view of the
`
`prior art.
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`50. As an initial observation, the assertion of obviousness in the petition
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`materials is based on alleged overlapping ranges between the ’196 PCT and the
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`challenged claims. But the petition materials fail to identify ranges that overlap for
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`each of the claim components.
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`51. For example, claim 1 recites “a conjugated lipid that inhibits
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`aggregation of particles.” Rather than identifying disclosure in the ’196 PCT that
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`is specific for a conjugated lipid range, the petition materials cite to a range
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`provided for “a bilayer stabilizing component.” Pet. 39; EX1007 ¶117.
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`52. The ’196 PCT makes clear that a “bilayer stabilizing component” is
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`not the same as a “conjugated lipid that inhibits aggregation of particles.” See, e.g.,
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`EX1002 ¶92 (“Suitable BSCs include, but are not limited to, polyamide oligomers,
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`peptides, proteins, detergents, lipid-derivatives, PEG-lipids, …”). Bilayer
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`stabilizing components include a broad class of structurally and chemically diverse
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`molecules. Numerous bilayer stabilizing components (e.g., polyamide oligomers,
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`peptides, proteins, detergents, and lipid-derivatives) would not be considered a
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`conjugated lipid by a person of ordinary skill in the art.
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`53. While the ’196 PCT lists a general range for the bilayer stabilizing
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`component category, a person of ordinary skill in the art would not have
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`interpreted the stated range (e.g., 0.5% to 25%) as being applicable to each listed
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`bilayer stabilizing component example. For example, a skilled artisan would have
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`appreciated that if the bilayer stabilizing component were a detergent, 25% would
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`have been an unreasonably high level. This is because at this concentration of
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`detergent the lipids would be solubilized and no longer form a lipid particle.
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`54. The ’196 PCT discloses seven nucleic acid-lipid particle compositions
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`— all of which have either 7.5 or 15 mol % cationic lipid and 10 mol % conjugated
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`lipid. EX1002 ¶¶216, 223, 228, 232.
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`55. Therefore, the petition materials fail to identify in ’196 PCT “a
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`conjugated lipid that inhibits aggregation of particles” as required by claim 1.
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`56.
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`In my opinion, as explained in further detail below, there would have
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`been no good reason why a person of ordinary skill in the art would combine the
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`different range disclosures for different lipid components from the ’196 PCT so as
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`to arrive at the claimed nucleic acid-lipid particle. Nor would one would
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`reasonably expect such formulations to work. The petition materials fail to
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`demonstrate otherwise.
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`57. Those in the field at the time recognized that the properties of any
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`lipid particle are conferred not by the amount of any individual component but by
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`the interaction of the combined components as a whole. Furthermore, if the skilled
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`person were to vary one component (by taking the amount of that component
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`specified for a particular formulation), it would then be necessary to decide which
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`of the other components would need to be varied in order to accommodate the
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`change in proportions of the overall composition.
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`58. The effects of making changes to the proportion of other components
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`in the lipid particle would be unpredictable. Such changes, even if apparently
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`minor in nature, would have little assurance of producing a functional lipid particle
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`suitable for systemic use. The idea of simply “cherry-picking” specific amounts of
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`individual components from different formulations, or the different ranges in the
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`’196 PCT, when designing lipid particles is therefore something which would have
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`made no technical sense to the skilled person.
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`59. Dr. Janoff states that “determining the optimal proportion of cationic
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`lipid for a given lipid combination would be a simple matter of varying the
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`proportion using prior art methodologies.” EX1007 ¶110. I disagree. As explained
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`above, the properties of a formulation are not conferred by the amount of one
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`single component. Properties such as safety and efficacy are conferred by the
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`combination of components in the entire formulation.
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`60. Moreover, Dr. Janoff’s stated reason disregards the state of the art at
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`the time of the invention. Making safe and effective nucleic acid-lipid particle
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`formulations was not simply a matter of “varying the proportion” of cationic lipid
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`in prior art formulations. As discussed above, the field of genetic medicine was
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`hindered by the lack of effective and safe nucleic acid delivery vehicles. That the
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`field struggled for 20 years to find such a delivery vehicle speaks to the difficulty
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`of the task. See generally EX2015. Had the solution been a matter of simply
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`optimizing the cationic lipid proportion, it would not have taken such an enormous
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`investment of money and time.
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`61. As discussed elsewhere herein, the high cationic lipid levels claimed
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`would have been disfavored in view of well-established toxicity concerns.
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`Moreover, inclusion of a conjugated lipid in a formulation with high cationic lipid
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`would have been expected to occur at much higher levels than claimed.
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`62. Conjugated lipid had been incorporated into lipid particles to help
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`shield positive charge and reduce nonspecific interactions with blood components,
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`leading to enhanced systemic clearance. Lipid particle compositions at the time
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`typically used much higher levels of conjugated lipid than is claimed by the ’435
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`patent, such as 10% P