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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. IN SUPPORT OF
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`
`
`
`PROTIVA - EXHIBIT 2040
`Moderna Therapeutics, Inc. v. Protiva Biotherapeautics, Inc.
`IPR2018-00739
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`QUALIFICATIONS ........................................................................................ 1
`I.
`SCOPE OF WORK.......................................................................................... 2
`II.
`III. LEGAL STANDARDS ................................................................................... 3
`IV. CLAIM CONSTRUCTION ............................................................................ 6
`V. WRITTEN DESCRIPTION SUPPORT FOR AMENDED CLAIMS ........... 7
`VI. THE AMENDMENTS ARE RESPONSIVE TO THE GROUNDS OF
`CHALLENGE ............................................................................................... 15
`A.
`“serum-stable” ..................................................................................... 16
`B.
`“a cationic lipid comprising from 50 mol % to 75 mol % of the
`total lipid present in the particle” ........................................................ 20
`“wherein the particle is formulated such that that the nucleic
`acid is not substantially degraded after exposure of the particle
`to a nuclease at 37ºC for 20 minutes” ................................................. 21
`VII. CONCLUDING STATEMENTS .................................................................. 23
`
`
`C.
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`-i-
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`I, David H. Thompson, declare as follows:
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`I.
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`QUALIFICATIONS
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`1.
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` 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.
`
`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 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.
`
`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.
`
`SCOPE OF WORK
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`7.
`
`I understand that a petition was filed with the United States Patent and
`
`Trademark Office for inter partes review of U.S. Patent No. 9,364,435 (“the ’435
`
`patent,” EX1001).
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`8.
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`I further understand that the Patent Trial and Appeal Board (“PTAB”
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`or the “Board”) has decided to institute inter partes review of claims 1-20 of the
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`’435 patent based on the disclosures of WO2005/007196 (“the ’196 PCT,”
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`EX1002); U.S. Patent Publication No. 2006/134189 (“the ’189 PCT,” EX1003);
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`Lin, Alison J. 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, 84 BIOPHYSICAL JOURNAL 3307 (2003)
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`(“Lin,” EX1005); Ahmad, Ayesha et al., New multivalent cationic lipids reveal bell
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`curve for transfection efficiency versus membrane charge density: lipid–DNA
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`complexes for gene delivery, 7 J GENE MED 739 (2005) (“Ahmad,” EX1006); and
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`U.S. Patent Publication No. 2006/0240554 (“the ’554 publication,” EX1004).
`
`9.
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`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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`-2-
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`
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`petition. I have also been asked to provide my opinion on the patentability of
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`substitute claims that have been submitted to the Board in Patent Owner’s
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`Contingent Motion to Amend. In connection with this analysis, I have reviewed the
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`’435 patent and the prior art cited against the patentability of claims 1-20. I have
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`also reviewed and considered the petition, Dr. Janoff’s Declaration and deposition
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`transcript, and the Board’s Decision on Institution of Inter Partes Review, and may
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`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
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`11.
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`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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`-3-
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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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`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 secondary
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`evidence bearing on obviousness.
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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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`-4-
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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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`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 secondary considerations of nonobviousness, I have
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`been advised that any objective evidence may be considered as an indication that
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`the claimed invention would not have been obvious at the time the claimed
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`-5-
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`invention was made. I understand that the purpose of secondary considerations is
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`to prevent a hindsight analysis of the obviousness of the claims.
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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 a secondary consideration. 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.
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`I have been further advised that in order for evidence of secondary
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`considerations to be significant, there must be a sufficient nexus between the
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`claimed invention and the evidence of secondary considerations. I understand that
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`this nexus serves to provide a link between the merits of the claimed invention and
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`the evidence of secondary considerations provided.
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`22.
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`I have been advised of the requirement for a written description of the
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`invention. This requirement is satisfied when the application describes the claimed
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`invention in sufficient detail that one skilled in the art can reasonably conclude that
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`the inventor had possession of the claimed invention. I understand that newly
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`added claim limitations must be supported in the specification through express,
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`implicit, or inherent disclosure.
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`IV. CLAIM CONSTRUCTION
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`23. My opinions herein are based on the plain and ordinary meaning of
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`the claims as would be understood by a person of ordinary skill in the art in view
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`of the specification. I note that the term “serum-stable” is defined in the
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`-6-
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`
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`specification of the ’435 patent. EX1001, 13:32-35 (“‘Serum-stable’ in relation to
`
`nucleic acid-lipid particles such as SNALP means that the particle is not
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`significantly degraded after exposure to a serum or nuclease assay that would
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`significantly degrade free DNA or RNA.”).
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`V. WRITTEN DESCRIPTION SUPPORT FOR AMENDED CLAIMS
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`24. The ’435 patent was filed Aug. 18, 2014, as U.S. Application No.
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`14/462,441 (“the ’441 application,” EX2045). The ’435 patent also claims priority
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`through a series of three continuation applications: U.S. Application No.
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`13/928,309 filed June 26, 2013, (“the ’309 application,” EX2044); U.S.
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`Application No. 13/253,917 filed October 5, 2011, (“the ’917 application,”
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`EX2043); and U.S. Application No. 12/424,367 filed April 15, 2009 (“the ’367
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`application,” EX2042). The ’441 application, as well as each continuation, further
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`claims priority to Provisional Application No. 61/045,228 filed April 15, 2008
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`(“the ’228 provisional,” EX2041).
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`25.
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`I have reviewed the content of the applications referenced above for
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`disclosure of the invention claimed in the proposed substitute claims. As explained
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`in further detail below, it is my opinion that each of these applications disclose the
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`invention claimed in the proposed substitute claims such that a person of skill
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`would recognize that the inventors were in possession of the claimed invention.
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`-7-
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`26.
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`I note that the ’441 application, the ’309 application, the ’917
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`application, and the ’367 application are substantially identical—i.e., the
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`applications have identical specifications and even identical original claims in
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`some instances. Thus, in my analysis below I provide citations to exemplary
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`written description support in the ’441 application and the ’228 provisional. Where
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`citations are provided for the ’441 application, the same support can also be found
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`in the three continuations applications (the ’309 application, the ’917 application,
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`and the ’367 application) at the same cited paragraphs.
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`27.
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`I understand that a full claim listing of the proposed substitute claims
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`has been provided in Appendix A of Patent Owner’s Motion to Amend.
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`28. Proposed substitute claim 21 claims a serum-stable nucleic acid-lipid
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`particle. Specifically, substitute claim 21 recites:
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`21. A serum-stable nucleic acid-lipid particle comprising:
`(a) a nucleic acid;
`(b) a cationic lipid comprising from 50 mol % to 75 mol % of
`the total lipid present in the particle;
`(c) a non-cationic lipid comprising from 23 mol % to 49.5
`mol% of the total lipid present in the particle; and
`(d) a conjugated lipid that inhibits aggregation of particles
`comprising from 0.5 mol % to 2 mol % of the total lipid present in the
`particle;
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`-8-
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`
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`wherein the particle is formulated such that that the nucleic acid
`is not substantially degraded after exposure of the particle to a
`nuclease at 37ºC for 20 minutes.
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`The claimed lipid particles are disclosed in the ’228 and ’367 applications, as well
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`as the other continuation applications. Moreover, these earlier disclosures would
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`convey to a person of ordinary skill in the art possession of the claimed invention.
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`29. The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of “a serum-stable nucleic acid-lipid particle.” For
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`example, the inventive lipid particles are described as serum-stable nucleic acid-
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`lipid particles. EX2041 ¶90 (“‘Serum-stable’ in relation to nucleic acid-lipid
`
`particles means that the particle is not significantly degraded after exposure to a
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`serum or nuclease assay that would significantly degrade free DNA or RNA.”);
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`EX2045 ¶89 (“‘Serum-stable’ in relation to nucleic acid-lipid particles such as
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`SNALP means that the particle is not significantly degraded after exposure to a
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`serum or nuclease assay that would significantly degrade free DNA or RNA.”); see
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`also EX2041 ¶¶90, 176, 183, 187, 196; EX2045 ¶¶14, 17, 22, 49, 94, 141, 149,
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`194, 240, 287, 307.
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`30. The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a
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`nucleic acid.” Specifically the earlier applications disclose that the inventive lipid
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`particles are “stable nucleic acid-lipid particles encapsulating a nucleic acid.”
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`-9-
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`
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`EX2041 ¶10; EX2045 ¶17 (“[T]he present invention provides serum-stable nucleic
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`acid-lipid particles (SNALP) comprising a nucleic acid…”); see also EX2041
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`¶¶19, 25-29; EX2045 ¶¶17-18, 61, 76, 140, 289, 307, 329, 331.
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`31. The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a
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`cationic lipid comprising from 50 mol % to 75 mol % of the total lipid present in
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`the particle.” Specifically, the ’228 provisional explains that “[t]he cationic lipid
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`typically comprises from … about 50 mol % to about 75 mol % … of the total lipid
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`present in the particle.” EX2041 ¶14; EX2045 ¶247 (same); see also EX2041
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`¶139; EX2045 ¶116.
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`32.
`
` The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a non-
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`cationic lipid comprising from 23 mol % to 49.5 mol% of the total lipid present in
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`the particle.” EX2041 ¶¶21, 22, 146, Tables 2, 4, 6; see also EX2045 ¶¶126, 129,
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`131, Tables 2, 4, 6.
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`33. The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of a serum-stable nucleic acid-lipid particle comprising
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`“a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol
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`% to 2 mol % of the total lipid present in the particle.” For example, the ’228
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`application discloses “a conjugated lipid that inhibits aggregation of particles
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`-10-
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`
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`comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the
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`particle.” EX2041 ¶10; EX2045 ¶284 (same); see also EX2041 ¶¶18, 173; EX2045
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`¶¶18, 139.
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`34. The earlier-filed applications would convey to a person of ordinary
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`skill in the art possession of a serum-stable nucleic acid-lipid particle comprising
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`“wherein the particle is formulated such that that the nucleic acid is not
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`substantially degraded after exposure of the particle to a nuclease at 37ºC for 20
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`minutes.” For example the ’228 application expressly states that “the nucleic acid
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`in the nucleic acid-lipid particle is not substantially degraded after exposure of the
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`particle to a nuclease at 37°C for 20 minutes.” EX2041 ¶¶19; EX2045 ¶140
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`(same); see also EX2041 ¶¶19, 22, claim 25. Moreover, the earlier-filed
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`applications expressly state that “‘[s]erum-stable’ in relation to nucleic acid-lipid
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`particles means that the particle is not significantly degraded after exposure to a
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`serum or nuclease assay that would significantly degrade free DNA or RNA.
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`Suitable assays include, for example, a standard serum assay, a DNAse assay, or an
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`RNAse assay.” EX2041 ¶90; EX2045 ¶89 (same).
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`35. Accordingly, a person of ordinary skill in the art would understand
`
`claim 21 to have sufficient written description support in the original and earlier
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`disclosures of the ’435 patent, including the ’228 and ’367 applications.
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`-11-
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`
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`36. Claims 22 through 40 are amended only with respect to their
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`dependency. The table below summarizes exemplary written description support
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`for claims 22-40 in the ’228 and ’367 applications. As mentioned, where citations
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`are provided for the ’367 application, the same support can also be found in the
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`three continuations applications at the same cited paragraphs.
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`Claims
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`Specification Support
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`22. The nucleic acid-lipid particle of claim 21, wherein
`the nucleic acid comprises an interfering RNA, mRNA,
`an antisense oligonucleotide, a ribozyme, a plasmid, an
`immunostimulatory oligonucleotide, or mixtures
`thereof.
`
`EX2041 ¶¶11, 70, 113-
`120; EX2045 ¶¶5, 53,
`69, 74, 97, 161, 228-230
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`23. The nucleic acid-lipid particle of claim 22, wherein
`the interfering RNA comprises a small interfering RNA
`(siRNA), an asymmetrical interfering RNA (aiRNA), a
`microRNA (miRNA), or mixtures thereof.
`
`EX2041 ¶¶74, 55, 95,
`109, Table 1; EX2045
`¶¶5, 69, 151-152, 209-
`219
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`24. The nucleic acid-lipid particle of claim 21, wherein
`the cationic lipid comprises from 50 mol % to 65 mol %
`of the total lipid present in the particle.
`
`EX2041 ¶¶10, 14, 139;
`EX2045 ¶¶16, 18, 48,
`116, 247
`
`25. The nucleic acid-lipid particle of claim 21, wherein
`the non-cationic lipid comprises a mixture of a
`phospholipid and cholesterol or a derivative thereof.
`
`EX2041 ¶¶15, 16, 21-
`22, 141-149; EX2045
`¶¶20, 122, 133-134,
`146, 256-258
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`-12-
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`
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`26. The nucleic acid-lipid particle of claim 25, wherein
`the phospholipid comprises
`dipalmitoylphosphatidylcholine (DPPC),
`distearoylphosphatidylcholine (DSPC), or a mixture
`thereof.
`
`EX2041 ¶¶16, 22, 142,
`149, 243, Tables 2, 4, 6,
`claim 18; EX2045 ¶¶79,
`124, 250, 258
`
`27. The nucleic acid-lipid particle of claim 25, wherein
`the phospholipid comprises from 3 mol % to 15 mol %
`of the total lipid present in the particle.
`
`EX2041 ¶¶16, 149, 231,
`Tables 2, 4, 6, claim 16;
`EX2045 ¶133
`
`28. The nucleic acid-lipid particle of claim 25, wherein
`the cholesterol or derivative thereof comprises from 30
`mol % to 40 mol % of the total lipid present in the
`particle.
`
`EX2041 ¶¶15, 16, 147-
`148; EX2045 ¶¶125,
`132-133, 258
`
`29. The nucleic acid-lipid particle of claim 21, wherein
`the conjugated lipid that inhibits aggregation of particles
`comprises a polyethyleneglycol (PEG)-lipid conjugate.
`
`EX2041 ¶¶17-18, 74,
`78, 150-53; EX2045
`¶¶135, 138-139
`
`30. The nucleic acid-lipid particle of claim 29, wherein
`the PEG-lipid conjugate comprises a PEG-
`diacylglycerol (PEG-DAG) conjugate, a PEG-
`dialkyloxypropyl (PEG-DAA) conjugate, or a mixture
`thereof.
`
`EX2041 ¶¶18, 21-22,
`151, 161, 163, 192;
`EX2045 ¶¶135, 145-
`146, 260-261, 273-274,
`303
`
`31. The nucleic acid-lipid particle of claim 30, wherein
`the PEG-DAA conjugate comprises a PEG-
`dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-
`
`EX2041 ¶¶18, 163, 195,
`231, 287, 301-9;
`EX2045 ¶¶135, 274,
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`-13-
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`
`
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`distearyloxypropyl (PEG-DSA) conjugate, or a mixture
`thereof.
`
`412
`
`32. The nucleic acid-lipid particle of claim 21, wherein
`the conjugated lipid that inhibits aggregation of particles
`comprises from 1 mol % to 2 mol % of the total lipid
`present in the particle.
`
`EX2041 ¶¶10, 21-22,
`173; EX2045 ¶¶18, 139,
`145-146
`
`33. The nucleic acid-lipid particle of claim 21, wherein
`the nucleic acid is fully encapsulated in the nucleic acid-
`lipid particle.
`
`EX2041 ¶¶10, 19, 74,
`77, 202; EX2045 ¶¶15,
`74, 76, 96, 140-142,
`163, 239, 313
`
`34. A pharmaceutical composition comprising a nucleic
`acid-lipid particle of claim 21 and a pharmaceutically
`acceptable carrier.
`
`EX2041 ¶¶23, 27, 198-
`199, 207; EX2045 ¶¶21,
`148, 318
`
`35. A method for introducing a nucleic acid into a cell,
`the method comprising: contacting the cell with a
`nucleic acid-lipid particle of claim 21.
`
`EX2041 ¶¶24-25, 196;
`EX2045 ¶¶22, 149, 307
`
`36. A method for the in vivo delivery of a nucleic acid,
`the method comprising: administering to a mammalian
`subject a nucleic acid-lipid particle of claim 21.
`
`EX2041 ¶¶24, 28-29,
`203, claims 46, 48;
`EX2045 ¶¶23-24, 149
`
`37. A method for treating a disease or disorder in a
`mammalian subject in need thereof, the method
`comprising: administering to the mammalian subject a
`therapeutically effective amount of a nucleic acid-lipid
`
`EX2041 ¶¶29, 58;
`EX2045 ¶¶24, 57, 151
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`-14-
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`
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`particle of claim 21.
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`38. The method of claim 37, wherein the disease or
`disorder is a viral infection.
`
`EX2041 ¶¶121-22, 125;
`EX2045 ¶¶195-196,
`199, 212, 218
`
`39. The method of claim 37, wherein the disease or
`disorder is a liver disease or disorder.
`
`EX2041 ¶¶2, 121, 126;
`EX2045 ¶¶6, 195, 200
`
`40. The method of claim 37, wherein the disease or
`disorder is cancer.
`
`EX2041 ¶¶2, 9, 94, 129,
`219, 234, 287; EX2045
`¶¶6, 13, 93, 195, 330
`
`37. Accordingly, a person of ordinary skill in the art would understand
`
`claims 22-40 to have sufficient written description support in the ’228 and ’367
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`applications, and that such support is carried through the entire chain of priority
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`applications.
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`VI. THE AMENDMENTS ARE RESPONSIVE TO THE GROUNDS OF CHALLENGE
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`38. A person of ordinary skill in the art would recognize that the
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`additional limitations in substitute claim 21 relative to original claim 1 further
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`distinguish the substitute claim over the prior art cited in the petition materials.
`
`Specifically, the prior art fails to teach a serum-stable nucleic acid-lipid particle
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`having cationic lipid levels in the range of 50 mol % to 75 mol %, wherein the
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`particle is formulated such that that the nucleic acid is not substantially degraded
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`after exposure of the particle to a nuclease at 37ºC for 20 minutes.
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`-15-
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`
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`A.
`“serum-stable”
`39. The “serum-stable” limitation is responsive to arguments presented in
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`the petition and the institution decision.
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`40. A person of skill in the art would understand that serum stability of
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`nucleic acid-lipid particles is a concern if the particles will interact with serum,
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`such as when the particles are administered systemically (e.g., intravenously).
`
`The ’435 patent describes serum stability as a property of nucleic acid-lipid
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`particles intended for systemic use.
`
`“Systemic delivery,” as used herein, refers to delivery of lipid
`particles that leads to a broad biodistribution of an active agent or
`therapeutic agent such as an interfering RNA within an
`organism. …To obtain broad biodistribution generally requires a
`blood life time such that the agent is not rapidly degraded or cleared
`(such as by first pass organs (liver, lung, etc.) or by rapid, nonspecific
`cell binding) before reaching a disease site distal to the site of
`administration.
`
`EX1001, 13:38-49. Moreover, the ’435 patent describes serum-stable nucleic acid-
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`lipid particles as “extremely useful for systemic applications” which “can exhibit
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`extended circulation lifetimes following intravenous (i.v.) injection.” Id., 11:36-38.
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`By contrast, serum stability is not necessary for nucleic acid-lipid particles
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`intended for in vitro or local delivery of nucleic acids to cells. See, e.g., EX1008 at
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`4 (“Most of our understanding of lipid-mediated gene delivery derives from
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`characterization work on lipoplexes prepared in low-salt solution and transfection
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`tests on cells in the absence of interfering substances such as serum.”).
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`41. The prior art cited in the petition and by Dr. Janoff does not disclose
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`serum-stable nucleic acid-lipid particles with cationic lipid levels greater than 50
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`mol %. That is, to the extent that the prior art discloses lipid particles formulated
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`for systemic administration, none of these formulations are within the scope of
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`claim 21.
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`42. For example, in Ground 1, the petition relies on ranges of cationic
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`lipid that would not be expected to be suitable for systemic administration.
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`Specifically the petition and Dr. Janoff rely on cationic lipid ranges of about 2% to
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`about 60% and about 40% to about 50%. EX1007 ¶110 (citing EX1002 ¶88). The
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`former range is not indicated for any particular use and the latter is indicated only
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`for local delivery. See EX1002 ¶88. But the ’196 PCT teaches that the proportions
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`of lipid components should depend on use and, for systemic use, nucleic acid-lipid
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`particles should contain between 5% and 15% cationic lipid.
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`Depending on the intended use of the nucleic acid-lipid particles, the
`proportions of the components are varied …. For example, for
`systemic delivery, the cationic lipid may comprise from about 5% to
`about 15% of the total lipid present ….
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`EX1002 ¶88. That is, the nucleic acid-lipid particles of the ’196 PCT that are
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`formulated for systemic use have cationic lipid levels outside the scope of claim
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`21.
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`43. With respect to Ground 2, the petition and Dr. Janoff argue that a
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`person of skill in the art would have increased the cationic lipid level in nucleic
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`acid-lipid particles of the ’196 PCT according to the levels present in the lipoplex
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`formulations of Lin and Ahmad. See, e.g., EX1007 ¶139 (“A POSITA would
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`understand the testing of Lin to suggest that the cationic lipid mol% of nucleic
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`acid-lipid particles can impact transfection efficiency and that for certain lipid
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`components a mol% greater than 50% may increase the transfection efficiency of
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`the carrier particles.”). However, it was understood at the time that lipoplexes were
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`not suitable for systemic use. The lipoplex formulations of Lin and Ahmad are
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`described as not suitable for transfecting cells in the presence of serum. EX1005 at
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`9 (“However, the current work is not expected to be predictive of transfection
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`behavior in blood for systemic in vivo applications in the presence of serum.”);
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`EX1006 at 747 (describing results as relevant for ex vivo applications only). A
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`person of ordinary skill in the art would not have had reason to modify prior art
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`nucleic acid-lipid particles based on formulations that were known to be unsuitable
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`for systemic delivery.
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`44. With respect to Ground 3, the petition and Dr. Janoff do not address
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`whether L054-derived nanoparticles are formulated for systemic administration.
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`The ’554 publication distinguishes between embodiments formulated for in vitro
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`use and those formulated for in vivo use. See, e.g., EX1004 ¶¶136, 462.
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`Furthermore, the ’554 publication stresses that serum-stability is a critical property
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`of in vivo formulations. See, e.g., EX1004 ¶¶14, 15, 158. However, L054 was only
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`tested in vitro. See EX1004 ¶395 (“FIG. 16 shows a non-limiting example of in
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`vitro efficacy of siNA nanoparticles …”) (emphasis added). Specifically, the L054
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`formulation was not evaluated for serum stability — a property identified as
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`critical for embodiments formulated for systemic (in vivo) use. See EX1004 ¶158
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`(providing a serum stability test “for determining whether a formulated molecular
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`composition will be effective for delivery of a biologically active molecule into a
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`biological system, …”), ¶592 (Example 7 Evaluation of Serum Stability of
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`Formulated siNA Compositions). Furthermore, while another exemplary
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`formulation (outside the scope of the ’435 claims) was tested in vivo, the L054
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`formulation was not. EX1004 ¶596.
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`45. Furthermore, a person of ordinary skill in the art would have expected
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`particles derived from L054 to be too toxic for systemic use. Such a skilled artisan
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`would have expected DMOBA, the cationic lipid used in the L054 lipid mixture
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`(see Table IV), to be toxic. In particular, a person of ordinary skill in the art would
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`have appreciated that the dimethylamino group on the aryl ring is a good leaving
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`group upon protonation and, as such, has potential to alkylate cysteines and lysines
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`on cellular proteins. See EX1004, Table IV (DMOBA structure). Additionally,
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`DMOBA would have been expected to accumulate in liver and spleen because the
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`arylether groups would be expected to make elimination through mammalian
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`detoxification pathways more difficult. The resulting accumulation and protein
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`modifications would result in organ toxicity rendering formulations using DMOBA
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`inappropriate for systemic use.
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`B.
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` “a cationic lipid comprising from 50 mol % to 75 mol % of the
`total lipid present in the particle”
`46. Narrowing the range of cationic lipid to 50 mol % to 75 mol % (and
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`non-cationic lipid to 23 mol % to 49.5 mol %) is responsive to Ground 1. The ’435
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`patent discloses efficacy and tolerance data for nucleic acid-lipid particles
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`spanning the amended range (i.e., 54 mol % to 70 mol %). See, e.g., EX1001,
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`Table 2, 4, and 6. Furthermore, post-filing date data includes nucleic acid-lipid
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`particle formulations with 50 mol % and 57 mol % cationic lipid. See e.g. EX2017,
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`Figure 7 (testing several 1:57 formulations); EX2018, Figure 5 (same); EX2019
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`¶46, Table 1, (testing the 1:50 formulation directed at the commercial product,
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`Onpattro™ (i.e., patisiran)); Semple et al., Rational Design of Cationic Lipids for
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`siRNA Delivery, 28 Nature Biotechnology 172-178, 177 (2010) (“Semple,”
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`EX2021)(testing 1:57 formulations). That is, the data demonstrating the
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`unexpected efficacy and tolerance of the claimed nucleic acid-lipid particle
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`formulations is nearly co-extensive with the claimed range. The narrowed range
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`further supports a conclusion of nexus with the unexpected results.
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`C.
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`“wherein the particle is formulated such that that the nucleic acid
`is not substantially degraded after exposure of the particle to a
`nuclease at 37ºC for 20 minutes”
`47. The amendment reciting that the serum-stable nucleic acid-lipid
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`particles are those particles that are “formulated such that the nucleic acid is not
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`substantially degraded after exposure of the particle to a nuclease at 37ºC for 20
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`minutes” is responsive to arguments presented in the petition and the institution
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`decision.
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`48. As explained in the ’435 patent, nucleic acids are protected from
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`degradation by a nuclease when encapsulated in serum-stable nucleic acid-lipid
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`particles.
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`In preferred embodiments, a SNALP comprising a nucleic acid such
`as an interfering RNA (e.g., siRNA) is fully encapsulated within the
`lipid portion of the particle, thereby protecting the nucleic acid from
`nuclease degradation. In certain instances, the nucleic acid in the
`SNALP is not substantially degraded after exposure of the particle to
`a nuclease at 37°C. for at least about 20, 30, 45, or 60 minutes.
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`EX1001, 22:55-62, see also id., 47:12-16. A person of ordinary skill in the art
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`would understand that the claimed serum-stable nucleic acid-lipid particles are
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`limited to such particles that can