UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Ex parte BRA YDON CHARLES GUILD, FRANK DEROSA, and
`MICHAEL HEARTLEIN
`
`Appeal 2016-008388
`Application 13/800,501
`Technology Center 1600
`
`Before RICHARD J. SMITH, RACHEL H. TOWNSEND, and
`DAVID COTTA, Administrative Patent Judges.
`
`TOWNSEND, Administrative Patent Judge.
`
`DECISION ON APPEAL
`
`This is an appeal under 35 U.S.C. § 134 involving claims to a method
`
`of delivery of messenger RNA for in vivo production of protein, which have
`
`been rejected as anticipated and/or obvious. 1 We have jurisdiction under 35
`
`U.S.C. § 6(b ).
`
`We reverse.
`
`STATEMENT OF THE CASE
`
`Individuals suffering from diseases that result from protein and/or
`
`enzyme deficiencies "may have underlying genetic defects that lead to the
`
`1 Appellant is the Applicant Shire Human Genetic Therapies, Inc., which
`according to the Appeal Brief, is the real party in interest. (Appeal Br. 2.)
`
`Moderna Ex 1025-p. 1
`Moderna v Protiva
`IPR2018-00739
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Ex parte BRA YDON CHARLES GUILD, FRANK DEROSA, and
`MICHAEL HEARTLEIN
`
`Appeal 2016-008388
`Application 13/800,501
`Technology Center 1600
`
`Before RICHARD J. SMITH, RACHEL H. TOWNSEND, and
`DAVID COTTA, Administrative Patent Judges.
`
`TOWNSEND, Administrative Patent Judge.
`
`DECISION ON APPEAL
`
`This is an appeal under 35 U.S.C. § 134 involving claims to a method
`
`of delivery of messenger RNA for in vivo production of protein, which have
`
`been rejected as anticipated and/or obvious. 1 We have jurisdiction under 35
`
`U.S.C. § 6(b ).
`
`We reverse.
`
`STATEMENT OF THE CASE
`
`Individuals suffering from diseases that result from protein and/or
`
`enzyme deficiencies "may have underlying genetic defects that lead to the
`
`1 Appellant is the Applicant Shire Human Genetic Therapies, Inc., which
`according to the Appeal Brief, is the real party in interest. (Appeal Br. 2.)
`
`Moderna Ex 1025-p. 1
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`IPR2018-00739
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`
`
`Appeal 2016-008388
`Application 13/800,501
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`compromised expression of a protein or enzyme, including, for example, the
`
`non-synthesis of the protein, the reduced synthesis of the protein, or
`
`synthesis of a protein lacking or having diminished biological activity."
`(Spec. ,r 8.) "Novel therapies that increase the level or production of an
`affected protein or enzyme in target cells, such as hepatocytes, or that
`
`modulate the expression of nucleic acids encoding the affected protein or
`
`enzyme could provide a treatment or even a cure for metabolic disorders."
`(Spec. ,r 6.) The claims at issue concern methods of intracellular delivery of
`nucleic acids that can be translated into a gene product of interest following
`successful delivery to target tissue. (Spec. ,r 7.)
`Claims 1, 3, 4, 7, 10-14, 16, 18-28, and 30-38 are on appeal. Claim
`
`1 is representative and reads as follows:
`
`1. A method of delivery of messenger RNA (mRNA) for in
`vivo production of protein, comprising
`administering systemically to a subject in need of
`delivery a composition comprising an mRNA encoding a
`protein, encapsulated within a liposome such that the
`administering of the composition results in the prolonged stable
`expression of the protein encoded by the mRNA in the liver;
`wherein the protein encoded by the mRN A is an enzyme,
`a hormone, a receptor or an antibody; and
`wherein the liposome comprises one or more cationic
`lipids, one or more non-cationic lipids, one or more cholesterol(cid:173)
`based lipids and one or more PEG-modified lipids and has a
`size less than about 100 nm.
`
`(Appeal Br. 32.)
`
`2
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`Moderna Ex 1025-p. 2
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`IPR2018-00739
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`
`
`Appeal 2016-008388
`Application 13/800,501
`
`The following grounds of rejection by the Examiner are before us on
`
`review:
`
`Claims 1, 3, 4, 7, 14, 22, 31-34, and 37 under 35 U.S.C. § 102(b) as
`
`anticipated by MacLachlan. 2
`
`Claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38 under 35 U.S.C.
`
`§ 103(a) as unpatentable over MacLachlan, Ye 3 and Okumura. 4
`
`Claims 1, 3, 4, 7, 10-14, 16, 18-28, and 30-38 under 35 U.S.C.
`
`§ 103(a) as unpatentable over MacLachlan, Ye, Okumura, and Kariko. 5
`
`Anticipation
`
`DISCUSSION
`
`According to the Examiner, MacLachlan teaches a method of
`
`delivering protein-encoding messenger RNA (mRNA) encapsulated within
`
`liposomes of the type recited in claim 1 via intravenous administration.
`
`(Final Action 3.) The Examiner recognizes that "the preferred embodiment
`
`in MacLachlan [] is using SNALPs 6 to deliver siRNA7 to silence genes of
`
`2 MacLachlan et al., US 2006/0008910 Al, published Jan. 12, 2006
`3 Ye et al. "Prolonged Metabolic Correction in Adult Omithine
`Transcarbamylase-deficient Mice with Adenoviral Vectors," 271 J. Biol.
`Chem., 3639-3646 (1996).
`4 Okumura et al., "Bax mRNA therapy using cationic liposomes for human
`malignant melanoma," 10 J. Gene Med., 910-917 (2008).
`5 Kariko et al., "Incorporation of Pseudouridine into mRNA Yields Superior
`Nonimmunogenic Vector With Increased Translational Capacity and
`Biological Stability," 16 (10) Mol. Ther. 1833-1840 (2008).
`6 SNALP is the acronym for "stabilized nucleic acid-lipid particles."
`(MacLachlan ,r,r 10, 57.)
`7 siRNA is the acronym used in MacLachlan for "small-interfering RNA."
`(MacLachlan ,r 77.) MacLachlan defines "interfering RNA," also called
`
`3
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`Appeal 2016-008388
`Application 13/800,501
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`interest." (Ans. 6.) But the Examiner contends that MacLachlan also
`
`teaches protein-encoding mRNA delivery with SNALP for protein
`
`expression in vivo because (a) it indicates SNALPs "are suitable for the
`
`delivery of nucleic acids ([0057]; [0084])," (b) it "define[s] that the term
`
`'nucleic acid' is used interchangeably with gene, cDNA, mRNA, and an
`
`interfering RNA ([0073])," and (c)
`
`in [0 142] and [0 148] MacLachlan et al. specifically teach gene
`(and not siRNA) delivery as follows:
`"Anti-angiogenic genes are able to inhibit
`neovascularization. These genes are particularly useful
`to treat cancers in which angiogenesis play a role in the
`pathological development of the disease". [0142]
`
`"Tumor suppressor genes are genes that are able to
`inhibit the growth of a cell, particularly tumor cells.
`Thus, delivery of these genes to tumor cells is useful in
`the treatment of cancer." [0148]
`[ And as] clearly taught by MacLachlan et al. and as commonly
`known in the prior art, inhibition of neovascularization and of
`tumor cell growth requires the activity of the antiangiogenic
`and tumor suppressor polypeptides/proteins, not their silencing.
`Thus, MacLachlan et al. teach using SNALPs for the in vivo
`delivery of genes encoding therapeutic polypeptides/proteins.
`(Ans. 6-8; see also Final Action 3, 7.) The Examiner thus concludes that
`
`"MacLachlan et al. is an anticipatory reference with respect to using SNALP
`
`technology to deliver mRNA for protein/enzyme production in vivo." (Ans.
`
`8 ( emphasis omitted).)
`
`RN Ai, as "double-stranded RNA that results in the degradation of specific
`mRNAs and can be used to interfere with translation from a desired mRNA
`target transcript." (Id.) MacLachlan further explains the siRNA is short
`RNAi that is "about 15-30 nucleotides in length." (Id.)
`
`4
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`Appeal 2016-008388
`Application 13/800,501
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`We disagree with the Examiner's factual finding that MacLachlan
`
`discloses encapsulating protein encoding mRNA in liposomes or
`
`systemically administering such liposomes for in vivo delivery of genes
`
`encoding therapeutic proteins.
`
`As Appellant points out (Appeal Br. 7-10; Reply Br. 3-8),
`
`MacLachlan's disclosure regarding the use of SNALP technology is solely
`
`directed to delivery of interfering RNA, notwithstanding that it broadly
`
`defines (a) the term "nucleic acid" to be interchangeably used with cDNA,
`mRNA encoded by a gene, and an interfering RNA molecule (MacLachlan ,r
`73), and (b) the term "gene" as referring "to a nucleic acid ( e.g., DNA or
`
`RNA) sequence that comprises partial length or entire length coding
`
`sequences necessary for the production of a polypeptide or precursor ... "(id.
`
`i175).
`
`In the "Field of the Invention," MacLachlan states that "[t]he present
`
`invention relates to" therapeutic delivery of encapsulated nucleic acid "to
`provide efficient RNA interference." (Id. ,r 2.) MacLachlan then explains
`that RNAi is a "sequence specific mechanism triggered by double stranded
`
`RNA( dsRNA) that induces degradation of complementary target single
`
`stranded mRNA and 'silencing' of the corresponding translated sequences."
`(Id. ,r 3.) In MacLachlan's "Brief Summary of the Invention" it is stated:
`The present invention comprises novel, stable nucleic acid-lipid
`particles (SNALP) encapsulating one or more interfering RNA
`molecules, methods of making the SNALPs and methods of
`deliver[in]g and/or administering the SNALPs.
`(Id. ,r 12.) In the "Detailed Description of the Invention," MacLachlan
`states:
`
`The present invention demonstrates the unexpected success of
`encapsulating short inteifering RNA (siRNA) molecules in
`
`5
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`IPR2018-00739
`
`
`
`Appeal 2016-008388
`Application 13/800,501
`
`SNALPs comprising cationic lipids of Formula I, II, or mixture
`thereof. The SNALPs described herein can be used to deliver
`an siRNA to a cell to silence a target sequence of interest.
`SN ALP comprising any of a broad range of concentrations of
`additional cationic lipids, noncationic lipids, and other lipids
`can be used to practice the present invention. The SNALP can
`be prepared with any nucleic acid comprising an inteifering
`RNA sequence, from any source and comprising any
`polynucleotide sequence ....
`(Id. ,r 53 (emphasis added).)
`"Interfering RNA sequence" or "RNAi" is defined by MacLachlan as
`
`referring to "double-stranded RNA that results in the degradation of specific
`
`mRNAs and can be used to interfere with translation from a desired mRNA
`
`target transcript" and siRNA is defined as being about "15-30 nucleotides in
`length" and is considered short RN Ai. (Id. ,r 77 .)
`MacLachlan goes on to describe the SNALP constituents in the
`
`Detailed Description of the Invention section: the Lipid portion (Section
`
`III.A. and B. of the "Detailed Description of the Invention"), (Id. i-fi-f86-92),
`the Bilayer Stabilizing Component (Section III.C.), (Id. ,r,r 93-117) and, the
`Nucleic Acid Component (Section III.D.), (Id. ,r,r 118-148). In the
`introductory paragraph of section III.D., the "Nucleic Acid Component" of
`
`the SNALP, MacLachlan again specifies that "[t]he nucleic acid component
`
`of the present invention comprises an interfering RNA that silences ( e.g.,
`partially or completely inhibits) expression of a gene of interest." (Id. f
`
`6
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`Moderna Ex 1025-p. 6
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`Appeal 2016-008388
`Application 13/800,501
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`119.) 8 This section III.D. is divided into three further subsections, the first
`
`two being a discussion of selecting siRNA sequences (III.D.1) (Id. i-fi-fl20-
`124) and generating siRNA (III.D.2) (Id. ,r,r 125-131 ). The third section,
`III.D.3. (Id. i-fi-fl33-148), is a potential list of genes of interest that the RNAi
`
`might target so as to silence expression of that gene of interest. That list of
`
`genes of interest to silence expression of includes, inter alia, genes
`
`associated with viral infection and survival (Id. i-fi-fl34-135), genes
`associated with metabolic diseases and disorders (Id. ,r,r 136-137),
`angiogenic and anti-angiogenic genes (Id. ,r,r 140-142), and tumor
`suppressor genes (Id. ,r,r 147-148). Contrary to the Examiner's position,
`these are not identified as genes or mRNA to be encapsulated for delivery to
`
`target tissue.
`
`In light of the foregoing, we disagree with the Examiner that delivery
`
`of interfering RNA, such as siRNA, is merely the preferred embodiment of
`
`MacLachlan (Ans. 11 ), and that using SNALPs for delivery of other types of
`
`nucleic acid such as mRNA encoding a gene of interest is embraced; rather,
`
`delivery of interfering RNA is "the invention" of MacLachlan and is all that
`
`is described.
`
`MacLachlan discusses the preparation of SNALPs with the foregoing
`constituents in section IV (Id. ,r,r 149-202) and administration of the
`
`8 MacLachlan notes that the:
`interfering RNA can be provided in several forms. For example
`an interfering RNA can be provided as one or more isolated
`small-interfering RNA (siRNA) duplexes, longer double(cid:173)
`stranded RNA (dsRNA) or as siRNA or dsRNA transcribed
`from a transcriptional cassette in a DNA plasmid.
`(MachLachlan ,r 119.)
`
`7
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`Moderna Ex 1025-p. 7
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`Appeal 2016-008388
`Application 13/800,501
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`SNALPs in section V (Id. ,r,r 203-209). While MacLachlan refers to the
`encapsulated genetic material as nucleic acid generally ( or the plasmid) in
`
`sections IV and V, it is clear from MacLachlan's description of "the present
`
`invention" throughout the Specification that the nucleic acid generically
`
`referred to in sections IV and Vis necessarily RNAi. (See, e.g., id. at
`abstract, ,r,r 2, 12 ("The present invention comprises novel, stable nucleic
`acid-lipid particles (SNALP) encapsulating one or more interfering RNA
`
`molecules, methods of making the SNALPs and methods of deliver[in Jg
`
`and/or administering the SNALPs."), 17, 53 ("The SNALP can be prepared
`
`with any nucleic acid comprising an interfering RNA sequence, from any
`
`source and comprising any polynucleotide sequence, and can be prepared
`
`using any of a large number of methods."), 119 ("The nucleic acid
`
`component of the present invention comprises an interfering RNA that
`
`silences ( e.g., partially or completely inhibits) expression of a gene of
`
`interest").) In short, sections IV and V concern making and using the
`
`stabilized nucleic acid-lipid particles encapsulating one or more interfering
`
`RNA molecules - i.e., the invention in the MacLachlan patent. Sections IV
`
`and V do not concern making and using stabilized nucleic acid-lipid
`
`particles encapsulating mRNA or other non-interfering RNA molecules.
`
`In light of the foregoing, we agree with Appellant that MacLachlan
`
`does not disclose delivering protein encoding mRNA using SN ALP.
`
`Consequently, we conclude that the Examiner has not provided evidence that
`
`MacLachlan discloses every limitation of the claimed invention. Thus, we
`
`reverse the Examiner's rejection of independent claim 1, and claims 3, 4, 7,
`
`14, 22, 31-34, and 37 depending therefrom, under 35 U.S.C. § 102(b) as
`
`being anticipated by MacLachlan.
`
`8
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`Moderna Ex 1025-p. 8
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`IPR2018-00739
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`
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`Appeal 2016-008388
`Application 13/800,501
`
`Obviousness
`
`II
`
`The Examiner's assertion that the combination of MacLachlan, Ye,
`
`and Okumura renders claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38
`
`obvious applies MacLachlan as discussed above in connection with
`
`anticipation, and relies on Ye and Okumura for teaching the limitations of
`
`claims 10-12, 16, 18-21, 23-28, 30, 35, 36, and 38 and rendering those
`
`claims obvious. (Final Action 5 ("The teachings of MacLachlan et al. are
`
`applied as above for claims 1, 3, 4, 7, 14, 22, 31-34, and 37."); see, e.g.,
`
`Ans. 13-14 (
`
`As set forth above, MacLachlan et al. do teach using SNALPs
`to deliver an mRNA encoding an enzyme for therapeutic
`purposes; prolonged stable expression in the liver necessarily
`follows intravenous administration as taught by MacLachlan et
`al. For this reason, the argument that the cited secondary
`references do not cure the deficiencies of MacLachlan et al. is
`not found persuasive; there is no deficiency to be cured in the
`teachings of Maclachlan et al.);
`Ans. 21 ("the primary reference already anticipates in vivo delivery of
`
`liposomal mRNA"); Ans. 22 ("using SNALP technology to deliver mRNA
`
`is anticipated by MacLachlan et al."); Ans. 27 ("expression in liver must
`
`necessarily follow systemic administration as taught by MacLachlan et al.
`
`because all that is required to achieve expression in liver is to systemically
`
`administer SNALPs encapsulating mRNA"); Ans. 30-31 (
`
`At the time the instant invention was made, systemic delivery
`of an enzyme-encoding mRNA encapsulated into 50 nm
`cationic liposomes comprising one or more cationic lipids, one
`or more neutral lipids (i.e., non-cationic lipids), cholesterol (i.e.,
`cholesterol-based lipid), and one or more PEG-modified lipids
`was taught and thus anticipated by MacLachlan et al.).)
`
`9
`
`Moderna Ex 1025-p. 9
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`IPR2018-00739
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`Appeal 2016-008388
`Application 13/800,501
`
`Likewise, in addressing claim 13 as being obvious over MacLachlan,
`
`Ye, Okumura, and Kariko, the Examiner continues to apply MacLachlan as
`
`discussed above with respect to anticipation, relying on Kariko for
`
`disclosure of the limitation added by claim 13. (Final Action 6 ("The
`
`teachings of MacLachlan et al., Ye et al., and Okumura et al. are applied as
`
`above for claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38."; see also Ans.
`
`23: ("Kariko et al. cannot discourage from pursuing a method already used
`
`by the primary reference.") (emphasis omitted).)
`
`For the reasons discussed above, we disagree with the Examiner's
`
`assertion that MacLachlan discloses using SNALP technology to
`
`encapsulate mRNA for in vivo delivery or administering such an
`
`encapsulated mRNA, and reverse the Examiner's determination that
`
`MacLachlan anticipates claims 1, 3, 4, 7, 14, 22, 31-34, and 37. The
`
`Examiner does not rely on Ye or Okumura to remedy the noted deficiency of
`
`MacLachlan's disclosure. 9 As such, to the extent that the Examiner has
`
`rejected these claims and claims 10-12, 16, 18-21, 23-28, 30, 35, 36, and 38
`
`as obvious over the combined teachings of MacLachlan, Ye, and Okumura,
`
`9 We take no position on whether delivering protein-encoding messenger
`RNA (mRNA) encapsulated within liposomes of the type recited in claims 1
`and 25 via intravenous administration would have been obvious in view of
`the references cited by the Examiner or made of record by Appellant (see,
`e.g., Ans. 28:
`In fact Lu et al. teach successful mRNA transfection in vivo at
`comparable or higher levels than DNA transfection by using the same
`cationic liposomes. Lu et al. teach that gene therapy could be
`achieved by using mRNA (see Abstract; p. 250, column 2, first
`paragraph; p. 251, Fig. 7 and paragraph bridging columns 1 and 2),
`as that rejection is not before us.
`
`10
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`Moderna Ex 1025-p. 10
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`Appeal 2016-008388
`Application 13/800,501
`
`we reverse. Furthermore, the Examiner does not rely on Kariko to remedy
`
`the noted deficiency ofMacLachlan's disclosure regarding claims 1, 3, 4, 7,
`
`14, 22, 31-34, and 37 discussed above. As such, to the extent that the
`
`Examiner has rejected these claims and claims 10-13, 16, 18-21, 23-28, 30,
`
`35, 36, and 38 as obvious over the combined teachings MacLachlan, Ye,
`
`Okumura, and Kariko, we reverse.
`
`SUMMARY
`
`We reverse the rejection of claims 1, 3, 4, 7, 14, 22, 31-34, and 37
`
`under 35 U.S.C. § 102(b) as anticipated by MacLachlan.
`
`We reverse the rejection of claims 1, 3, 4, 7, 10-12, 14, 16, 18-28,
`
`and 30-38 under 35 U.S.C. § 103(a) as unpatentable over MacLachlan, Ye
`
`and Okumura.
`
`We reverse the rejection of claims 1, 3, 4, 7, 10-14, 16, 18-28, and
`
`30-38 under 35 U.S.C. § 103(a) as unpatentable over MacLachlan, Ye,
`
`Okumura, and Kariko.
`
`TIME PERIOD FOR RESPONSE
`
`No time period for taking any subsequent action in connection with
`
`this appeal may be extended under 37 C.F.R. § 1.136(a).
`
`REVERSED
`
`11
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`
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