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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION,
`Patent Owner.
`_____________________________
`
`Case IPR2019-00554
`Patent No. 8,058,069
`_____________________________
`
`DECLARATION OF DAVID H. THOMPSON, PH. D.
`
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`ARBUTUS - EXHIBIT 2031
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
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`

`

`
`
`2. 
`
`B. 
`
`C. 
`
`TABLE OF CONTENTS
`QUALIFICATIONS ........................................................................................ 1 
`I. 
`SCOPE OF WORK.......................................................................................... 2 
`II. 
`III.  LEGAL STANDARDS ................................................................................... 3 
`IV.  BACKGROUND ............................................................................................. 6 
`V. 
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 8 
`VI.  CLAIM CONSTRUCTION ............................................................................ 9 
`VII.  THE PETITION FAILS TO DEMONSTRATE THE
`OBVIOUSNESS OF THE CLAIMS IN VIEW OF OVERLAPPING
`RANGES ....................................................................................................... 12 
`A. 
`The References Relied Upon Do Not Provide an Affirmative
`Teaching of Lipid Ranges Overlapping with Claimed Ranges .......... 12 
`1. 
`Ground 1—The ’196 PCT and the ’189 Publication Fail
`to Disclose the Phospholipid Range of Claim 1 ....................... 13 
`Ground 3—The ’554 Publication Fails to Disclose or
`Suggest the Phospholipid Range of Claim 1 ............................ 16 
`The Formulation of Nucleic Acid-Lipid Particles Was Not a
`Matter of Routine Optimization .......................................................... 19 
`The Broad Ranges of the Prior Art Do Not Support Routine
`Optimization ........................................................................................ 23 
`Petitioner Does Not Explain Selecting the Claimed
`Composition from the Prior Art Ranges ............................................. 24 
`1. 
`Claim as a Whole/Interaction of Components .......................... 25 
`2. 
`Cationic Lipids Were Known to be Toxic ................................ 27 
`The Claimed Particles Demonstrated Unexpected Results ................. 30 
`
`D. 
`
`E. 
`
`-i-
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`1. 
`
`2. 
`
`B. 
`
`The ’069 Patent Reports Extensive Testing of Numerous
`Formulations within the Claimed Range .................................. 30 
`Post-Filing Publications Provide Testing Data for a
`Broad Range of Lipids and Cargo Molecules ........................... 42 
`VIII.  THE PATENTABILITY OF THE CLAIMS ARE FURTHER
`SUPPORTED BY OTHER OBJECTIVE INDICIA ..................................... 49 
`A. 
`Long-Felt Need – the delivery problem was not solved for over
`20 years ................................................................................................ 49 
`Skepticism – those in the art questioned the safety of the
`SNALP as a suitable delivery platform ............................................... 53 
`Commercial Success – the claimed nucleic acid-lipid particle is
`the first FDA approved siRNA drug ................................................... 54 
`IX.  THE PETITION FAILS TO SHOW THE CLAIMS ARE
`ANTICIPATED ............................................................................................. 56 
`A.  Ground 1—Neither the ’196 PCT or the ’189 Publication
`Anticipate the Claimed Ranges ........................................................... 56 
`Ground 3—The ’554 Publication Is Not Anticipatory ........................ 58 
`B. 
`X.  GROUND 2 FAILS ....................................................................................... 60 
`A. 
`Lin and Ahmad Do Not Supply the Missing Motivation for
`Ground 2 .............................................................................................. 61 
`Petitioner Ignores Content of Lin and Ahmad .................................... 65 
`B. 
`XI.  THE DEPENDENT CLAIMS HAVE NOT BEEN SHOWN TO BE
`UNPATENTABLE IN ANY OF THE GROUNDS OF CHALLENGE ...... 66 
`A. 
`Claim 8 ................................................................................................ 66 
`B. 
`Claim 14 .............................................................................................. 67 
`C. 
`Claim 15 .............................................................................................. 68 
`D. 
`Claim 16 .............................................................................................. 68 
`
`C. 
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`-ii-
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`E. 
`Claim 17 .............................................................................................. 69 
`Claim 18 .............................................................................................. 70 
`F. 
`Claim 20 .............................................................................................. 70 
`G. 
`Claim 21 .............................................................................................. 70 
`H. 
`Claim 22 .............................................................................................. 71 
`I. 
`XII.  CONCLUDING STATEMENTS .................................................................. 71 
`
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`-iii-
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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
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`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
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`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
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`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.
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`4.
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`I am listed as a co-inventor on 7 United States patents. I have also
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`published more than 149 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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`
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`II.
`
`6.
`
`A copy of my Curriculum Vitae, attached as EX2032.
`
`SCOPE OF WORK
`7.
`I understand that Moderna (“Petitioner”) filed a petition with the
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`United States Patent and Trademark Office for inter partes review of U.S. Patent
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`No. 8,058,069 (“the ’069 patent,” EX1001), the subject of this proceeding.
`
`8.
`
`I further understand that the Patent Trial and Appeal Board (“PTAB”
`
`or the “Board”) has decided to institute inter partes review of claims 1-22 of the
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`’069 patent under 35 U.S.C. §§ 102 and 103 based on the disclosures of
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`WO2005/007196 (“the ’196 PCT,” EX1003), US 2006/134189 (“the ’189 PCT,”
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`EX1004), 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,” EX1006), 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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`EX1007), and US 2006/0240554 (“the ’554 publication,” EX1005).
`
`9.
`
`I have been specifically asked to provide my expert opinions on the
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`patentability of the claims of the ’069 patent in view of the asserted grounds in the
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`petition. In connection with this analysis, I have reviewed the ’069 patent and the
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`prior art cited against the patentability of claims 1-22. I have reviewed and
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`considered the petition materials, including the petition, Dr. Janoff’s declaration
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`and references cited therein and may cite these 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 the burden is on Petitioner to demonstrate the
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`unpatentability of the challenged claims.
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`12.
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`I have been advised that anticipation is about prior invention and
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`therefore a single prior art reference must be found to disclose all elements of the
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`claimed invention arranged as in the claim. I have been further advised that it is not
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`enough that the prior art references include multiple, distinct teachings that may
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`somehow be combined to achieve the claimed invention. Rather, it is my
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`understanding that the reference must clearly and unequivocally disclose the
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`claimed invention or direct a person of ordinary skill in the art to the claimed
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`invention without any need for picking, choosing, and combining various
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`disclosures that are not directly related to each other in the reference.
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`-3-
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`13.
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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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`14.
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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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`15.
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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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`16.
`
`I have been advised that, in determining the level of ordinary skill in
`
`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.
`
`17.
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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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`independently known in the prior art. In evaluating whether such a claim would
`
`have been obvious, I may consider whether there is a reason that would have
`
`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.
`
`18.
`
`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
`
`not consider what is known today or what is learned from the teaching of the
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`patent.
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`19.
`
`I have been advised that any obviousness rationale for modifying or
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`combining prior art must include a showing that a person of ordinary skill would
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`have had a reasonable expectation of success.
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`20.
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`In addition, I have been advised that overlapping ranges may invoke a
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`rebuttable presumption of obviousness under the rationale of “routine
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`optimization,” wherein it is only a matter of routine experimentation to arrive at
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`-5-
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`the claimed range based on not overly broad overlapping ranges disclosed in the
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`prior art.
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`21. 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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`22.
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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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`23.
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`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.
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`IV. BACKGROUND
`24. An objective of genetic therapy at the time, and to this day, is the
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`development of nucleic acids to treat systemic diseases such as cancer,
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`inflammation, virus infection, and cardiovascular disease. While genetic therapy
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`holds the promise of highly specific targeting of disease pathways, it was known
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`-6-
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`that this promise would only be realized through the development of appropriate
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`delivery vehicles. Delivery is critical because a therapeutic agent is useless if it
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`does not reach its target. This is particularly true with nucleic acids — large,
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`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 is the
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`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., EX2020, 4 (“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.”); EX2018, 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.”).
`
`25. 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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`lipoplexes). See EX1001, 2:8-18 (defining “[c]ationic liposome complexes” as
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`lipoplexes); EX2009, 2:27-28 (same). Lipoplexes were found to be unsuitable for
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`many applications, particularly systemic uses, due in large part to the toxic nature
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`of the cationic lipids. See, e.g., EX1009, 5.
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`-7-
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`26. Additionally, it was appreciated that the cationic lipid component of
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`lipid carrier particles were toxic, immunogenic, and caused unwanted aggregation
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`of lipid particles. As Dr. Zamore of Alnylam stated, “I wouldn’t want anyone
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`injecting cationic lipids into my bloodstream.” EX2016, 42; see also EX1009, 9
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`(“[T]he polycations in either lipoplexes or polyplexes have the intrinsic property of
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`causing significant aggregation in biological matrices full of negatively charged
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`molecules ….”); see also EX1005, ¶136; Section VII.D.2.
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`27. At the filing date of the patent, those working in the field sought lipid
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`particles that were substantially non-toxic and therefore suitable for systemic
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`applications. 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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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
`28.
`It is my understanding that in the final written decision in Moderna,
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`Inc. et al. v. Arbutus Biopharma Corp., IPR2018-00739 (“the ’739 IPR”), the
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`Board defined a person of ordinary skill in the art as follows:
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`Accordingly, we find in the record as a whole that a person of
`ordinary skill in the art would have specific experience with, and/or be
`generally familiar with, lipid particle formation and use in the context
`of delivering therapeutic payloads, and would have a Ph.D., an M.D.,
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`or a similar advanced degree in an allied field (e.g., biophysics,
`microbiology, biochemistry) or an equivalent combination of
`education and experience.
`29. The specifications ’435 patent and the ’069 patent share the same
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`disclosure. Moreover, it is my understanding that Dr. Janoff agreed that he applied
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`the same level of skill in both his declaration addressing the ’435 patent and the
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`’069 patent. Accordingly, for purposes of this declaration, I have applied the
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`definition of a person of ordinary skill in the art made by the Board as to the ’435
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`patent in this declaration addressing the ’069 patent.
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`VI. CLAIM CONSTRUCTION
`30.
`I understand there has been disagreement regarding the proper
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`construction of the claim term “nucleic acid-lipid particle.” My opinions herein as
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`to why the challenged claims are not anticipated nor obvious do not depend on the
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`Board adopting a particular construction of this term. It is my opinion that
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`regardless of how the Board construes the above term, Petitioner has failed to
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`demonstrate the unpatentability of the claimed nucleic acid-lipid particles for the
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`reasons I discuss below. That being said, I provide analysis of the proper
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`interpretation of the term below to the extent it is helpful.
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`31.
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`I have been informed by counsel that claim terms should be construed
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`based on how they would be understood by an ordinary artisan when read in light
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`of the specification and the prosecution history.
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`32.
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`It is my opinion that “nucleic acid-lipid particle” should be construed
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`as necessarily including a nucleic acid encapsulated within the particle, thereby
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`protecting it from enzymatic degradation, consistent with the disclosure of the
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`specification.
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`33. As taught by the disclosure, a “nucleic acid-lipid particle” expressly
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`includes a nucleic acid. According to the ʼ069 patent, “nucleic acids, when present
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`in the lipid particles of the present invention, are resistant in aqueous solution to
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`degradation with a nuclease.” EX1001, 11:41-44. The ’069 patent describes
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`nucleic acid encapsulation in the lipid particle as conferring resistance to such
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`enzymatic degradation. EX1001, 11:10-12 (“[T]he active agent or therapeutic
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`agent may be encapsulated in the lipid, thereby protecting the agent from
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`enzymatic degradation.”); see also EX2009, 4:15-19 (describing resistance to
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`nuclease enzymatic degradation as indicating nucleic encapsulation in the
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`liposomes).
`
`34. Moreover, I have been informed that during prosecution of the
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`underlying application of the ’069 patent the applicants specifically touted
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`encapsulation of the nucleic acid. For example, applicants explained that the
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`claimed “SNALP formulations advantageously impart increased activity of the
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`encapsulated nucleic acid (e.g., an interfering RNA such as siRNA) and improved
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`tolerability of the formulations in vivo.” EX1016, 38 (emphasis in original).
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`-10-
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`Encapsulation was also argued in the ’739 IPR. In my opinion, that prosecution
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`history reinforces the teaching of the specification that the claimed nucleic acid-
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`lipid particles necessarily require encapsulation of the nucleic acid.
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`35.
`
`I have been further informed that Dr. Janoff does not undertake his
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`own claim construction analysis in his declaration. EX1008, ¶88. Rather he
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`merely adopts the Board’s preliminary construction in the ’739 IPR. Id.
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`36. As I previously testified, I believe that construction is unduly broad as
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`it relies on an incomplete reading of the specification and would seem to
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`encompass an empty lipid particle. The portion of the specification relied upon by
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`the Board in its construction of “nucleic acid-lipid particle” is directed at the term
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`“lipid particle,” and not “nucleic acid-lipid particle” as required by the claims. ’739
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`IPR, Paper 15 (Institution Decision), 10-11.
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`37. As disclosed in the ’069 specification, a “lipid particle” “may [include
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`a nucleic acid] encapsulated in the lipid portion of the particle, thereby protecting it
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`from enzymatic degradation.” EX1001, 11:4–12. A “nucleic acid-lipid particle,”
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`however, does include a nucleic acid encapsulated in the lipid portion of the
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`particle, thereby protecting it from enzymatic degradation. EX1001, 11:22-32,
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`11:51-55.
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`-11-
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`VII. THE PETITION FAILS TO DEMONSTRATE THE OBVIOUSNESS
`OF THE CLAIMS IN VIEW OF OVERLAPPING RANGES
`A. The References Relied Upon Do Not Provide an Affirmative
`Teaching of Lipid Ranges Overlapping with Claimed Ranges
`I understand that the petition materials assert the cited references
`
`38.
`
`disclose ranges for lipid components (cationic lipid, phospholipid, cholesterol,
`
`conjugated lipid) that overlap with the ranges for the lipid components recited in
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`the challenged claims of the ’069 patent. See e.g., EX1008, ¶119 (“given the
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`explicit disclosure of encompassing ranges, this limitation is prima facie
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`obvious…”); Pet. 33 (same).
`
`39.
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`I have reviewed the cited references and am unable to find disclosure
`
`of lipid ranges corresponding to all the lipid components in the challenged claims.
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`For example, claim 1 of the ’069 patent recites phospholipid “from 4 mol % to 10
`
`mol % of the total lipid present in the particle,” yet none of the cited references
`
`disclose a phospholipid range that overlaps with this claimed range. In fact, none
`
`of the ’196 PCT or ’189 Publication (Ground 1) or the ’554 Publication (Ground 3)
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`affirmatively discloses a phospholipid range at all. Besides no express disclosure
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`of a phospholipid range, the assumptions made in the petition materials to contrive
`
`a phospholipid range are unwarranted and unreasonable.
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`-12-
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`
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`1. Ground 1—The ’196 PCT and the ’189 Publication Fail to
`Disclose the Phospholipid Range of Claim 1
`40. Dr. Janoff addresses the claimed phospholipid range in ¶¶118-119 of
`
`his declaration. I have reviewed that testimony and the citations therein, and
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`neither the ’196 PCT or the ’189 publication expressly disclose a phospholipid
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`range.
`
`41. Dr. Janoff relies on the disclosure of a range for non-cationic lipid of
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`from 20% to about 85% of the total lipid present in the particle. EX1008, ¶118
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`(citing EX1003, ¶¶89, 91; EX1004, ¶¶152, 159). The ’196 PCT disclosure is not
`
`limited to phospholipids; rather, phospholipids are merely an example of a non-
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`cationic lipid component that may be used. In addition, the non-cationic lipid range
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`disclosed by the ’196 PCT does not even comes close to the claimed 4-10% range.
`
`42. Similarly, ’189 publication states that the non-cationic lipid “typically
`
`comprises from about 5 mol % to about 90 mol %, from about 10 mol % to about
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`85 mol %, from about 20 mol % to about 80 mol %, from about 30 mol% to about
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`70 mol %, from about 40 mol % to about 60 mol % or about 48 mol% of the total
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`lipid present in the particle,” again failing to expressly teach a phospholipid range,
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`or a range that is close to the claimed 4-10% range. EX1004, ¶152.
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`43. Dr. Janoff’s reliance of the ’618 patent does not cure the above
`
`deficiencies. Specifically, Dr. Janoff relies on the nucleic acid lipid complex with
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`56% cationic lipid, 14% phospholipid and 30% cholesterol. EX1008, ¶118 (citing
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`-13-
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`

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`EX1017, 34:54-35:23). Dr. Janoff, however, does not explain how a complex
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`having 14% phospholipid suggests his range of 0 to 20% phospholipid. Dr. Janoff
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`also does not explain how that complex relates to the claimed particles, as the
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`phospholipid amount of 14% does not fall within the claimed range of 4-10%, and
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`the particle does not contain a conjugated lipid as required by the claims.
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`44. Thus, neither the ’189 PCT or the ’189 publication expressly disclose
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`any range for a phospholipid component. It is also my opinion that to the extent
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`that Dr. Janoff attempts to manufacture a phospholipid range (e.g., EX1008,
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`¶¶118-119), that manufactured range is based on unwarranted and unreasonable
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`assumptions grounded in the use of hindsight.
`
`45. Petitioner provides the following Table:
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`
`
`Cationic Lipid
`
`Cholesterol
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`Phospholipid PEG
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`’069 claims
`
`50-65%
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`Prior disclosures 60%
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`30-40%
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`20-40%
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`4-10%
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`0.5-2%
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`0-19.5%
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`0.5-25%
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`Pet. 39.
`46. The choice of 60% cationic lipid is unexplained. Dr. Janoff does not
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`provide any reason for its selection (e.g., EX1008, ¶¶118-119), and it is my
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`understanding that the only reason provided in the petition is that it is at the high
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`end of the disclosed range (Pet. 39). Setting the cationic lipid at 60% serves as the
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`linchpin for the remainder of Dr. Janoff’s analysis.
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`47. Dr. Janoff, however, does not account for the amount of conjugated
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`lipid in his declaration. Based on the table above, accommodating 19.5%
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`phospholipid is only mathematically possible if assuming the highest possible
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`cationic lipid (60%) together with the lowest possible cholesterol (20%) and lowest
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`possible conjugated lipid (0.5%). There is no explanation for any of this, which
`
`appears driven by hindsight. Moreover, selecting the highest possible cationic
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`lipid (60%) together with the lowest possible number in the ranges for conjugated
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`lipid disclosed by the ’196 PCT and the ’189 publication would have been viewed
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`as counterintuitive.
`
`48. 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 ’069
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`patent, such as 10% PEG (i.e., 5- to 20-times more than the claimed formulations).
`
`For example, Doxil, the first FDA approved liposome formulation contained 5%
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`PEG-conjugated lipid. EX2034. Likewise, lipid particles for the delivery of nucleic
`
`acids commonly used 10% PEG. EX2035, 174; EX2036, 1021; EX1003, ¶¶216,
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`223, 228, 232.
`
`49. The ’196 PCT also discloses exemplary compositions with conjugated
`
`lipid. Those compositions are consistent with the understanding in the art, and all
`
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`
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`have much higher levels of conjugated lipid than is claimed. See EX1003, ¶¶216,
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`223, 228, 232 (examples of particles all having 10% conjugated PEG-lipid).
`
`50.
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`In addition, Dr. Janoff’s testimony is not consistent with the petition.
`
`As can be seen in the Table reproduced above in ¶46, the petition asserts a
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`phospholipid range of 0-19.5% (which includes an assumption 0.5% conjugated
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`lipid), while Dr. Janoff asserts a range of 0-20% (which does not take into account
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`any amount of conjugated lipid).
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`2. Ground 3—The ’554 Publication Fails to Disclose or
`Suggest the Phospholipid Range of Claim 1
`51. Dr. Janoff addresses the claimed phospholipid range in ¶¶157-158 of
`
`his declaration. I have reviewed that testimony and the citations therein, and
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`neither expressly disclose a phospholipid range.
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`52. Dr. Janoff relies on the disclosure of a range for non-cationic lipid of
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`from 20% to about 85% of the total lipid present in the particle. EX1008, ¶157
`
`(citing EX1005, ¶¶313, 315, 455). Like the ’196 PCT, the disclosure of the ’554
`
`publication is not limited to phospholipids; rather, phospholipids are merely an
`
`example of a noncationic lipid component that may be used. Specifically, the non-
`
`cationic lipid may be any of a variety of neutral uncharged, zwitterionic, or anionic
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`lipids that are capable of producing a stable complex. EX1008, ¶157 (citing
`
`EX1005, ¶¶313, 315, 455). In addition, the disclosed non-cationic lipid ranges do
`
`not even come close to the claimed 4-10% range.
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`53. Dr. Janoff’s reliance on the L106 formulation of Table IV as including
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`cholesterol at a 30% proportion does not cure the above deficiencies. EX1008,
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`¶157. The L106 formulation contains 67% DMOBA (cationic lipid), 30%
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`cholesterol, and 3% 2KPEG-Cholesterol, but does not contain any phospholipid.
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`EX1005, Table IV. Dr. Janoff does not explain why the ordinary artisan would
`
`look to the L106 formulation in formulating particles containing a phospholipid. In
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`addition, both cationic and conjugated lipid amounts are outside the claimed
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`ranges, and Dr. Janoff does not explain the relevance of such a formulation to the
`
`claimed particles.
`
`54.
`
`It is my understanding that the Board in its Institution Decision also
`
`cites to L054, which “includes the cationic lipid DMOBA, cholesterol, the
`
`phospholipid DSPC, and the [] PEG-n-DMG in a molar ratio of 50/20/28/2.” Paper
`
`8 (“Institution Decision” or “DI”), 36 (citing EX1005, Table IV). But an ordinary
`
`artisan would not understand a single formulation as defining a range for the lipid
`
`components making up that formulation. Neither the Board nor Dr. Janoff explains
`
`how a single formulation having 28% phospholipid suggests a phospholipid range
`
`of 0-20%. Moreover, the percentage of phospholipid is 28%, well above the
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`claimed range of 4-10%.
`
`55. Petitioner provides the following Table:
`
`
`
`Cationic Lipid
`
`Cholesterol
`
`Phospholipid PEG
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`-17-
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`

`
`
`’069 claims
`
`50-65%
`
`’554 Publication 60%
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`30-40%
`
`20-40%
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`4-10%
`
`0-19%
`
`0.5-2%
`
`1-20%
`
`Pet. 58.
`56. The choice of 60% cationic lipid is unexplained. Dr. Janoff does not
`
`provide any reason for its selection (e.g., EX1008, ¶¶157-158), and it is my
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`understanding that the only reason provided by the petition is that it is at the high
`
`end of the disclosed range (Pet. 57). Again, setting the cationic lipid at 60% then
`
`serves as the linchpin for the remainder of Dr. Janoff’s analysis.
`
`57. As with Ground 1, Dr. Janoff again does not account for the amount
`
`of conjugated lipid in his declaration. Based on the table above, accommodating
`
`19% phospholipid is only mathematically possible if assuming the highest possible
`
`cationic lipid (60%) together with the lowest possible cholesterol (20%) and lowest
`
`possible conjugated lipid (1%). There is no explanation for selecting the highest
`
`possible cationic lipid (60%) together with the lowest possible number in the
`
`ranges for conjugated lipid disclosed by the ’554 publication, which would have
`
`been viewed as counterintuitive.
`
`58.
`
`In addition, Dr. Janoff’s testimony is not consistent with the petition.
`
`As can be seen in the Table reproduced in ¶56, above, the petition asserts a
`
`phospholipid range of 0-19% (which takes into account the conjugated lipid) (Pet.
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`
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`57-58), while Dr. Janoff asserts a range of 0-20% (which does not take into
`
`account the conjugated lipid) (EX1008, ¶157).
`
`B.
`
`The Formulation of Nucleic Acid-Lipid Particles Was Not a
`Matter of Routine Optimization
`59. As explained in detail below and illustrated throughout the literature
`
`at the time, developing lipid carrier particles for nucleic acids was by no means
`
`considered a simple or routine matter of optimizing variables. Those in the field at
`
`the time had been struggling for years to find active formulations that were not
`
`prohibitively toxic. Moreover, such lipid particles are multi-component systems.
`
`The interaction of the various components was not well understood at the time and
`
`there was little guidance available in the art. I have seen nothing in the record
`
`demonstrating otherwise.
`
`60. Dr. Janoff’s declaration includes only a single conclusory sentence
`
`regarding determining an “optimal proportion” of cationic lipid, one component of
`
`the formulation. EX1008, ¶112. Dr. Janoff cites nothing to support this incorrect
`
`and conclusory statement.
`
`61.
`
`It is my opinion that at the time of invention formulating nucleic acids
`
`was not a matter of simple optimization. Varying a single component in a
`
`multicomponent system was simply not a viable strategy at the time. In fact, both