`
`
`
`
`
`
`
`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.
`
`-i-
`
`
`
`
`
`I, David H. Thompson, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
` I am a Professor of Chemistry at Purdue University and Director of
`
`the Medicinal Chemistry Group in the Purdue Center for Cancer Research. My
`
`primary research interests include development of transiently-stable carrier
`
`systems for drug and nucleic acid delivery.
`
`2.
`
`I received my Ph.D. in Organic Chemistry from Colorado State
`
`University in 1984. I also hold a Bachelor of the Arts in Biology and a Bachelor of
`
`Science in Chemistry from the University of Missouri, Columbia.
`
`3.
`
`I have been a visiting professor at numerous institutions including,
`
`Chulalongkorn University, Department of Pharmaceutics; Technical University of
`
`Denmark, Department of Micro & Nanotechnology; Japan Advanced Institute of
`
`Science & Technology, Department of Biomaterials; Osaka University,
`
`Department of Applied Chemistry; University of Florida, Department of
`
`Pharmaceutics; and University of British Columbia, Department of Biochemistry.
`
`4.
`
`I am listed as a co-inventor on 7 United States patents. I have also
`
`published more than 140 peer reviewed scientific papers.
`
`5.
`
`I have studied, taught, practiced, and conducted research involving the
`
`formulation, use, characterization, and delivery of lipid particles. I have expertise
`
`with the delivery of therapeutic agents using lipid particles.
`
`1
`
`
`
`
`
`6.
`
`A copy of my Curriculum Vitae, attached as EX2010, contains further
`
`details on my education, experience, publications, and other qualifications to
`
`render an expert opinion in this matter.
`
`II.
`
`SCOPE OF WORK
`
`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).
`
`8.
`
`I further understand that the Patent Trial and Appeal Board (“PTAB”
`
`or the “Board”) has decided to institute inter partes review of claims 1-20 of the
`
`’435 patent based on the disclosures of WO2005/007196 (“the ’196 PCT,”
`
`EX1002); U.S. Patent Publication No. 2006/134189 (“the ’189 PCT,” EX1003);
`
`Lin, Alison J. et al., Three-Dimensional Imaging of Lipid Gene-Carriers:
`
`Membrane Charge Density Controls Universal Transfection Behavior in Lamellar
`
`Cationic Liposome-DNA Complexes, 84 BIOPHYSICAL JOURNAL 3307 (2003)
`
`(“Lin,” EX1005); Ahmad, Ayesha et al., New multivalent cationic lipids reveal bell
`
`curve for transfection efficiency versus membrane charge density: lipid–DNA
`
`complexes for gene delivery, 7 J GENE MED 739 (2005) (“Ahmad,” EX1006); and
`
`U.S. Patent Publication No. 2006/0240554 (“the ’554 publication,” EX1004).
`
`9.
`
`I have been specifically asked to provide my expert opinions on the
`
`patentability of the claims of the ’435 patent in view of the asserted Grounds in the
`
`-2-
`
`
`
`
`
`petition. I have also been asked to provide my opinion on the patentability of
`
`substitute claims that have been submitted to the Board in Patent Owner’s
`
`Contingent Motion to Amend. In connection with this analysis, I have reviewed the
`
`’435 patent and the prior art cited against the patentability of claims 1-20. I have
`
`also reviewed and considered the petition, Dr. Janoff’s Declaration and deposition
`
`transcript, and the Board’s Decision on Institution of Inter Partes Review, and may
`
`cite these documents in this declaration.
`
`10.
`
`I am being compensated at a rate of $600 per hour for my work in this
`
`matter. I am also being reimbursed for reasonable and customary expenses
`
`associated with my work in this investigation. My compensation is not contingent
`
`on the outcome of this matter or the specifics of my testimony.
`
`III. LEGAL STANDARDS
`
`11.
`
`I have been advised that a claimed invention is not patentable under
`
`an anticipation theory (35 U.S.C. § 102) if all claim elements are found in a single
`
`prior art reference. I further understand that anticipation is about prior invention
`
`and therefore the single prior art reference must be found to disclose all elements
`
`of the claimed invention arranged as in the claim. I also understand that picking,
`
`choosing, and combining various embodiments disclosed within a single reference
`
`is not proper under an anticipation theory.
`
`-3-
`
`
`
`
`
`12.
`
`I understand that differences between the prior art reference and a
`
`claimed invention, however slight, invoke the question of obviousness, not
`
`anticipation.
`
`13.
`
`I have been advised that a claimed invention is not patentable under
`
`35 U.S.C. § 103 if it is obvious. A patent claim is unpatentable if the claimed
`
`invention would have been obvious to a person of ordinary skill in the field at the
`
`time the claimed invention was made. This means that even if all of the
`
`requirements of the claim cannot be found in a single prior art reference that would
`
`anticipate the claim, a person of ordinary skill in the relevant field who knew about
`
`all this prior art would have come up with the claimed invention.
`
`14.
`
`I have further been advised that the ultimate conclusion of whether a
`
`claim is obvious should be based upon several factual determinations. That is, a
`
`determination of obviousness requires inquiries into: (1) the level of ordinary skill
`
`in the field; (2) the scope and content of the prior art; (3) what difference, if any,
`
`existed between the claimed invention and the prior art; and (4) any secondary
`
`evidence bearing on obviousness.
`
`15.
`
`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,
`
`I should consider: (1) the levels of education and experience of persons working in
`
`-4-
`
`
`
`
`
`the field; (2) the types of problems encountered in the field; and (3) the
`
`sophistication of the technology.
`
`16.
`
`I have been advised that a patent claim composed of several elements
`
`is not proved obvious merely by demonstrating that each of its elements was
`
`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
`
`concepts from the prior art in the same way as in the claimed invention.
`
`17.
`
`I have also been advised, however, that I must be careful not to
`
`determine obviousness using the benefit of hindsight; many true inventions might
`
`seem obvious after the fact. I should put myself in the position of a person of
`
`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
`
`patent.
`
`18. Finally, I have been advised that any obviousness rationale for
`
`modifying or combining prior art must include a showing that a person of ordinary
`
`skill would have had a reasonable expectation of success.
`
`19. With regard to secondary considerations of nonobviousness, I have
`
`been advised that any objective evidence may be considered as an indication that
`
`the claimed invention would not have been obvious at the time the claimed
`
`-5-
`
`
`
`
`
`invention was made. I understand that the purpose of secondary considerations is
`
`to prevent a hindsight analysis of the obviousness of the claims.
`
`20.
`
`I have been advised that there are several factors that may be
`
`considered as a secondary consideration. These factors include the long-felt need,
`
`skepticism, unexpected results and commercial success of the invention.
`
`21.
`
`I have been further advised that in order for evidence of secondary
`
`considerations to be significant, there must be a sufficient nexus between the
`
`claimed invention and the evidence of secondary considerations. I understand that
`
`this nexus serves to provide a link between the merits of the claimed invention and
`
`the evidence of secondary considerations provided.
`
`22.
`
`I have been advised of the requirement for a written description of the
`
`invention. This requirement is satisfied when the application describes the claimed
`
`invention in sufficient detail that one skilled in the art can reasonably conclude that
`
`the inventor had possession of the claimed invention. I understand that newly
`
`added claim limitations must be supported in the specification through express,
`
`implicit, or inherent disclosure.
`
`IV. CLAIM CONSTRUCTION
`
`23. My opinions herein are based on the plain and ordinary meaning of
`
`the claims as would be understood by a person of ordinary skill in the art in view
`
`of the specification. I note that the term “serum-stable” is defined in the
`
`-6-
`
`
`
`
`
`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
`
`significantly degraded after exposure to a serum or nuclease assay that would
`
`significantly degrade free DNA or RNA.”).
`
`V. WRITTEN DESCRIPTION SUPPORT FOR AMENDED CLAIMS
`
`24. The ’435 patent was filed Aug. 18, 2014, as U.S. Application No.
`
`14/462,441 (“the ’441 application,” EX2045). The ’435 patent also claims priority
`
`through a series of three continuation applications: U.S. Application No.
`
`13/928,309 filed June 26, 2013, (“the ’309 application,” EX2044); U.S.
`
`Application No. 13/253,917 filed October 5, 2011, (“the ’917 application,”
`
`EX2043); and U.S. Application No. 12/424,367 filed April 15, 2009 (“the ’367
`
`application,” EX2042). The ’441 application, as well as each continuation, further
`
`claims priority to Provisional Application No. 61/045,228 filed April 15, 2008
`
`(“the ’228 provisional,” EX2041).
`
`25.
`
`I have reviewed the content of the applications referenced above for
`
`disclosure of the invention claimed in the proposed substitute claims. As explained
`
`in further detail below, it is my opinion that each of these applications disclose the
`
`invention claimed in the proposed substitute claims such that a person of skill
`
`would recognize that the inventors were in possession of the claimed invention.
`
`-7-
`
`
`
`
`
`26.
`
`I note that the ’441 application, the ’309 application, the ’917
`
`application, and the ’367 application are substantially identical—i.e., the
`
`applications have identical specifications and even identical original claims in
`
`some instances. Thus, in my analysis below I provide citations to exemplary
`
`written description support in the ’441 application and the ’228 provisional. Where
`
`citations are provided for the ’441 application, the same support can also be found
`
`in the three continuations applications (the ’309 application, the ’917 application,
`
`and the ’367 application) at the same cited paragraphs.
`
`27.
`
`I understand that a full claim listing of the proposed substitute claims
`
`has been provided in Appendix A of Patent Owner’s Motion to Amend.
`
`28. Proposed substitute claim 21 claims a serum-stable nucleic acid-lipid
`
`particle. Specifically, substitute claim 21 recites:
`
`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;
`
`-8-
`
`
`
`
`
`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.
`
`The claimed lipid particles are disclosed in the ’228 and ’367 applications, as well
`
`as the other continuation applications. Moreover, these earlier disclosures would
`
`convey to a person of ordinary skill in the art possession of the claimed invention.
`
`29. The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of “a serum-stable nucleic acid-lipid particle.” For
`
`example, the inventive lipid particles are described as serum-stable nucleic acid-
`
`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
`
`serum or nuclease assay that would significantly degrade free DNA or RNA.”);
`
`EX2045 ¶89 (“‘Serum-stable’ in relation to nucleic acid-lipid particles such as
`
`SNALP means that the particle is not significantly degraded after exposure to a
`
`serum or nuclease assay that would significantly degrade free DNA or RNA.”); see
`
`also EX2041 ¶¶90, 176, 183, 187, 196; EX2045 ¶¶14, 17, 22, 49, 94, 141, 149,
`
`194, 240, 287, 307.
`
`30. The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a
`
`nucleic acid.” Specifically the earlier applications disclose that the inventive lipid
`
`particles are “stable nucleic acid-lipid particles encapsulating a nucleic acid.”
`
`-9-
`
`
`
`
`
`EX2041 ¶10; EX2045 ¶17 (“[T]he present invention provides serum-stable nucleic
`
`acid-lipid particles (SNALP) comprising a nucleic acid…”); see also EX2041
`
`¶¶19, 25-29; EX2045 ¶¶17-18, 61, 76, 140, 289, 307, 329, 331.
`
`31. The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a
`
`cationic lipid comprising from 50 mol % to 75 mol % of the total lipid present in
`
`the particle.” Specifically, the ’228 provisional explains that “[t]he cationic lipid
`
`typically comprises from … about 50 mol % to about 75 mol % … of the total lipid
`
`present in the particle.” EX2041 ¶14; EX2045 ¶247 (same); see also EX2041
`
`¶139; EX2045 ¶116.
`
`32.
`
` The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of a serum-stable nucleic acid-lipid comprising “a non-
`
`cationic lipid comprising from 23 mol % to 49.5 mol% of the total lipid present in
`
`the particle.” EX2041 ¶¶21, 22, 146, Tables 2, 4, 6; see also EX2045 ¶¶126, 129,
`
`131, Tables 2, 4, 6.
`
`33. The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of a serum-stable nucleic acid-lipid particle comprising
`
`“a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol
`
`% to 2 mol % of the total lipid present in the particle.” For example, the ’228
`
`application discloses “a conjugated lipid that inhibits aggregation of particles
`
`-10-
`
`
`
`
`
`comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the
`
`particle.” EX2041 ¶10; EX2045 ¶284 (same); see also EX2041 ¶¶18, 173; EX2045
`
`¶¶18, 139.
`
`34. The earlier-filed applications would convey to a person of ordinary
`
`skill in the art possession of a serum-stable nucleic acid-lipid particle comprising
`
`“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.” For example the ’228 application expressly states that “the nucleic acid
`
`in the nucleic acid-lipid particle is not substantially degraded after exposure of the
`
`particle to a nuclease at 37°C for 20 minutes.” EX2041 ¶¶19; EX2045 ¶140
`
`(same); see also EX2041 ¶¶19, 22, claim 25. Moreover, the earlier-filed
`
`applications expressly state that “‘[s]erum-stable’ in relation to nucleic acid-lipid
`
`particles means that the particle is not significantly degraded after exposure to a
`
`serum or nuclease assay that would significantly degrade free DNA or RNA.
`
`Suitable assays include, for example, a standard serum assay, a DNAse assay, or an
`
`RNAse assay.” EX2041 ¶90; EX2045 ¶89 (same).
`
`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
`
`disclosures of the ’435 patent, including the ’228 and ’367 applications.
`
`-11-
`
`
`
`
`
`36. Claims 22 through 40 are amended only with respect to their
`
`dependency. The table below summarizes exemplary written description support
`
`for claims 22-40 in the ’228 and ’367 applications. As mentioned, where citations
`
`are provided for the ’367 application, the same support can also be found in the
`
`three continuations applications at the same cited paragraphs.
`
`Claims
`
`Specification Support
`
`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
`
`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
`
`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
`
`-12-
`
`
`
`
`
`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,
`
`-13-
`
`
`
`
`
`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
`
`-14-
`
`
`
`
`
`particle of claim 21.
`
`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
`
`applications, and that such support is carried through the entire chain of priority
`
`applications.
`
`VI. THE AMENDMENTS ARE RESPONSIVE TO THE GROUNDS OF CHALLENGE
`
`38. A person of ordinary skill in the art would recognize that the
`
`additional limitations in substitute claim 21 relative to original claim 1 further
`
`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
`
`having cationic lipid levels in the range of 50 mol % to 75 mol %, 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.
`
`-15-
`
`
`
`
`
`A.
`“serum-stable”
`39. The “serum-stable” limitation is responsive to arguments presented in
`
`the petition and the institution decision.
`
`40. A person of skill in the art would understand that serum stability of
`
`nucleic acid-lipid particles is a concern if the particles will interact with serum,
`
`such as when the particles are administered systemically (e.g., intravenously).
`
`The ’435 patent describes serum stability as a property of nucleic acid-lipid
`
`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-
`
`lipid particles as “extremely useful for systemic applications” which “can exhibit
`
`extended circulation lifetimes following intravenous (i.v.) injection.” Id., 11:36-38.
`
`By contrast, serum stability is not necessary for nucleic acid-lipid particles
`
`intended for in vitro or local delivery of nucleic acids to cells. See, e.g., EX1008 at
`
`4 (“Most of our understanding of lipid-mediated gene delivery derives from
`
`-16-
`
`
`
`
`
`characterization work on lipoplexes prepared in low-salt solution and transfection
`
`tests on cells in the absence of interfering substances such as serum.”).
`
`41. The prior art cited in the petition and by Dr. Janoff does not disclose
`
`serum-stable nucleic acid-lipid particles with cationic lipid levels greater than 50
`
`mol %. That is, to the extent that the prior art discloses lipid particles formulated
`
`for systemic administration, none of these formulations are within the scope of
`
`claim 21.
`
`42. For example, in Ground 1, the petition relies on ranges of cationic
`
`lipid that would not be expected to be suitable for systemic administration.
`
`Specifically the petition and Dr. Janoff rely on cationic lipid ranges of about 2% to
`
`about 60% and about 40% to about 50%. EX1007 ¶110 (citing EX1002 ¶88). The
`
`former range is not indicated for any particular use and the latter is indicated only
`
`for local delivery. See EX1002 ¶88. But the ’196 PCT teaches that the proportions
`
`of lipid components should depend on use and, for systemic use, nucleic acid-lipid
`
`particles should contain between 5% and 15% cationic lipid.
`
`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 ….
`
`-17-
`
`
`
`
`
`EX1002 ¶88. That is, the nucleic acid-lipid particles of the ’196 PCT that are
`
`formulated for systemic use have cationic lipid levels outside the scope of claim
`
`21.
`
`43. With respect to Ground 2, the petition and Dr. Janoff argue that a
`
`person of skill in the art would have increased the cationic lipid level in nucleic
`
`acid-lipid particles of the ’196 PCT according to the levels present in the lipoplex
`
`formulations of Lin and Ahmad. See, e.g., EX1007 ¶139 (“A POSITA would
`
`understand the testing of Lin to suggest that the cationic lipid mol% of nucleic
`
`acid-lipid particles can impact transfection efficiency and that for certain lipid
`
`components a mol% greater than 50% may increase the transfection efficiency of
`
`the carrier particles.”). However, it was understood at the time that lipoplexes were
`
`not suitable for systemic use. The lipoplex formulations of Lin and Ahmad are
`
`described as not suitable for transfecting cells in the presence of serum. EX1005 at
`
`9 (“However, the current work is not expected to be predictive of transfection
`
`behavior in blood for systemic in vivo applications in the presence of serum.”);
`
`EX1006 at 747 (describing results as relevant for ex vivo applications only). A
`
`person of ordinary skill in the art would not have had reason to modify prior art
`
`nucleic acid-lipid particles based on formulations that were known to be unsuitable
`
`for systemic delivery.
`
`-18-
`
`
`
`
`
`44. With respect to Ground 3, the petition and Dr. Janoff do not address
`
`whether L054-derived nanoparticles are formulated for systemic administration.
`
`The ’554 publication distinguishes between embodiments formulated for in vitro
`
`use and those formulated for in vivo use. See, e.g., EX1004 ¶¶136, 462.
`
`Furthermore, the ’554 publication stresses that serum-stability is a critical property
`
`of in vivo formulations. See, e.g., EX1004 ¶¶14, 15, 158. However, L054 was only
`
`tested in vitro. See EX1004 ¶395 (“FIG. 16 shows a non-limiting example of in
`
`vitro efficacy of siNA nanoparticles …”) (emphasis added). Specifically, the L054
`
`formulation was not evaluated for serum stability — a property identified as
`
`critical for embodiments formulated for systemic (in vivo) use. See EX1004 ¶158
`
`(providing a serum stability test “for determining whether a formulated molecular
`
`composition will be effective for delivery of a biologically active molecule into a
`
`biological system, …”), ¶592 (Example 7 Evaluation of Serum Stability of
`
`Formulated siNA Compositions). Furthermore, while another exemplary
`
`formulation (outside the scope of the ’435 claims) was tested in vivo, the L054
`
`formulation was not. EX1004 ¶596.
`
`45. Furthermore, a person of ordinary skill in the art would have expected
`
`particles derived from L054 to be too toxic for systemic use. Such a skilled artisan
`
`would have expected DMOBA, the cationic lipid used in the L054 lipid mixture
`
`(see Table IV), to be toxic. In particular, a person of ordinary skill in the art would
`
`-19-
`
`
`
`
`
`have appreciated that the dimethylamino group on the aryl ring is a good leaving
`
`group upon protonation and, as such, has potential to alkylate cysteines and lysines
`
`on cellular proteins. See EX1004, Table IV (DMOBA structure). Additionally,
`
`DMOBA would have been expected to accumulate in liver and spleen because the
`
`arylether groups would be expected to make elimination through mammalian
`
`detoxification pathways more difficult. The resulting accumulation and protein
`
`modifications would result in organ toxicity rendering formulations using DMOBA
`
`inappropriate for systemic use.
`
`B.
`
` “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
`
`non-cationic lipid to 23 mol % to 49.5 mol %) is responsive to Ground 1. The ’435
`
`patent discloses efficacy and tolerance data for nucleic acid-lipid particles
`
`spanning the amended range (i.e., 54 mol % to 70 mol %). See, e.g., EX1001,
`
`Table 2, 4, and 6. Furthermore, post-filing date data includes nucleic acid-lipid
`
`particle formulations with 50 mol % and 57 mol % cationic lipid. See e.g. EX2017,
`
`Figure 7 (testing several 1:57 formulations); EX2018, Figure 5 (same); EX2019
`
`¶46, Table 1, (testing the 1:50 formulation directed at the commercial product,
`
`Onpattro™ (i.e., patisiran)); Semple et al., Rational Design of Cationic Lipids for
`
`siRNA Delivery, 28 Nature Biotechnology 172-178, 177 (2010) (“Semple,”
`
`EX2021)(testing 1:57 formulations). That is, the data demonstrating the
`
`-20-
`
`
`
`
`
`unexpected efficacy and tolerance of the claimed nucleic acid-lipid particle
`
`formulations is nearly co-extensive with the claimed range. The narrowed range
`
`further supports a conclusion of nexus with the unexpected results.
`
`C.
`
`“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
`
`particles are those particles that are “formulated such that the nucleic acid is not
`
`substantially degraded after exposure of the particle to a nuclease at 37ºC for 20
`
`minutes” is responsive to arguments presented in the petition and the institution
`
`decision.
`
`48. As explained in the ’435 patent, nucleic acids are protected from
`
`degradation by a nuclease when encapsulated in serum-stable nucleic acid-lipid
`
`particles.
`
`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.
`
`-21-
`
`
`
`
`
`EX1001, 22:55-62, see also id., 47:12-16. A person of ordinary skill in the art
`
`would understand that the claimed serum-stable nucleic acid-lipid particles are
`
`limited to such particles that can
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
