DETAILED ACTION
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 .
This action is in response to the papers filed December 11, 2025. Currently, claims 1, 7, 10, 12-13, 18, 25, 27-29, 32, 35, 64-65 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority
This application claims priority to
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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 1, 7, 10, 25, 35, 64 are rejected under 35 U.S.C. 103 as being unpatentable over Lieberman et al (US 20080153737) in view of OTS (8/19/2016, retrieved from https://www.oligotherapeutics.org/location-location-location-galnac-targeted-delivery-hepatocytes/).
Lieberman teaches a method in which B16 melanoma cells (skin cells) were transfected with a plasmid expression vector encoding HIV gp160 protein and then implanted subcutaneously into mice. After the development of env-expressing tumors, the mice were injected either intratumorally or intravenously with a siRNA compounds targeting c-myc, MDM2, and VEGF mRNA that each were conjugated electrostatically to a single chain anti-env antibody (F105-P) fused to protamine for siRNA binding. This resulted in decreased growth of env-expressing tumors. See paragraphs 134-139, 142, 152, 160, and Fig. 13.
Lieberman also teaches methods in which Jurkat cells, HeLa cells, or CD4+ T cells were infected with HIV to induce cell surface expression of env, and were then contacted with siRNAs conjugated to an antibody (F105-P) directed against env. See paragraphs 129-133. Lieberman taught that different receptors could be targeted, and that antibody could be replaced by another cell surface receptor ligand (paragraph 166). Thus, Lieberman discloses a general method of providing receptor-mediated transfection to a variety of different types of cells by ectopically expressing a receptor in those cells and then targeting that receptor with a nucleic acid/receptor ligand conjugate.
Lieberman did not teach the use of the asialoglycoprotein receptor (ASGPR) and N-acetylgalactosamine (GalNAc)as a receptor ligand pair.
OTS reviewed the use of GalNAc and ASGPR for targeted delivery of oligonucleotides to the liver, and taught that the combination of GalNAc and ASGPR as a ligand receptor pair had been under development from 1999 through 2016. Use of the GalNAc targeting ligand provided substantial increases in delivery efficiency to hepatocytes that naturally express ASGPR in vitro and in vivo compared to oligonucleotides lacking a GalNAc targeting ligand. GalNAc-antisense oligonucleotide (ASO) conjugates have been designed that are metabolized quickly once internalized, releasing the ASO from the complex and thus avoiding potential steric interference with the machinery that mediates gene silencing (fifth paragraph). In a phase I clinical trial, a 32-fold improvement in efficiency of a GalNAc linked ASO compared to the parent ASO was observed in the study participants (third paragraph from end of text). GalNAc conjugates appear to provide specific delivery to ASGPR-expressing hepatocytes without transfection of non-target cells such as endothelial or Kupffer cells (second to last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the invention to have used ectopic expression of ASGPR in desired non-liver cells in combination with GalNAc conjugation to achieve specific delivery of oligonucleotide GalNAc conjugates to desired cells. One of ordinary skill aware of the teachings of Lieberman would be well aware that ectopic expression of a cell surface receptor in a cell of choice could serve as a means for ligand-directed oligonucleotide delivery to the cell. It would have been readily apparent to one of ordinary skill that such modification of a target cell would simplify multiple administrations of oligonucleotide to cells that are difficult to transfect thereby facilitating study of gene function in such cells. One would have been motivated to select the ASGPR/GalNAc receptor ligand pair in view of its demonstrated specificity and the fact that it was well characterized, although the substitution of this receptor/ligand pair for the ligand receptor pair of Lieberman would have been no more than the simple substitution of one known element for another to obtain predictable results, and was therefore prima facie obvious (MPEP2141(II)(B)).
Response to Arguments
The response traverses the rejection. The response asserts the substitution of ASGPR/GalNAc receptor ligand pair for the HIV env protein/F105-P Ab pair is not a simple substitution. The response argues the references do not disclosure ectopic expression of the ASGPR. This argument has been considered but is not convincing because at the time the invention was made, it was known ASGPR was detected on hepatocytes basolaterally and extra-hepatic cells namely peritoneal macrophages, rat and human testes, human-sperm, human intestinal epithelial cells and peripheral blood monocytes (See D’Souza et al. 2015). Thus, the ordinary artisan would have been motivated to have used the ASGPR and GalNAc receptor ligand in non-liver cells.
The response argues the substitution did not lead to “predictable results”. This argument has been reviewed but is not persuasive. The art teaches ASGPR was detected on hepatocytes basolaterally and extra-hepatic cells namely peritoneal macrophages, rat and human testes, human-sperm, human intestinal epithelial cells and peripheral blood monocytes (See D’Souza et al. 2015). The art teaches the asialoglycoprotein receptor (ASGPR) and N-acetylgalactosamine (GalNAc)as a receptor ligand pair may be used to improve efficiency of GalNAc linked ASO compared to the parent ASO was observed in the study participants. Thus, the ordinary artisan would have been motivated to have substituted the GalNAc linked ASO compared to the asialoglycoprotein receptor (ASGPR) and N-acetylgalactosamine (GalNAc)as a receptor ligand pair for the receptor/ligand pair of Lieberman. The art would have expected the liver and non-liver cells that each express ASGPR would function similarly, absent unexpected results. Thus for the reasons above and those already of record, the rejection is maintained.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Lieberman et al (US 20080153737) and OTS as applied to claims 1, 7, 10, 25, 35, 64 above, and further in view of Prakash et al (US 20140343123).
The teachings of Lieberman and OTS are discussed above and can be combined to render obvious a method of delivering oligonucleotide/GalNAc conjugates to a non-liver cell by ectopically expressing ASGPR in the non-liver cell. OTS disclosed the use of triantennary GalNAc ligands (e.g. paragraphs 4-6).
These references do not teach a GalNAc ligand of the structure recited in claim 12.
Prakash taught a variety of GalNAc ligands for facilitating delivery of oligonucleotides, such as antisense oligonucleotides and siRNAs, through binding ASGPR, including Formula XI at page 103, paragraph 1113, and claim 204. Formula (XI) is identical to the structure set forth in instant claim 46. This ligand is also referred to as “GalNAc3-7a” and was used successfully to improve oligonucleotide delivery to ASGPR-expressing cells in a variety of examples e.g. Table 76 at page 464 and Table 99 at page 474).
It would have been obvious to one of ordinary skill in the art at the time of the invention to have selected Formula (XI) (GalNAc3-7a ) of Prakash as a GalNAc ligand in the invention of Lieberman as modified. The GalNAc ligands of Prakash are all designed to bind the ASGPR, and GalNAc3-7a was demonstrated to be useful in improving the delivery of conjugated oligonucleotides. Therefore the selection of Formula (XI) (GalNAc3-7a ) would have been no more than the selection of one alternative from a group of equivalents and the invention as a whole was prima facie obvious.
Response to Arguments
The response states that Applicant has not addressed all the issues of the dependent claims but believes that each claim is patentable on its own merits.
This argument has been considered but is not convincing for the reasons provided above. Thus for the reasons above and those already of record, the rejection is maintained.
Claim 65 is rejected under 35 U.S.C. 103 as being unpatentable over Lieberman et al (US 20080153737) and OTS as applied to claims 1, 7, 10, 25, 35, 64 above, and further in view of Zalachoras et al (Front. Mol. Neurosci. 4(10), 12 pages, 2011) and Kanmogne et al (J. Neuropath. Exp. Neurol. 61(11): 992-1000).
The teachings of Lieberman and OTS are discussed above and can be combined to render obvious a method of delivering oligonucleotide/GalNAc conjugates to a non-liver cell by ectopically expressing ASGPR in the non-liver cell. OTS disclosed the use of triantennary GalNAc ligands (e.g. paragraphs 4-6).
These references did not teach oligonucleotide delivery to the CNS, brain, or brain neurons.
Zalachoras reviewed methods of targeting RNAs in brain using antisense oligonucleotides (AONs), noting that AONs are particularly promising in relation to brain research (abstract). Zalachoras taught that in all instances of RNA or DNA interference in the brain, delivery is an issue, due largely to the difficulties in penetrating the blood brain barrier (page 4, first sentence of first paragraph, and first two sentences of paragraph bridging columns on page 5). However, once AONs are within the CNS they are taken up extremely fast by neurons and glia (see abstract and page 4, first full paragraph). The rapid uptake allows multiple rounds of administration at different stages of an experiment (first sentence of paragraph bridging pages 4 and 5). Methods of delivery to brain that avoid the blood brain barrier include direct injection into a specific brain region (if spatial specificity is important), injection into cerebrospinal fluid if broad distribution is more important, and intraventricular delivery into the cerebrospinal fluid (see paragraph bridging columns and first two paragraphs of right column on page 5).
One of ordinary skill in the art would appreciate that, in instances where multiple AON administrations to a specific brain region are desired, it could be advantageous to use a method of ectopic expression of a non-native receptor in the specific desired region, followed by administration of an AON conjugated to a ligand of the receptor. Such a method would require an invasive local administration of vector encoding the receptor to the desired brain region, but could be followed thereafter by relatively less invasive rounds of administration of AON conjugates to cerebrospinal fluid (and not directly into brain tissue) with the reasonable expectation of preferential delivery to neurons expressing the receptor. If the vector expressing the receptor provides stable expression (e.g. a lentiviral vector), then one could then reasonably expect that delivery of the AON conjugates would be enriched in the region of interest that expresses the receptor over multiple rounds of AON conjugate administration. That being said, it should be noted that those of ordinary skill appreciated that the GP160 receptor of Lieberman is neurotoxic (see Kanmogne at tile and abstract). Therefore one would have found motivation to use a different receptor/ligand combination, such as the ASGPR/GalNAc combination of OTC. Thus the invention as a whole was prima facie obvious.
Response to Arguments
The response states that Applicant has not addressed all the issues of the dependent claims but believes that each claim is patentable on its own merits.
This argument has been considered but is not convincing for the reasons provided above. Thus for the reasons above and those already of record, the rejection is maintained.
Claims 13, 18 are rejected under 35 U.S.C. 103 as being unpatentable over Lieberman et al (US 20080153737) and OTS as applied to claims 1, 7, 10, 25, 35, 64 above, and further in view of Doudna et al (US 20140068797).
Lieberman taught a method in which B16 melanoma cells (skin cells) were stably transfected with a plasmid expression construct encoding HIV gp160 protein and then implanted subcutaneously into mice. After the development of env-expressing tumors, the mice were injected either intratumorally or intravenously with a siRNA compounds targeting c-myc, MDM2, and VEGF mRNA that each were conjugated electrostatically to a single chain anti-env antibody (F105-P) fused to protamine for siRNA binding. This resulted in decreased growth of env-expressing tumors. See paragraphs 134-139, 142, 152, 160, and Fig. 13.
Lieberman did not teach a method in which the expression construct encoding the cell surface receptor was administered to the cell as a CRISPR system homology directed repair insertion cassette comprising a nucleic acid encoding the cell surface receptor.
Doudna taught methods of stably modifying mammalian cells through the use of CRISPR system homology directed repair. See abstract paragraphs 24, 150, 153, 258, 299, and 300, and e.g. claim 79.
It would have been obvious to one of ordinary skill in the art at the time of the invention to have used the method of Doudna to integrate a gp160 expression cassette of Lieberman into the B16 melanoma cells of Lieberman. One would have been motivated to do so in order to provide stable expression of the gp160 without the necessity to maintain the presence of an episomal expression construct, e.g. by antibiotic selection. Moreover, the use of the system of Doudna to modify the cells of Lieberman would have been recognized as an alternative approach to achieving the desired stable expression of Gp120 in the B16 melanoma cells, and so would have been no more than the simple substitution of one approach to predictably gaining stable gene expression for another. Thus the invention was prima facie obvious.
Response to Arguments
The response states that Applicant has not addressed all the issues of the dependent claims but believes that each claim is patentable on its own merits.
This argument has been considered but is not convincing for the reasons provided above. Thus for the reasons above and those already of record, the rejection is maintained.
Claims 27-29, 32 are rejected under 35 U.S.C. 103 as being unpatentable over over Lieberman et al (US 20080153737) and OTS as applied to claims 1, 7, 10, 25, 35, 64 above, and further in view of Baer et al (WO 91/04753) and Bandaru et al (US 20160024495).
Lieberman taught a method in which B16 melanoma cells (skin cells) were transfected with a plasmid expression vector encoding HIV gp160 protein and then implanted subcutaneously into mice. After the development of env-expressing tumors, the mice were injected either intratumorally or intravenously with a siRNA compounds targeting c-myc, MDM2, and VEGF mRNA that each were conjugated electrostatically to a single chain anti-env antibody (F105-P) fused to protamine for siRNA binding. This resulted in decreased growth of env-expressing tumors. See paragraphs 134-139, 142, 152, 160, and Fig. 13.
Lieberman did not teach delivery of modified single stranded compounds.
Baer taught methods of targeting antisense oligonucleotides to particular cells by conjugating the antisense oligonucleotide to an antibody directed against a cell surface moiety. See abstract , page 1, lines 8-12, and page 7, lines 18-24. Baer discussed antisense oligonucleotides against c-myc (page 2, lines 1-12).
Bandaru taught antisense oligonucleotides directed against c-myc (see abstract and paragraph 1). The antisense oligonucleotides may be conjugated to a moiety that increases cellular uptake of the oligonucleotide such as an antibody to a target protein (paragraphs 164 and 167). The oligonucleotides may be LNA or 2’-MOE gapmers (paragraphs 46-48 and 56). The oligonucleotides may be uniformly phosphorothioate modified and nucleobases may include 5’-methylcytosines substituted for cytosines (paragraphs 66 and 137).
It would have been obvious to one of ordinary skill in the art at the time of the invention to have substituted a c-myc antisense oligonucleotide-antibody conjugate for the c-myc siRNA-antibody conjugate of Lieberman. Doing so would have been no more than the combination of prior art elements according to known methods to yield predictable results, or the simple substitution of one known element for another to obtain predictable results. See MPEP 2141(III)(A and B). One would have had a reasonable expectation of success because the antisense oligonucleotides of Bandaru had been shown to inhibit myc expression and decrease the proliferation of cancer cells (paragraph 236) similarly to the siRNAs of Lieberman, the antibody of Lieberman had been shown to successfully target tumor cells expressing HIV env to deliver an oligonucleotide cargo, and because Baer provided guidance on how to construct oligonucleotide-antibody conjugates (page 10, line 5 to page 11, line 32).
Response to Arguments
The response states that Applicant has not addressed all the issues of the dependent claims but believes that each claim is patentable on its own merits.
This argument has been considered but is not convincing for the reasons provided above. Thus for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable over the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
April 2, 2026