Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This office action is a response to applicant’s communication submitted June 29, 2026, wherein claim 162 is introduced. This application is a continuation of US application 18/409330, now pending, filed January 10, 2024, which is a continuation of US application 16/092685, now US patent 11896672, filed October 10, 2018, which is a national stage application of PCT/CA2017/050447, filed April 11, 2017, which claims benefit of provisional applications 62/438310, filed December 22, 2016, 62/417156, filed November 3, 2016, and 62/321034, filed April 11, 2016.
Claims 162-166 are pending in this application.
Claims 162-166 as amended are examined on the merits herein.
The following rejections of record in the previous action are maintained:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 162-166 are rejected under 35 U.S.C. 103 as being unpatentable over Heartlein et al. (PCT international publication WO2014/152940, Reference of record in previous action) in view of Prakash et al. (US pre-grant publication 2015/0315594, of record in previous action)
Independent claim 162 claims a compound formulated for delivering an mRNA to the liver of an animal comprising a compound comprising the following targeting ligand structure:
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. This claim is infringed by compositions either comprising an mRNA conjugated to this ligand, or comprising some other compound having this structural feature that can be used to deliver mRNA. Dependent claim 166 further requires that the composition comprise a pharmaceutically acceptable carrier. Independent claim 163 claims a method of delivering an mRNA to the liver of a subject comprising administering to the subject both the mRNA and a compound having the same structural moiety. Dependent claims 164 and 165 further specify that the subject is human.
Heartlein et al. discloses an improved mRNA therapy. (p. 2 paragraphs 5-6) In one embodiment the mRNA is associated with a transfer vehicle. (p. 87 paragraphs 100-101) The transfer vehicle can be bound to a targeting ligand to encourage localization to a particular target cell or tissue, for example in hepatocytes. (p. 90 paragraph 107-108) Galactose is described as a specific ligand to target the mRNA to hepatocytes. (p. 91 paragraph 110) Heartlein further describes specific embodiments wherein the subject is a human. (p. 92 paragraph 111)Regarding claim 166, Heartlein describes formulating the conjugate3s as compositions with pharmaceutically acceptable carriers. (p. 78 paragraph 78 – p. 79 paragraph 80) Heartlein et al. does not specifically describe an embodiment wherein the transfer vehicle contains the ligand structure pictured in present claims 162 and 163.
Prakash et al. discloses compositions and methods for modulating expression of ANGPTL3 mRNA and protein. (p. 2 paragraph 9) In one embodiment the modulator is an oligonucleotide modified with a conjugate group. (p. 2 paragraph 11) In a particular embodiment, when the compound is administered to a subject, the conjugated targeting moiety results in increased delivery, uptake, and activity in hepatocytes, or in the liver. (p. 4 paragraph 26) In particular embodiments Prakash et al. discloses a method for treating a subject, for example a human, by administering this compound to the subject. (p. 12 paragraphs 56-57)
Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to use the ligands described as Prakash as the targeting ligand attached to the mRNA transfer vehicle described by Heartlein et al. One of ordinary skill in the art would have found this to be obvious because Heartlein generally suggests using known ligands including saccharides such as galactose and mannose, as targeting ligands, which would have suggested to one of ordinary skill in the art to use any ligands known in the art to be capable of inducing localization and uptake of nucleic acids, including those described by Prakash for use with small interfering RNAs.
Prakash et al. further discloses an embodiment wherein the conjugate has a formula A-B-C-D-(E-F)q, wherein A is an antisense oligonucleotide, B and C are a cleavable group and a linker, D is a branching group, E is a tether , and F is a ligand. (p. 4 paragraphs 28-36) When q=3 this conjugate is a trivalent conjugate, similar to those recited in the present claims. (p. 4 paragraph 39) Various trivalent conjugates are pictured wherein the ligand F is N-acetylgalactosamine, which is the same ligand appearing in the presently claimed compounds. (pp. 5-11) In a particular example a conjugate group is pictured as follows:
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In this structure both the “branching” moiety D and the “ligand” moiety F are the same as the structures recited in the present claims. The only difference concerns the “tether” moiety which is a C6-alkylene rather than an oligoethylene glycol as presently claimed. Prakash et al. additionally discloses another preferred embodiment having an oligoethylene glycol tether which differs from the present claims only in that it has only three ethylene glycol units rather than four. (p. 56 paragraph 485)
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However, Prakash et al. additionally discloses that a variety of different tether structures can be used in the disclosed conjugates, including oligoethylene glycols of a length encompassing the tethers recited in the presently claimed structures. (p. 47 paragraph 444) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to modify the specific embodiments disclosed by Prakash et al. to use different tethers such as the one presently claimed, in view of the various embodiments of the tether moiety disclosed by Prakash.
Therefore the invention taken as a whole is prima facie obvious.
For these reasons the rejection as deemed proper and maintained.
Claims 162-166 are rejected under 35 U.S.C. 103 as being unpatentable over Yin et al. (PCT international publication WO2015/191693, Reference of record in previous action) in view of Prakash et al. (US pre-grant publication 2015/0315594, of record in previous action)
Independent claim 162 claims a compound formulated for delivering an mRNA to the liver of an animal comprising a compound comprising the following targeting ligand structure:
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. This claim is infringed by compositions either comprising an mRNA conjugated to this ligand, or comprising some other compound having this structural feature that can be used to deliver mRNA. Independent claim 163 claims a method of delivering an mRNA to the liver of a subject comprising administering to the subject both the mRNA and a compound having the same structural moiety. Dependent claims 164 and 165 further specify that the subject is human.
Yin et al. discloses a gene editing system comprising a guide RNA and a nucleic acid editing system. (p. 1 paragraph 1) In a particular embodiment the nucleic acid editing system is an mRNA expressing Cas9. (p. 10 paragraph 45) These nucleic acids can be associated with delivery vehicles, including cell-targeting or tissue-targeting ligands. (p. 17 paragraphs 65-66) the RNA can further be conjugated to a targeting ligand such as GalNAc. (p. 18 paragraphs 72-73) In one embodiment the subject being treated is a human. (p. 2 paragraph 9) Regarding claim 166, Yin describes formulating the conjugate with a delivery system, for example a lipid, which is a pharmaceutical excipient according to claim 166. (p. 2 paragraph 11) Yin et al. does not specifically disclose an embodiment wherein the targeting ligand has the specific structure recited in the present claims.
Prakash et al. discloses compositions and methods for modulating expression of ANGPTL3 mRNA and protein. (p. 2 paragraph 9) In one embodiment the modulator is an oligonucleotide modified with a conjugate group. (p. 2 paragraph 11) In a particular embodiment, when the compound is administered to a subject, the conjugated targeting moiety results in increased delivery, uptake, and activity in hepatocytes, or in the liver. (p. 4 paragraph 26) In particular embodiments Prakash et al. discloses a method for treating a subject, for example a human, by administering this compound to the subject. (p. 12 paragraphs 56-57)
Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to use the ligands described as Prakash as the targeting ligand attached to the delivery vehicle or gRNA in the compositions described by Yin et al. One of ordinary skill in the art would have found this to be obvious because Yin generally suggests using known ligands including saccharides such as GalNAc as targeting ligands, which would have suggested to one of ordinary skill in the art to use any ligands known in the art to be capable of inducing localization and uptake of nucleic acids, including those described by Prakash for use with small interfering RNAs.
Prakash et al. further discloses an embodiment wherein the conjugate has a formula A-B-C-D-(E-F)q, wherein A is an antisense oligonucleotide, B and C are a cleavable group and a linker, D is a branching group, E is a tether , and F is a ligand. (p. 4 paragraphs 28-36) When q=3 this conjugate is a trivalent conjugate, similar to those recited in the present claims. (p. 4 paragraph 39) Various trivalent conjugates are pictured wherein the ligand F is N-acetylgalactosamine, which is the same ligand appearing in the presently claimed compounds. (pp. 5-11) In a particular example a conjugate group is pictured as follows:
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In this structure both the “branching” moiety D and the “ligand” moiety F are the same as the structures recited in the present claims. The only difference concerns the “tether” moiety which is a C6-alkylene rather than an oligoethylene glycol as presently claimed. Prakash et al. additionally discloses another preferred embodiment having an oligoethylene glycol tether which differs from the present claims only in that it has only three ethylene glycol units rather than four. (p. 56 paragraph 485)
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However, Prakash et al. additionally discloses that a variety of different tether structures can be used in the disclosed conjugates, including oligoethylene glycols of a length encompassing the tethers recited in the presently claimed structures. (p. 47 paragraph 444) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to modify the specific embodiments disclosed by Prakash et al. to use different tethers such as the one presently claimed, in view of the various embodiments of the tether moiety disclosed by Prakash.
Therefore the invention taken as a whole is prima facie obvious.
Response to Arguments
Applicant’s arguments, submitted June 29, 2026, with respect to the above grounds of rejection, and the declaration under 37 CFR 1.132 by James Heyes, have been fully considered and not found to be persuasive to remove the rejection.
As an initial matter, both Applicant’s arguments and the declaration contain arguments concerning an embodiment wherein mRNA is directly conjugated to a targeting moiety, and allege that one of ordinary skill in the art would not have had a reasonable expectation of success in creating such a construct that would be stable and effective in vivo. It is agreed that as presently amended both independent claims 162 and 163 claim embodiments wherein the targeting ligand and the mRNA are separate molecules, and that the claims are not directed to a direct covalent conjugate of the mRNA to the targeting ligand. Therefore these arguments are moot.
With respect to the other arguments, describing the embodiment wherein the mRNA and the targeting ligand are separate molecular entities, Applicant argues that the lipid nanoparticles described by Heartlein do not need a targeting moiety because they would naturally bind ApoE in the blood and be targeted to hepatocytes without the addition of any further ligand such as GalNAc.
However, this argument runs contrary to the suggestions in the prior art references themselves. Looking to the disclosure of Heartlein, (p. 90 paragraph 107 – p. 91 paragraph 110) the reference specifically suggests including targeting ligands in the transfer vehicle, including carbohydrate ligands. There is no suggestion that the nanoparticles would pick up endogenous targeting moieties in vivo as alleged by Applicant. Contrary to Applicant’s arguments, one of ordinary skill in the art would have seen the reference as suggesting that the attachment of specific targeting ligands to the transfer vehicle would be expected to produce an additional benefit with respect to targeting specific cells such as hepatocytes. Therefore one of ordinary skill in the art would have expected that attaching one of the carbohydrate targeting ligands described by Prakash would be useful for targeting the lipid nanoparticles described by Heartlein.
Similarly, regarding the rejection over Yin in view of Prakash, Applicant argues that the delivery vehicles described by Yin do not include GalNAc ligands as claimed herein. Specifically, Applicant points to the references US2010/0303723 and US2012/0156135 (cited in PTO-1449) which hare incorporated by reference into the disclosure of Yin, arguing that neither of these references teach or suggest the structure of the GalNAc ligand. However, this argument rests on a misinterpretation of the disclosure of the prior art. Both US2010/0303723 and US2012/0156135 describe a wide variety of targeting ligands, including carbohydrates, and are relied upon for the general teaching of particles functionalized with targeting ligands. More relevant to the disclosure of the present application is the fact that Yin specifically discloses GalNAc as a targeting ligand for targeting RNA to the liver. (p. 18 paragraph 73) While US2010/0303723 and US2012/0156135 are reasonably relied upon for the general teaching of functionalized lipid nanoparticles, the specific teaching of Yin regarding the use of GalNAc ligands for liver targeting is more relevant to the question of whether one of ordinary skill in the art would have found it to be obvious to attach Prakash’s trivalent GalNac ligand either to a lipid nanoparticle or a guide RNA.
It is further noted that, while as presently amended the mRNA and the targeting ligand are separate molecules, the RNA to which the ligand is conjugated in the disclosure of Yin is not the mRNA itself but rather a guide RNA, which is a separate molecular entity, and not a part of the mRNA. Therefore a composition containing a mRNA and a GalNAc conjugated guide RNA would infringe the claims as presently pending.
For these reasons the rejections are deemed proper and maintained.
Conclusion
No claims are allowed in this action. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 7/14/2026
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