`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`U.S. Patent No. 9,364,435
`
`Issued: June 14, 2016
`
`Named Inventor: Edward Yaworski, Kieu Lam, Lloyd Jeffs,
`Lorne Palmer, Ian MacLachlan
`
`Title: Lipid Formulations for Nucleic Acid Delivery
`___________
`
`PETITION FOR INTER PARTES REVIEW
`
`OF U.S. PATENT NO. 9,364,435
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
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`

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`TABLE OF CONTENTS
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`Page
`
`INTRODUCTION ........................................................................................ 1 
`I. 
`II.  MANDATORY NOTICES .......................................................................... 4 
`A.  Notice of real party-in-interest (37 C.F.R. § 42.8(b)(1)) ...................... 4 
`B.  Notice of related matters (37 C.F.R. § 42.8(b)(2)) ............................... 4 
`C.  Designation of lead and back-up counsel (37 C.F.R.
`§ 42.8(b)(3)) .......................................................................................... 4 
`D.  Service information (37 C.F.R. § 42.8(b)(4)) ....................................... 4 
`E.  Payment of fees (37 C.F.R. § 42.103) .................................................. 4 
`F.  Certification of grounds for standing (37 C.F.R. § 42.104(a)) ............. 5 
`III.  CHALLENGE AND RELIEF REQUESTED.............................................. 5 
`A.  Ground 1: Claims 1-20 are obvious in view of patent
`owner’s prior disclosures in the ’196 PCT and ’189
`publication............................................................................................. 5 
`B.  Ground 2: Claims 1-20 are obvious in view of patent
`owner’s prior disclosures in light of Lin and/or Ahmad ...................... 5 
`C.  Ground 3: Claims 1-20 are anticipated by or obvious in
`view of the ’554 publication ................................................................. 5 
`IV.  PRIORITY DATE ........................................................................................ 5 
`V. 
`PERSONS HAVING ORDINARY SKILL IN THE ART .......................... 5 
`VI.  BACKGROUND .......................................................................................... 6 
`A.  Lipid carrier particles for nucleic acid payloads .................................. 6 
`B.  The ’435 patent claims are directed to known lipid
`components ........................................................................................... 6 
`C.  The optimal lipid component proportions in a nucleic acid-
`lipid particle varies ................................................................................ 8 
`D.  The intrinsic record shows that the ’435 patent was granted
`on alleged unexpected results that are not applicable to the
`claimed ranges .................................................................................... 12 
`1.  The ’435 Patent: representative claim ........................................ 13 
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`4. 
`
`2.  The ’435 patent: prior art admissions ........................................ 13 
`3. 
`’435 patent: The prosecution history confirms patent
`owner’s reliance on unexpected results ...................................... 14 
`’435 patent: The intrinsic record shows that the certain
`examples of formulations covered by the claims perform
`worse than the prior art ............................................................... 16 
`a)  Example 2 shows that certain in vitro examples of
`claimed formulations performed worse than the
`admitted prior art ................................................................. 17 
`b)  Examples 3-4 show that examples of particles with
`lipid components in the claimed ranges were no more
`effective than examples of formulations with less than
`50% cationic lipid ............................................................... 20 
`5.  The ’435 patent: The testing shows that even slight
`variations of the lipid component proportions and/or the
`species of lipid components impact efficacy .............................. 22 
`VII.  CLAIM CONSTRUCTION ....................................................................... 23 
`A.  Claim 1: “Nucleic acid-lipid particle” ................................................ 24 
`B.  Claim 1: “Cationic Lipid” .................................................................. 24 
`VIII.  PRIOR ART ................................................................................................ 24 
`A.  Patent owner’s prior disclosures are prior art under 35
`U.S.C. § 102(b) ................................................................................... 24 
`B.  The ’554 publication is prior art under 35 U.S.C. § 102(b) ............... 27 
`C.  Lin is prior art under 35 U.S.C. § 102(b) ........................................... 28 
`D.  Ahmad is prior art under 35 U.S.C. § 102(b) ..................................... 30 
`IX.  THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST
`ONE CLAIM OF THE ’435 PATENT IS UNPATENTABLE ................. 32 
`A.  Ground 1: Claims 1-20 are obvious in view of Patent
`Owner’s prior disclosures in the ’196 PCT and
`’189 publication .................................................................................. 32 
`1.  The components in claim 1 are disclosed in the ’196 PCT ........ 33 
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`a)  Claim element 1(a): a nucleic acid-lipid particle
`comprising: .......................................................................... 33 
`b)  Claim element 1(b): a nucleic acid .................................... 33 
`c)  Claim element 1(c): a cationic lipid comprising from
`50 mol% to 85 mol% of the total lipid present in the
`particle ................................................................................. 33 
`d)  Claim element 1(d): a non-cationic lipid comprising
`from 13 mol% to 49.5 mol% of the total lipid present
`in the particle ....................................................................... 38 
`e)  Claim element 1(e): a conjugated lipid that inhibits
`aggregation of particles comprising from 0.5 mol% to
`2 mol% of the total lipid present in the particle. ................. 39 
`2.  Claim 2: the nucleic acid-lipid particle of claim 1, wherein
`the nucleic acid comprises an interfering RNA, mRNA, an
`anti-sense oligonucleotide, a ribozyme, a plasmid, an
`immunostimulatory oligonucleotide, or mixtures thereof .......... 40 
`3.  Claim 3: the nucleic acid-lipid particle of claim 2, wherein
`the interfering RNA comprises a small interfering RNA
`(siRNA), an asymmetrical interfering RNA (aiRNA), a
`microRNA (miRNA), or mixtures thereof .................................. 41 
`4.  Claim 4: the nucleic acid-lipid particle of claim 1, wherein
`the cationic lipid comprises from 50 mol% to 65 mol% of
`the total lipid present in the particle ............................................ 41 
`5.  Claim 5: the nucleic acid-lipid particle of claim 1, wherein
`the non-cationic lipid comprises a mixture of a
`phospholipid and cholesterol or a derivative thereof .................. 41 
`6.  Claim 6: the nucleic acid-lipid particle of claim 5, wherein
`the phospholipid comprises
`dipalmitoylphosphatidylcholine (DPPC),
`distearoylphosphatidylcholine (DSPC), or a mixture
`thereof .......................................................................................... 42 
`7.  Claim 7: the nucleic acid-lipid particle of claim 5, wherein
`the phospholipid comprises from 3 mol% to 15 mol% of
`the total lipid present in the particle ............................................ 42 
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`8.  Claim 8: the nucleic acid-lipid particle of claim 5, wherein
`the cholesterol or derivative thereof comprises from 30
`mol% to 40 mol% of the total lipid present in the particle ......... 43 
`9.  Claim 9: The nucleic acid-lipid particle of claim 1,
`wherein the conjugated lipid that inhibits aggregation of
`particles comprises a polyethyleneglycol (PEG)-lipid
`conjugate ..................................................................................... 44 
`10.  Claim 10: The nucleic acid-lipid particle of claim 9,
`wherein the PEG-lipid conjugate comprises a PEG-
`diacylglycerol (PEG-DAG) conjugate, a PEG-
`dialkyloxypropyl (PEG-DAA) conjugate, or a mixture
`thereof .......................................................................................... 44 
`11.  Claim 11: The nucleic acid-lipid particle of claim 10,
`wherein the PEG-DAA conjugate comprises a PEG-
`dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-
`distearyloxypropyl (PEG-DSA) conjugate, or a mixture
`thereof .......................................................................................... 45 
`12.  Claim 12: The nucleic acid-lipid particle of claim 1,
`wherein the conjugated lipid that inhibits aggregation of
`particles comprises from 1 mol% to 2 mol% of the total
`lipid present in the particle .......................................................... 45 
`13.  Claim 13: The nucleic acid-lipid particle of claim 1,
`wherein the nucleic acid is fully encapsulated in the
`nucleic acid-lipid particle ............................................................ 45 
`14.  Claim 14: A pharmaceutical composition comprising a
`nucleic acid-lipid particle of claim 1 and a
`pharmaceutically acceptable carrier ............................................ 46 
`15.  Claim 15: A method for introducing a nucleic acid into a
`cell, the method comprising: contacting the cell with a
`nucleic acid-lipid particle of claim 1 ........................................... 46 
`16.  Claim 16: 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 1 ....... 46 
`17.  Claim 17: A method for treating a disease or disorder in a
`mammalian subject in need thereof, the method
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`comprising: administering to the mammalian subject a
`therapeutically effective amount of a nucleic acid-lipid
`particle of claim 1 ........................................................................ 47 
`18.  Claim 18: The method of claim 17, wherein the disease or
`disorder is a viral infection .......................................................... 47 
`19.  Claim 19: The method of claim 17, wherein the disease or
`disorder is a liver disease or disorder .......................................... 47 
`20.  Claim 20: The method of claim 17, wherein the disease or
`disorder is cancer ......................................................................... 48 
`B.  Ground 2: Claims 1-20 are obvious in view of the patent
`owner’s prior disclosures in light of Lin and/or Ahmad .................... 48 
`1.  Claim element 1(c): a cationic lipid comprising from 50
`mol% to 85 mol% of the total lipid present in the particle ......... 49 
`2.  Claim 4: the nucleic acid-lipid particle of claim 1, wherein
`the cationic lipid comprises from 50 mol% to 65 mol% of
`the total lipid present in the particle ............................................ 50 
`3.  Motivation to combine ’196 PCT with Lin and/or Ahmad ........ 50 
`C.  Ground 3: Claims 1-20 are anticipated by or obvious in view
`of the ’554 publication ........................................................................ 51 
`1.  The components in claim 1 are disclosed in the ’554
`publication ................................................................................... 52 
`a)  Claim element 1(a): a nucleic acid-lipid particle
`comprising: .......................................................................... 52 
`b)  Claim element 1(b): a nucleic acid .................................... 52 
`c)  Claim element 1(c): a cationic lipid comprising from
`50 mol% to 85 mol% of the total lipid present in the
`particle ................................................................................. 53 
`d)  Claim element 1(d): a non-cationic lipid comprising
`from 13 mol% to 49.5 mol% of the total lipid present
`in the particle ....................................................................... 54 
`e)  Claim element 1(e): a conjugated lipid that inhibits
`aggregation of particles comprising from 0.5 mol% to
`2 mol% of the total lipid present in the particle .................. 55 
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`2.  Claim 2: the nucleic acid-lipid particle of claim 1, wherein
`the nucleic acid comprises an interfering RNA, mRNA, an
`anti-sense oligonucleotide, a ribozyme, a plasmid, an
`immunostimulatory oligonucleotide, or mixtures thereof .......... 56 
`3.  Claim 3: the nucleic acid-lipid particle of claim 2, wherein
`the interfering RNA comprises a small interfering RNA
`(siRNA), an asymmetrical interfering RNA (aiRNA), a
`microRNA (miRNA), or mixtures thereof .................................. 57 
`4.  Claim 4: the nucleic acid-lipid particle of claim 1, wherein
`the cationic lipid comprises from 50 mol% to 65 mol% of
`the total lipid present in the particle ............................................ 57 
`5.  Claim 5: the nucleic acid-lipid particle of claim 1, wherein
`the non-cationic lipid comprises a mixture of a
`phospholipid and cholesterol or a derivative thereof .................. 58 
`6.  Claim 6: the nucleic acid-lipid particle of claim 5, wherein
`the phospholipid comprises
`dipalmitoylphosphatidylcholine (DPPC),
`distearoylphosphatidylcholine (DSPC), or a mixture
`thereof .......................................................................................... 58 
`7.  Claim 7: the nucleic acid-lipid particle of claim 5, wherein
`the phospholipid comprises from 3 mol% to 15 mol% of
`the total lipid present in the particle ............................................ 58 
`8.  Claim 8: the nucleic acid-lipid particle of claim 5, wherein
`the cholesterol or derivative thereof comprises from 30
`mol% to 40 mol% of the total lipid present in the particle ......... 59 
`9.  Claim 9: The nucleic acid-lipid particle of claim 1,
`wherein the conjugated lipid that inhibits aggregation of
`particles comprises a polyethyleneglycol (PEG)-lipid
`conjugate ..................................................................................... 60 
`10.  Claim 10: The nucleic acid-lipid particle of claim 9,
`wherein the PEG-lipid conjugate comprises a PEG-
`diacylglycerol (PEG-DAG) conjugate, a PEG-
`dialkyloxypropyl (PEG-DAA) conjugate, or a mixture
`thereof .......................................................................................... 60 
`
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`11.  Claim 11: The nucleic acid-lipid particle of claim 10,
`wherein the PEG-DAA conjugate comprises a PEG-
`dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-
`distearyloxypropyl (PEG-DSA) conjugate, or a mixture
`thereof .......................................................................................... 61 
`12.  Claim 12: The nucleic acid-lipid particle of claim 1,
`wherein the conjugated lipid that inhibits aggregation of
`particles comprises from 1 mol% to 2 mol% of the total
`lipid present in the particle .......................................................... 61 
`13.  Claim 13: The nucleic acid-lipid particle of claim 1,
`wherein the nucleic acid is fully encapsulated in the
`nucleic acid-lipid particle ............................................................ 62 
`14.  Claim 14: A pharmaceutical composition comprising a
`nucleic acid-lipid particle of claim 1 and a
`pharmaceutically acceptable carrier ............................................ 62 
`15.  Claim 15: A method for introducing a nucleic acid into a
`cell, the method comprising: contacting the cell with a
`nucleic acid-lipid particle of claim 1 ........................................... 62 
`16.  Claim 16: 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 1 ....... 63 
`17.  Claim 17: 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
`particle of claim 1 ........................................................................ 63 
`18.  Claim 18: The method of claim 17, wherein the disease or
`disorder is a viral infection .......................................................... 63 
`19.  Claim 19: The method of claim 17, wherein the disease or
`disorder is a liver disease or disorder .......................................... 64 
`20.  Claim 20: The method of claim 17, wherein the disease or
`disorder is cancer ......................................................................... 64 
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`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Clemens,
`622 F.2d 1029 (C.C.P.A. 1980) ...................................................................... 3, 34
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 36, 37
`
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 ....................................................................................................... 2
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim
`
`Rules
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 4
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 4
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 4
`
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 4
`
`37 C.F.R. § 42.88(b)(2) .............................................................................................. 4
`
`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
`
`37 C.F.R. § 42.103 ..................................................................................................... 4
`
`37 C.F.R. § 42.104(a) ................................................................................................. 5
`
`Statutes
`
`35 U.S.C. § 102(b) ............................................................................................passim
`
`35 U.S.C § 103 ......................................................................................... 2, 32, 48, 51
`
`35 U.S.C. §§ 311–319 ................................................................................................ 1
`
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`
`LIST OF EVIDENCE AND EXHIBITS RELIED UPON IN THE PETITION
`
`Reference
`
`Exhibit
`No.
`1001 U.S. Patent No. 9,364,435
`1002
`International Publication No. WO 2005/007196
`1003 U.S. Publication No. US2006/0134189
`1004 U.S. Publication No. US2006/0240554
`1005 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,
`3307–16 (2003) (“Lin”)
`1006 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 739–48 (2005) (“Ahmad”)
`1007 Declaration of Dr. Andrew S. Janoff
`1008 Gao, Xiang et al., Nonviral Gene Delivery: What We Know and What Is Next,
`9 AAPS JOURNAL Article 9, pp. E92-E104 ( 2007) (“Gao”)
`1009 Bennett, Michael J. et al., Cholesterol Enhances Cationic Liposome-Mediated
`DNA Transfection of Human Respiratory Epithelial Cells, 15 Bioscience
`Reports, pp. 47-53 (1995) (“Bennett”)
`1010 Heyes, James et al., Cationic lipid saturation influences intracellular delivery
`of encapsulated nucleic acids, 107 JOURNAL OF CONTROLLED RELEASE 276–
`87 (2005) (“Heyes”)
`1011 U.S. Patent No. 5,753,613
`1012 U.S. Patent No. 7,939,505
`1013 U.S. Publication No. US2007/0042031
`1014 U.S. Publication No. US2006/0008910
`1015 Excerpts from ’069 Patent File History
`1016
`’435 Patent File History
`1017 U.S. Patent No. 5,264,618
`1018 Curriculum Vitae of Dr. Andrew S. Janoff
`
`
`
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`

`IPR Case No. Unassigned
`
`
`
`
`
` U.S. Patent No. 9,364,435
`
`In accordance with 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42.100 et seq.,
`
`Moderna Therapeutics, Inc. (“Moderna” or “Petitioner”) respectfully requests that
`
`the Board institute inter partes review and cancel claims 1–20 of U.S. Patent
`
`9,364,435 (“ʼ435 patent,” Ex. 1001).
`
`I.
`
`INTRODUCTION
`
`The ’435 patent is directed to a composition of nucleic acid-lipid particles
`
`(e.g., particles that can be used to deliver therapeutic nucleic acid payloads to a
`
`patient) comprising three lipid components (i.e., cationic lipid, non-cationic lipid
`
`and conjugated lipid), each of which fall within a claimed proportion with regard
`
`to the total lipid in the particles. See, e.g., Ex. 1001, claim 1.
`
`The ’435 patent is just one of many unrelated patents owned by Protiva
`
`Biotherapeutics, Inc. (“Patent Owner”), some of which date back to the early
`
`2000s, that disclose substantially the same nucleic acid-lipid particles with only
`
`inconsequential differences in claim scope. By obtaining overlapping claims in
`
`these unrelated patent families, Patent Owner has improperly extended its patent
`
`protection by years. Patent Owner is now using these patent families, including the
`
`’435 patent, to improperly block the public and industry participants from using
`
`basic combinations of nucleic acid-lipid particle components explicitly described
`
`long before the ’435 priority date.
`
`The Patent Owner’s own prior art disclosures in PCT Application No.
`
`
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`

`IPR Case No. Unassigned
`
`
`
`
`
` U.S. Patent No. 9,364,435
`
`PCT/CA2004/001051, Publication No. WO2005007196 A2 (“’196 PCT”) (Ex.
`
`1002) and U.S. Patent Publication No US2006/0134189 (“’189 publication”) (Ex.
`
`1003), and other prior art, including U.S. Patent Publication No. 2006/0240554
`
`(“’554 publication”) (Ex. 1004), show that the claimed composition of lipid
`
`components was available well before the priority date of the ’435 patent. These
`
`references disclose overlapping and encompassing ranges for each of the three
`
`lipid components, and, in the case of the ’554 publication, specific examples of
`
`nucleic acid-lipid particles meeting the claim limitations.
`
`Moreover, the disclosure of overlapping ranges for the three lipid
`
`components establishes a prima facie case of obviousness under 35 U.S.C § 103.
`
`See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“[E]ven a slight overlap
`
`in range establishes a prima facie case of obviousness.”).1 One skilled in the art
`
`would appreciate that generating lipid complexes with lipid components in the
`
`ranges claimed would have been simple matter of using prior art production
`
`
`1 The overlapping ranges establish a prima facie showing of obviousness. As
`
`detailed herein, the overlapping ranges, content of the cited art, knowledge of a
`
`POSITA and testing data also demonstrate invalidity by the preponderance of the
`
`evidence. In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364 (Fed. Cir. 2016)
`
`(petitioner’s burden of showing invalidity by preponderance of the evidence).
`
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`

`IPR Case No. Unassigned
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`
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`
`
` U.S. Patent No. 9,364,435
`
`methods to combine appropriate proportions of prior art lipid components. Id. at
`
`1330 (“The normal desire of scientists or artisans to improve upon what is already
`
`generally known provides the motivation to determine where in a disclosed set of
`
`percentage ranges is the optimum combination of percentages.”). Thus, each of the
`
`references renders the challenged claims obvious.
`
`During prosecution of the parent of the ’435 patent, U.S. Patent No.
`
`8,058,069 (“’069 patent”), which contains claims to similar nucleic acid-lipid
`
`particles with similar components in narrower ranges, the Patent Owner overcame
`
`cited prior art disclosing overlapping ranges based upon alleged unexpected test
`
`results attributable to a cationic lipid proportion greater than 50%. This testing,
`
`however, shows that data points falling within the broader ranges claimed in the
`
`’435 patent actually perform worse than the admitted prior art formulations—i.e.,
`
`there are no unexpected advantages. It is well-settled that “unexpected results”
`
`must be demonstrated for the entire claimed range to support patentability. In re
`
`Clemens, 622 F.2d 1029, 1035 (C.C.P.A. 1980) (“In order to establish unexpected
`
`results for a claimed invention, objective evidence of non-obviousness must be
`
`commensurate in scope with the claims which the evidence is offered to support.”).
`
`In addition, the prior art references Lin (Ex. 1005) and/or Ahmad (Ex. 1006)
`
`teach that there was a recognized potential benefit to using a cationic lipid
`
`proportion over 50%. One skilled in the art would have been motivated to
`
`
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`IPR Case No. Unassigned
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`
`
`
`
` U.S. Patent No. 9,364,435
`
`combine these disclosures with the ’196 PCT and/or ’189 publication as described
`
`herein further rendering the claims obvious.
`
`II. MANDATORY NOTICES
`
`NOTICE OF REAL PARTY-IN-INTEREST (37 C.F.R. § 42.8(b)(1))
`A.
`The real party-in-interest is Moderna Therapeutics, Inc.
`
`B.
`
`NOTICE OF RELATED MATTERS (37 C.F.R. § 42.8(b)(2))
`
`There are no pending Related Matters as defined in 37 C.F.R. § 42.88(b)(2).
`
`C.
`
`DESIGNATION OF LEAD AND BACK-UP COUNSEL (37 C.F.R.
`§ 42.8(b)(3))
`
`Lead Counsel: Michael Fleming
`
`(Reg. No. 67,933).
`
` Email:
`
`mfleming@irell.com.
`
`Backup Counsel: C. Maclain Wells (Reg. No. 48,991).
`
` Email:
`
`mwells@irell.com.
`
` Alan Heinrich
`
`(pro hac
`
`vice TBD).
`
` Email:
`
`aheinrich@irell.com.
`
`Address: Irell & Manella LLP, 1800 Avenue of the Stars, Suite 900, Los
`
`Angeles, CA 90067; Tel: (310) 277-1010; Fax: (310) 203-7199.
`
`D.
`
`SERVICE INFORMATION (37 C.F.R. § 42.8(b)(4))
`
`Please address all correspondence to the lead and backup counsel above.
`
`Petitioner agrees to electronic service at ModernaIPR@irell.com.
`
`E.
`
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`The Office is authorized to charge required fees to Deposit Account No. 09-
`
`0946.
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`IPR Case No. Unassigned
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`
`
`
`
` U.S. Patent No. 9,364,435
`
`F.
`
`CERTIFICATION OF GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Petitioner certifies that the ʼ435 patent is eligible for inter partes review and
`
`that Petitioner is neither barred nor estopped from requesting a review of the
`
`challenged claims on the grounds identified herein.
`
`III. CHALLENGE AND RELIEF REQUESTED
`Petitioner respectfully requests inter partes review and cancellation of all
`
`claims of the ʼ435 patent based on the grounds detailed below in Section IX.
`
`A. GROUND 1: CLAIMS 1-20 ARE OBVIOUS IN VIEW OF PATENT OWNER’S
`PRIOR DISCLOSURES IN THE ’196 PCT AND ’189 PUBLICATION
`
`B. GROUND 2: CLAIMS 1-20 ARE OBVIOUS IN VIEW OF PATENT OWNER’S
`PRIOR DISCLOSURES IN LIGHT OF LIN AND/OR AHMAD
`
`C. GROUND 3: CLAIMS 1-20 ARE ANTICIPATED BY OR OBVIOUS IN VIEW
`OF THE ’554 PUBLICATION
`
`IV. PRIORITY DATE
`
`The ʼ435 patent claims priority to provisional application No. 61/045,228,
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`filed on April 15, 2008. Ex. 1001, cover page. For purposes of this paper only,
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`Petitioner assumes (without conceding) that the ʼ435 patent is entitled to this date.
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`V.
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`PERSONS HAVING ORDINARY SKILL IN THE ART
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`A person having ordinary skill in the art (“POSITA”) would have specific
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`experience with lipid particle formation and use in the context of delivering
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`therapeutic nucleic acid payloads, and would have a Ph.D., an M.D. or a similar
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`advanced degree in an allied field (e.g., biophysics, microbiology, biochemistry) or
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`an equivalent combination of education and experience. See Ex. 1007, Declaration
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`IPR Case No. Unassigned
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`of Dr. Andrew S. Janoff (“Janoff Decl.”), ¶¶31-32. This level of skill is
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`representative of the inventors on the ’435 patent and authors/inventors of prior art
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`cited herein. Id.
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`VI. BACKGROUND
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`A.
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`LIPID CARRIER PARTICLES FOR NUCLEIC ACID PAYLOADS
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`Gene therapy—addressing disease at the level of the genetic cause, typically
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`with nucleic acids—is an area of intensive medical research. Therapeutic nucleic
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`acids can be used for both gene delivery (e.g., mRNA) and gene silencing (e.g.,
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`small interfering RNA (“siRNA”)). Id., ¶60; see also Ex. 1008 (Gao), E92; Ex.
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`1005 (Lin), 3307.
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`Long before the ’435 patent, it was known that systems comprised of
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`combinations of different types of lipids with nucleic acids could result in lipid-
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`nucleic acid particles, an accepted delivery strategy for nucleic acid therapeutics.
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`Id., ¶60; see also Ex. 1008 (Gao), E95. The ’435 patent refers to such nucleic acid-
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`lipid carrier particles as “stable nucleic acid-lipid particles” or “SNALPs.” Ex.
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`1001, 5:62-6:2.
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`B.
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`THE ’435 PATENT CLAIMS ARE DIRECTED TO KNOWN LIPID
`COMPONENTS
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`The ’435 patent discloses three lipid components: a “cationic lipid,” a “non-
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`cationic lipid,” and a “conjugated lipid.” See, e.g., id., claim 1. These lipid
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`components were known to be basic building blocks of nucleic acid-lipid particles
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`IPR Case No. Unassigned
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`long before the ’435 patent. Janoff Decl. ¶61; see also Ex. 1006 (Ahmad), 740,
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`746 (“[cationic lipids] for transfection typically consist of a mixture of cationic and
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`neutral (helper) lipid” and “strategies for optimization … could involve
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`introducing PEG-lipids … to block … unspecific interactions”);2 Ex. 1008 (Gao),
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`E95 (cationic lipid carrier particles “are often formulated with a noncharged
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`phospholipid or cholesterol as a helper lipid … PEG-lipid conjugates have been
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`incorporated … to minimize interaction with blood components ….”).
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`Cationic lipids are used because they interact with the negative charge on
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`nucleic acid payload facilitating formation of complexes. Janoff Decl. ¶62; see
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`also Ex. 1008 (Gao), E95. Effective delivery of the nucleic acid (called the
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`“transfection efficiency”) is thought to require fusion between the lipid complex
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`and a cell membrane.3 Janoff Decl. ¶62; see also Ex. 1009 (Bennett), 48; Ex. 1008
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`(Gao), E95. The positive charge on cationic lipids can interact with negative
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`charges on cell membranes. Janoff Decl. ¶62. This is believed to promote, in
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`some cases, the fusion event necessary for the effective delivery of the nucleic
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`acid. Id.; see also Ex. 1006 (Ahmad), 745 (“[A]n overall positive [cationic lipid]-
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`2 A PEG-lipid is an example of a conjugated lipid.
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`3 In the art, “[t]he term ‘fusogenic’ refers to the ability of a lipid particle … to fuse
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`with the membranes of a cell” thereby delivering its payload. Ex. 1001, 13:20-21.
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`IPR Case No. Unassigned
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`DNA charge is required to promote initial electrostatic interactions with cell
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`membranes.”).
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`Non-cationic “helper” lipids, e.g., certain phospholipids and/or cholesterols,
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`can be combined with the cationic lipid to influence the ability of the particles to
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`transfect cells. Janoff Decl. ¶63; see also Ex. 1008 (Gao), E95 (cationic lipids “are
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`often formulated with a noncharged phospholipid or cholesterol as a helper lipid to
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`form liposomes.”); Ex. 1009 (Bennett), 47 (helper lipids used).
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`In addition, a conjugated lipid, e.g., a PEG-lipid, can be added to increase in
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`vivo circulation time by providing a neutral, hydrophilic coating to the particle’s
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`exterior. Janoff Decl. ¶64; see also Ex. 1008 (Gao), E97 (“PEG-lipid conjugates
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`have been incorporated into the lipoplexes to minimize the nonspecific interaction
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`of lipoplexes with blood components.”); Ex. 1010 (Heyes), 277 (“PEG-lipids both
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`stabilize the particle during the formulation process and shield the cationic bi-
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`layer, preventing rapid systemic clearance.”).
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`C.
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`THE OPTIMAL LIPID COMPONENT PROPORTIONS IN A NUCLEIC ACID-
`LIPID PARTICLE VARIES
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`“The structure of lipoplexes is influenced by multiple factors, including the
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`charge ratio, the concentration of individual lipids and DNA, the structu