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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 5, 2025 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted December 5, 2025, wherein new claim 166 is introduced. This application is a continuation of US application 18/409330, currently 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 62/438410, foiled 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.
Response to Arguments: Applicant’s arguments, submitted December 5, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that Heartlein provides only prophetic examples regarding delivery of mRNA to the liver. Applicant further argues that Heartlein describes only galactose and mannose as liver targeting ligands and does not further describe N-acetylgalactosamine. (GalNAc) Applicant further characterizes Prakash’s teaching as a “generic teaching” which fails to teach or suggest the currently claimed invention.
However, contrary to Applicant’s assertion, the fact that delivery of mRNA to hepatocytes is a prophetic example of Heartlein’s disclosure would motivate one of ordinary skill in the art to look for any other prior art disclosures of possible ligands foe targeting nucleic acid conjugates to hepatocytes. Prakash repeatedly describes the trivalent GalNAc ligand as a “cell-targeting” moiety, (see paragraphs 460-488 for example) indicating that these conjugates do function to target the payload to a specific cell. Also, Applicant’s statement that Heartlein “fails to suggest the use of any ligands known in the art” is simply wrong. Paragraphs 108-110 of Heartlein, for example, very generally describe the use of a wide variety of possible targeting ligands. One of ordinary skill in the art, reading Heartlein’s disclosure, would have concluded that the disclosure of a different cell-targeting ligand, such as those described by Prakash, would suggest using said ligand with mRNA in conjugates such as those described by Heartlein.
Applicant further argues that the wide range of tethers described by Prakash’s disclosure makes the selection of the specific tether having four ethylene glycol units rather than three to be nonobvious in view of the number of selections required. However, in addition to looking to the generic description of tethers on p. 47 paragraph 444 as described by Applicant, one of ordinary skill in the art would have looked to the previously recited example
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as a lead compound for further chemical modification. This specific example, which would serve as a starting point, has the same general tether structure, as well as values of n=1 and p=3. Therefore arriving at the presently claimed tether would require only a modification of p from 3 to 4, which is within the routine modification and experimentation that one of ordinary skill in the art would carry out in determining how to best apply the teachings of the prior art.
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 included with PTO-892) 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 December 5, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that Yin et al. only discloses conjugating gRNA (guide RNA) rather than mRNA to GalNAc. However, Yin does teach chemical modification of the mRNA for other reasons. (e.g. p. 49) Yin also describes using vectors to deliver the gRNA and the editing system, which can be the mRNA. (e.g. paragraphs 52-63) These can include cell or tissue targeting ligands. (paragraph 66) Looking to the overall teaching of the reference, one of ordinary skill in the art would have concluded that the nucleic acid editing system, if it is a Cas9 mRNA, could also be attached to a targeting ligand in the same manner. Therefore the rejection is deemed proper and maintained.
Conclusion
No claims are allowed in this action.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 12/19/2025