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 .
Application Status
This action is written in response to applicant’s correspondence received on 1/14/2026. Claims 11-13, 23-25, 28, 52, 58, and 62-77 are pending. Claims 24, 52, 58, 64-65, 72, and 77 have been amended.. All pending claims are currently under examination.
Any rejection or objection not reiterated here has been overcome. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Claim Rejections - 35 USC § 103 – Maintained/Updated in Response to Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 11-13, 23-25, 28, 52, 58, and 62-77 are rejected under 35 U.S.C. 103 as being unpatentable over Thess (WO 2013/143700 A1) in view of Schlake (WO 2017/036580-A1, published March 9, 2017) and Ciaramella (WO 2015164674 A1).
Note that claims 11-13, 23-25, 28, 58, and 62-64 have been amended to now depend from claim 58. Claim 58 will therefore be addressed first in the rejections that follow even though it is not the first claim listed numerically.
Regarding claim 58, Thess teaches artificial nucleic acid molecules comprising, from 5’ to 3’, a 5’UTR, a coding region encoding a polypeptide (“ORF”), and a 3’UTR element (page 40, second paragraph). Furthermore, Thess teaches that their constructs can be RNA (page 3, third paragraph). Thess teaches that the RNA can comprise a 5’-CAP structure, 5’ of the 5’-UTR region (e.g., page 4, final paragraph). Furthermore, Thess teaches that the RNA can be mRNA comprising a 5’ methylated cap (page 10, final paragraph).
Furthermore, Thess teaches the 5’UTR of HSD17B4 as a preferred embodiment (e.g., claim 49). Thess also teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph). Thess identifies SEQ ID NO: 1415 as HSD17B4 on page 94, second paragraph.
Furthermore, Thess teaches the specific 5’UTR element HSD17B4 to be used as the 5’UTR of their artificial nucleic acid constructs (page 35, final paragraph). Furthermore, Thess reduces to practice HSD17B4 as a functional and robust 5’UTR (e.g., Figure 22). Thess further teaches Figure 26 showing HSD17B4 as a 5’UTR, and teaches concerning Figure 26 that:
“HSD17B4 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly, the combination of HSD17B4 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically,” page 90, second paragraph.
Thess therefore teaches that 5’UTR HSD17B4 increases expression levels of target proteins, and also teaches that the combination of 5’UTR HSD17B4 with a 3’UTR works synergistically to further increase expression levels (quote above). Thess further teaches a number of 3’UTR elements (SEQ ID NOs 1369-1393, and claim 2).
Thess, further teaches poly(A) sequences at the 3’ end of RNA molecules, which can be up to 400 A residues, which encompasses 10-200 adenosine residues (page 5, second paragraph). Thess further teaches preferred embodiments where the poly(A) tail is between 60-250 nucleotides (page 17, fifth paragraph).
Thess teaches that their composition can be comprised in a pharmaceutical composition (page 73, fourth paragraph). Thess teaches that the composition can comprise a lipid nanoparticle, where the lipid nanoparticle comprises a cationic lipid (page 73, second paragraph).
Regarding claim 58, Thess does not teach that the 3’UTR used in their artificial nucleic acids is a sequence that is at least 95% identical to SEQ ID NO: 24. Thess, while teaching lipid nanoparticles (LNPs) comprising cationic lipids, does not teach that the LNP comprises at least one cationic lipid, a neutral lipid, a sterol, and a PEG-lipid.
Schlake teaches artificial nucleic acid molecules comprising 5’ and 3’ UTR regions (Abstract). Schlake and Thess therefore directly overlap in scope and focus. Schlake teaches a number of 5’UTRs and 3’UTRs to be used in their constructs (e.g. page 176 – entire page – to the first paragraph of 177). Schlake also teaches PSMB3 as a preferred embodiment of 3’UTR (Table 6, SEQ ID NO 164), and also states that the 3’UTR PSMB3 is “considered to contribute high translation efficiency,” (page 223, first paragraph); Schlake therefore teaches a direct motivation to use 3’UTR PSMB3, to improve translation efficiency.
Furthermore, Schlake teaches that the 3’UTR of PSMB3 is SEQ ID NO 164 (Table 6, SEQ ID NO 164). SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 (i.e., instantly recited SEQ ID NO: 24).
Additionally, Schlake also teaches lipid nanoparticle delivery mechanisms used in pharmaceutical compositions (page 160, third paragraph). Furthermore, Schlake also teaches that conventional liposomes consist of a lipid bilayer composed of cationic, anionic, or neutral lipids, a sterol, and PEG (page 160 final paragraph into page 161 first paragraph). However, Schlake does not teach that the nanoparticle comprises each of a cationic and neutral lipid, a sterol, and a PEG-lipid, explicitly.
Ciaramella is a patent document which teaches the delivery of therapeutic polynucleic acids involving pharmaceutical compositions and lipid nanoparticle delivery mechanisms (Abstract, and throughout). Thess, Schlake, and Ciaramella therefore directly overlap in subject and field of endeavor because they all involve the delivery of nucleic acids using vectors and therapeutics. Ciaramella teaches embodiments of lipid nanoparticles used as pharmaceutical compositions comprising a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid (e.g., page 4, first paragraph and page 643, third paragraph). Ciaramella therefore teaches that lipid nanoparticles comprising a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid is a known embodiment of a lipid nanoparticle formulation useful for therapeutic delivery.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Thess with the teachings of Schlake and Ciaramella, to combine the 5’UTR HSD17B4 taught by Thess with the 3’UTR PSMB3 taught by Schlake to make an artificial RNA molecule with these two UTRs because such a combination is the simple substitution of one known element (the 3’UTRs taught by Thess) with another 3’UTR (the PSMB3 3’UTR element taught by Schlake) to obtain predictable results. Furthermore, a practitioner would be motivated to combine the teachings of Thess and Schlake, because Schlake specifically stated that the use of the 3’UTR PSMB3 is associated with high translational efficiency (page 223, first paragraph) and therefore teaches a motivation to use the 3’ UTR PSMB3. Additionally, as stated above, Thess directly teaches that 5’UTRs and 3’UTRs work synergistically to enhance protein expression. The combination of 5’UTR HSD17B4 (SEQ ID NO 1415, Thess) with 3’UTR PSMB3 (SEQ ID NO 164, Schlake) therefore not only yields predictable results but a practitioner would be motivated to combine the two UTRs for beneficial, synergistic results because increased translational efficiency are taught by both Thess and Schlake with their respective UTRs (Thess, page 90, second paragraph, and Schlake, page 223, first paragraph).
Additionally, the as Thess and Schlake are drawn to therapeutic compositions and nanoparticles, it would be further obvious to modify the LNP formulations rendered obvious by the combination of Thess and Schlake, which can comprise a cationic lipid, neutral lipid, sterol, and PEG-lipid, with the teachings of Ciaramella, to include the LNP embodiment comprising a cationic lipid, neutral lipid, sterol, and PEG-lipid, because such a combination is the simple substitution of one known prior art element for another to obtain predictable results. In the present case, a practitioner would simply substitute the LNPs taught by Thess/Schlake for the LNP embodiment already taught and known by Ciaramella. Furthermore, the result is predictable, because Thess/Schlake in fact teach each of the LNP features (cationic lipid, neutral lipid, sterol, and PEG-lipid), and therefore directly overlaps with the embodiment of Ciaramella which combines a cationic lipid, neutral lipid, sterol, and PEG-lipid to form an LNP. Thus, such an LNP formulation is already known in the art, and taught to be used for the same purpose as the methods of Thess/Schlake, i.e., for the delivery of nucleic acids.
Regarding claims 11 and 12, Thess teaches antigenic polypeptides to be used as genetic vaccines by delivering artificial nucleic acids which express peptides and/or proteins, where such antigenic polypeptides can be a tumor antigen (page 2, final paragraph to page 3, first paragraph).
Regarding claim 13, Thess teaches that the antigenic peptide can further be a bacterial antigen (e.g., page 2, second paragraph).
Regarding claim 23, Thess teaches that the RNA molecule is modified at the coding region to be codon modified to increase G/C content (e.g., claim 30 of Thess, page 275).
Regarding claim 24, Thess teaches that the molecule can comprise a 5’- methylated cap structure (e.g., page 21, final paragraph, page 10, final paragraph). Furthermore, Schlake teaches that the 5’-cap structure can be a cap1 (page 143, final paragraph).
Regarding claim 25, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Regarding claim 28, Thess teaches that the molecule can comprise a poly(A) sequence of 10 to 200 adenosine nucleotides (e.g., claim 16, page 270). Furthermore, Thess teaches that the poly(A) sequence can be at the 3’ terminus of the molecule (e.g., page 5, second paragraph).
Regarding claim 52, Thess teaches the concept of expressing a polypeptide in a subject by administering to the subject the artificial RNAs recited (page 82, third paragraph). Thess teaches administering to a subject compositions, for instance to isolated tissues or cells for therapy (page 13, second paragraph). Thess also teaches the concept of pharmaceutically effective amounts (page 17, third paragraph). The pharmaceutical composition recited in claim 52 comprises elements encompassed by those recited in claim 58. For a rejection of these claim limitations, see the rejection of claim 58.
Regarding claim 62, Thess teaches that the RNA molecule comprises a poly(A) sequence (page 65, line 7). Furthermore, Thess teaches that such RNA molecules can comprise poly(A) tails that are 10 to 200 nucleotides, which comprises “at least 60” consecutive adenosine nucleotides (e.g., claim 16, page 270 of Thess).
Regarding claim 63, Thess teaches genetic vaccinations which express peptides or proteins or peptides (e.g., page 2, final paragraph to page 3, first paragraph). Thess teaches that such vaccines could express viral antigens (page 20, second paragraph).
Regarding claim 64, Thess teaches pseudouridine nucleotide modification to be used with the invention (page 69, line 12). Thess teaches the RNA can be mRNA (page 10, final paragraph).
Regarding claim 65, Thess teaches that the RNA can be mRNA (page 20, third paragraph). Thess teaches that the poly(A) sequence can be at the 3’-terminus (e.g., page 5, second paragraph). Thess teaches that the poly(A) tail may comprise 60, 70, 80, 90, or 100 residues (page 61, third paragraph).
Regarding claim 66, Schlake teaches that the modification of RNA can comprise N1-methyl pseudouridine (page 142, second paragraph).
Regarding claim 67, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 68, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 69, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 70, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 71, Thess teaches that genetic vaccines can comprise pathogen fragments from viruses (page 2 final paragraph and page 20, second paragraph). Furthermore, Schlake teaches that pathogenic antigens can be derived from influenza (page 145, line 17).
Regarding claim 72, Schlake teaches that the 5’-CAP structure can be cap1 (page 143, final paragraph). Thess teaches that the cap can be methylated (page 10, final paragraph).
Regarding claim 73, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 74, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 75, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 76, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 77, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Response to Arguments
The Applicant’s arguments submitted 1/14/2026 have been fully considered but are not persuasive.
The Applicant argues that the results obtained by combining the presently recited 5’ and 3’-UTRs (HSD17B4 and PSMB3, respectively) yields unpredictable results because of the enhanced expression observed in their studies. This argument is not persuasive.
The Applicant argues that nothing in Thess would motivate a practitioner to select HSD17B4 in particular. This argument is not persuasive because Thess is referenced as teaching HSD17B4 as the primary reference (i.e., Thess is the primary reference, and therefore teaches HSD17B4 as a starting point for UTRs). Furthermore, as discussed above, Thess does teach a motivation to select HSD17B4 because they teach that it is a robust UTR that enhanced translation (page 90, second paragraph and Figure 22).
The Applicant argues that the results are not predictable when combining the recited UTR elements in an artificial nucleic acid. The Applicant points to Figures 1-11 of their specification, and Figure 9 of the co-owned patent 11,739,335. However, Figure 1, while showing that there is variability in expression levels, in fact shows that all of the combinations of UTRs are functional. Figures 1-11 broadly show that different combinations of UTRs function at variable rates. This is therefore not evidence of a lack of predictability, as the UTRs all appear to function. Furthermore, there is no evidence that the recited UTRs would be non-functional as UTR elements in an artificial nucleic acid. To the contrary, and despite the Applicant’s assertion that no evidence is provided of predictable results, the fact that Thess and Schlake have already taught and reduced to practice the recited UTRs is strong evidence of predictable results. A practitioner would therefore not only be motivated to incorporate the teachings of Schlake, but the teachings as they relate to the PSMB3 3’UTR are predictable, as said 3’-UTR has been reduced to practice and found to enhance expression.
Furthermore, with regards to the Applicant’s assertion that the recited construct was among the best performers with regard to the level of expression, this finding is in fact not surprising or unexpected given the fact that Thess and Schlake teach the known UTRs recited, and further teach that they are known to enhance expression levels (page 90, second paragraph of Thess, page 223, first paragraph of Schlake). The Applicant has therefore not uncovered an unpredictable result because the recited UTRs were already known to enhance the expression of proteins, as taught by Thess and Schlake (above 103 rejection). It is therefore not unexpected to see enhanced expression when using UTR elements which are known to enhance the expression of proteins.
Furthermore, even if it is argued that the finding that the combination of 5’UTR HSD17B4 and 3’UTR PSMB3 is an unexpected result, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In this case, a practitioner would have already been motivated to combine the 3’ UTR of PSMB3 because it was already known to increase translation efficiency, as taught by Schlake (page 223, first paragraph). This analysis extends to the finding that such enhanced expression could be seen across different cell types: a practitioner would already be motivated to use the recited UTRs, and even if it were considered to be unexpected that such enhanced expression was observed across different cell types, such a discovery would flow naturally from the teachings and motivations provided by Thess/Schlake. The finding that, indeed, incorporation of a 3’UTR which was already known to increase translational efficiency resulted in increased translation efficiency is therefore not unexpected, and even if it were a practitioner would have been motivated to make such a discovery given the strong suggestion taught by Schlake (that 3’UTR PSMB3 enhances translation efficiency, page 223, first paragraph). The Applicant has not provided an argument for why the results would be unexpected in light of the fact that the UTRs were already known to provide such an enhanced translational benefit, or why the combination of the UTRs would not function with a poly(A) tail or HSL.
Furthermore, regarding claim 59, the Applicant argues that the rejection is “traversed,” however, the Applicant has cancelled claim 59. Thus, the absence of the rejection of claim 59 herein is not an acknowledgement of the traversal of the rejection: the rejection of claim 59 is not reproduced in this action because the Applicant has cancelled claim 59.
Double Patenting – Updated in Response to Applicant’s Amendments
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 11-13, 23-25, 28, 52, 58, and 62-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 20, 25, 28, and 29 of copending Application No. 16/496,518 (‘518) in view of Thess (WO 2013/143700 A1), Schlake (WO 2017/036580-A1, published March 9, 2017), and Ciaramella (WO 2015164674 A1).
Regarding claim 58 (the independent claim of the instant application), claim 1 of ‘518 recites an artificial nucleic acid comprising a coding region, a 5’ UTR, and a 3’UTR. Claim 3 recites that the 5’UTR is from a HSD17B4 gene. Claim 5 recites that the 3’UTR is from a PSMB3 gene. Claim 20 of ‘518 recites that the nucleic acid comprises a 5’ Cap structure. Claim 25 of ‘518 recites that the artificial nucleic acid comprises an poly(A) tail with 10-200 nucleotides. Claim 28 recites that the composition is a pharmaceutical composition. Claim 29 recites that the composition comprises cationic lipids.
As evidenced by Thess, Thess teaches SEQ ID NO 1415, which is the DNA equivalent SEQ ID NO 2 in instant claim 58 (sequence listing of Thess). Thess teaches that SEQ ID NO 1415 is the 5’ UTR of HSD17B4 (page 94, second paragraph). Therefore, by reciting the 5’UTR of HSD17B4, ‘518 is reciting SEQ ID NO 2 of instant claim 58, as evidenced by Thess. Thess teaches the mRNA can be capped and methylated (page 10, final paragraph).
As evidenced by Schlake, Schlake teaches SEQ ID NO 164, which is the DNA equivalent of SEQ ID NO 24 in instant claim 58 (Table 6, SEQ ID NO 164). Schlake teaches that SEQ ID 164 is the 3’UTR of PSMB3 (Table 6). Therefore, by reciting the 3’UTR of PSMB3, ‘518 is reciting SEQ ID NO 24 of instant claim 58, as evidenced by Schlake.
Claims 1, 3, 5, 20, 25, 28, and 29 of ‘518 therefore recite the structure of the artificial RNA of instant claim 58. ‘518 further recites elements of the LNP recited in claim 58 (cationic lipids, claim 29).
‘518 does not recite that the LNP comprises a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid.
Schlake also teaches lipid nanoparticle delivery mechanisms used in pharmaceutical compositions (page 160, third paragraph). Furthermore, Schlake also teaches that conventional liposomes consist of a lipid bilayer composed of cationic, anionic, or neutral lipids, a sterol, and PEG (page 160 final paragraph into page 161 first paragraph). However, Schlake does not teach that the nanoparticle comprises each of a cationic and neutral lipid, a sterol, and a PEG-lipid, explicitly.
Ciaramella is a patent document which teaches the delivery of therapeutic polynucleic acids involving pharmaceutical compositions and lipid nanoparticle delivery mechanisms (Abstract, and throughout). ‘518, Thess, Schlake, and Ciaramella therefore directly overlap in subject and field of endeavor because they all involve the delivery of nucleic acids using vectors and therapeutics. Ciaramella teaches embodiments of lipid nanoparticles used as pharmaceutical compositions comprising a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid (e.g., page 4, first paragraph and page 643, third paragraph). Ciaramella therefore teaches that lipid nanoparticles comprising a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid is a known embodiment of a lipid nanoparticle formulation useful for therapeutic delivery.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of ‘518, Thess with the teachings of Schlake and Ciaramella, to combine the 5’UTR HSD17B4 taught by ‘518 and Thess with the 3’UTR PSMB3 taught by Schlake to make an artificial RNA molecule with these two UTRs because such a combination is the simple substitution of one known element (the 3’UTRs taught by Thess) with another 3’UTR (the PSMB3 3’UTR element taught by Schlake) to obtain predictable results. Furthermore, a practitioner would be motivated to combine the teachings of ‘518, Thess and Schlake, because Schlake specifically stated that the use of the 3’UTR PSMB3 is associated with high translational efficiency (page 223, first paragraph) and therefore teaches a motivation to use the 3’ UTR PSMB3. Additionally, as stated above, Thess directly teaches that 5’UTRs and 3’UTRs work synergistically to enhance protein expression. The combination of 5’UTR HSD17B4 (SEQ ID NO 1415, Thess) with 3’UTR PSMB3 (SEQ ID NO 164, Schlake) therefore not only yields predictable results but a practitioner would be motivated to combine the two UTRs for beneficial, synergistic results because increased translational efficiency are taught by both Thess and Schlake with their respective UTRs (Thess, page 90, second paragraph, and Schlake, page 223, first paragraph).
Additionally, ‘518, Thess and Schlake are drawn to therapeutic compositions and nanoparticles, it would be further obvious to modify the LNP formulations rendered obvious by the combination of ‘518, Thess and Schlake, which can comprise a cationic lipid, neutral lipid, sterol, and PEG-lipid, with the teachings of Ciaramella, to include the LNP embodiment comprising a cationic lipid, neutral lipid, sterol, and PEG-lipid, because such a combination is the simple substitution of one known prior art element for another to obtain predictable results. In the present case, a practitioner would simply substitute the LNPs taught by Thess/Schlake for the LNP embodiment already taught and known by Ciaramella. Furthermore, the result is predictable, because Thess/Schlake in fact teach each of the LNP features (cationic lipid, neutral lipid, sterol, and PEG-lipid), and therefore directly overlaps with the embodiment of Ciaramella which combines a cationic lipid, neutral lipid, sterol, and PEG-lipid to form an LNP. Thus, such an LNP formulation is already known in the art, and taught to be used for the same purpose as the methods of Thess/Schlake, i.e., for the delivery of nucleic acids.
With regards to the remaining claims, ‘518 does not recite each of the remaining elements of the claims. However, given that ‘518 recites artificial nucleic acids comprising heterologous 3’ and 5’ UTR elements which also encode a protein, a practitioner would be motivated to combine the teachings of Thess/Schlake/Ciaramella with the subject matter of ‘518. The teachings of Thess, Schlake, and Ciaramlla as they relate to the remaining claims are given below:
Regarding claims 11 and 12, Thess teaches antigenic polypeptides to be used as genetic vaccines by delivering artificial nucleic acids which express peptides and/or proteins, where such antigenic polypeptides can be a tumor antigen (page 2, final paragraph to page 3, first paragraph).
Regarding claim 13, Thess teaches that the antigenic peptide can further be a bacterial antigen (e.g., page 2, second paragraph).
Regarding claim 23, Thess teaches that the RNA molecule is modified at the coding region to be codon modified to increase G/C content (e.g., claim 30 of Thess, page 275).
Regarding claim 24, Thess teaches that the molecule can comprise a 5’-cap structure (e.g., page 21, final paragraph). Furthermore, Schlake teaches that the 5’-cap structure can be a cap1 (page 143, final paragraph).
Regarding claim 25, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Regarding claim 28, Thess teaches that the molecule can comprise a poly(A) sequence of 10 to 200 adenosine nucleotides (e.g., claim 16, page 270). Furthermore, Thess teaches that the poly(A) sequence can be at the 3’ terminus of the molecule (e.g., page 5, second paragraph).
Regarding claim 52, Thess teaches the concept of expressing a polypeptide in a subject by administering to the subject the artificial RNAs recited (page 82, third paragraph). Thess teaches administering to a subject compositions, for instance to isolated tissues or cells for therapy (page 13, second paragraph). Thess also teaches the concept of pharmaceutically effective amounts (page 17, third paragraph). The pharmaceutical composition recited in claim 52 comprises elements encompassed by those recited in claim 58. For a rejection of these claim limitations, see the rejection of claim 58.
Regarding claim 62, Thess teaches that the RNA molecule comprises a poly(A) sequence (page 65, line 7). Furthermore, Thess teaches that such RNA molecules can comprise poly(A) tails that are 10 to 200 nucleotides, which comprises “at least 60” consecutive adenosine nucleotides (e.g., claim 16, page 270 of Thess).
Regarding claim 63, Thess teaches genetic vaccinations which express peptides or proteins or peptides (e.g., page 2, final paragraph to page 3, first paragraph). Thess teaches that such vaccines could express viral antigens (page 20, second paragraph).
Regarding claim 64, Thess teaches pseudouridine nucleotide modification to be used with the invention (page 69, line 12).
Regarding claim 65, Thess teaches that the RNA can be mRNA (page 20, third paragraph). Thess teaches that the poly(A) sequence can be at the 3’-terminus (e.g., page 5, second paragraph). Thess teaches that the poly(A) tail may comprise 60, 70, 80, 90, or 100 residues (page 61, third paragraph).
Regarding claim 66, Schlake teaches that the modification of RNA can comprise N1-methyl pseudouridine (page 142, second paragraph).
Regarding claim 67, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 68, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 69, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 70, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 71, Thess teaches that genetic vaccines can comprise pathogen fragments from viruses (page 2 final paragraph and page 20, second paragraph). Furthermore, Schlake teaches that pathogenic antigens can be derived from influenza (page 145, line 17).
Regarding claim 72, Schlake teaches that the 5’-CAP structure can be cap1 (page 143, final paragraph).
Regarding claim 73, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 74, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 75, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 76, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 77, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Claims 11-13, 23-25, 28, 52, 58, and 62-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41 and 51-55 and 63 of copending Application No. 17/429,182 (‘182) in view of Thess (WO 2013/143700 A1), Schlake (WO 2017/036580-A1, published March 9, 2017), and Ciaramella (WO 2015164674 A1).
Regarding claim 58 (the independent claim of the instant application), claim 41 of ‘182 recites an RNA molecule with a coding region. Claim 41 recites that the coding RNA is complexed with an LNP. Claim 41 is further directed to a method of treatment where a composition is administered, and therefore recites a pharmaceutical composition. Claim 52 recites that the mRNA comprises a 5’-CAP structure and a poly(A) tail. Furthermore, claim 55 of ‘182 recites that the RNA of claim 41 further comprises a 5’UTR from an HDS17B4 gene and a 3’UTR that is from PSMB3. Claim 63 recites that the LNP comprises a cationic lipid, a neutral lipid, a sterol, and a PEG-lipid.
As evidenced by Thess, Thess teaches SEQ ID NO 1415, which is the DNA equivalent SEQ ID NO 2 in instant claim 58 (sequence listing of Thess). Thess teaches that SEQ ID NO 1415 is the 5’ UTR of HSD17B4 (page 94, second paragraph). Therefore, by reciting the 5’UTR of HSD17B4, ‘182 is reciting SEQ ID NO 2 of instant claim 58, as evidenced by Thess. Thess teaches that the mRNA can be methylated and capped at the 5’ end (page 10, final paragraph).
As evidenced by Schlake, Schlake teaches SEQ ID NO 164, which is the DNA equivalent of SEQ ID NO 24 in instant claim 58 (Table 6, SEQ ID NO 164). Schlake teaches that SEQ ID 164 is the 3’UTR of PSMB3 (Table 6). Therefore, by reciting the 3’UTR of PSMB3, ‘182 is reciting SEQ ID NO 24 of instant claim 58, as evidenced by Schlake.
Claims 41 and 51-55 and 63 of ‘182 therefore recite the structure of instant claim 58.
With regards to the remaining claims, ‘518 does not recite each of the remaining elements of the claims. However, given that ‘518 recites artificial nucleic acids comprising heterologous 3’ and 5’ UTR elements which also encode a protein, a practitioner would be motivated to combine the teachings of Thess/Schlake with the subject matter of ‘518. The teachings of Thess/Schlake/Ciaramella as they relate to the remaining claims are given below:
Regarding claims 11 and 12, Thess teaches antigenic polypeptides to be used as genetic vaccines by delivering artificial nucleic acids which express peptides and/or proteins, where such antigenic polypeptides can be a tumor antigen (page 2, final paragraph to page 3, first paragraph).
Regarding claim 13, Thess teaches that the antigenic peptide can further be a bacterial antigen (e.g., page 2, second paragraph).
Regarding claim 23, Thess teaches that the RNA molecule is modified at the coding region to be codon modified to increase G/C content (e.g., claim 30 of Thess, page 275).
Regarding claim 24, Thess teaches that the molecule can comprise a 5’-cap structure (e.g., page 21, final paragraph). Furthermore, Schlake teaches that the 5’-cap structure can be a cap1 (page 143, final paragraph).
Regarding claim 25, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Regarding claim 28, Thess teaches that the molecule can comprise a poly(A) sequence of 10 to 200 adenosine nucleotides (e.g., claim 16, page 270). Furthermore, Thess teaches that the poly(A) sequence can be at the 3’ terminus of the molecule (e.g., page 5, second paragraph).
Regarding claim 52, Thess teaches the concept of expressing a polypeptide in a subject by administering to the subject the artificial RNAs recited (page 82, third paragraph). Thess teaches administering to a subject compositions, for instance to isolated tissues or cells for therapy (page 13, second paragraph). Thess also teaches the concept of pharmaceutically effective amounts (page 17, third paragraph). The pharmaceutical composition recited in claim 52 comprises elements encompassed by those recited in claim 58. For a rejection of these claim limitations, see the rejection of claim 58.
Regarding claim 62, Thess teaches that the RNA molecule comprises a poly(A) sequence (page 65, line 7). Furthermore, Thess teaches that such RNA molecules can comprise poly(A) tails that are 10 to 200 nucleotides, which comprises “at least 60” consecutive adenosine nucleotides (e.g., claim 16, page 270 of Thess).
Regarding claim 63, Thess teaches genetic vaccinations which express peptides or proteins or peptides (e.g., page 2, final paragraph to page 3, first paragraph). Thess teaches that such vaccines could express viral antigens (page 20, second paragraph).
Regarding claim 64, Thess teaches pseudouridine nucleotide modification to be used with the invention (page 69, line 12).
Regarding claim 65, Thess teaches that the RNA can be mRNA (page 20, third paragraph). Thess teaches that the poly(A) sequence can be at the 3’-terminus (e.g., page 5, second paragraph). Thess teaches that the poly(A) tail may comprise 60, 70, 80, 90, or 100 residues (page 61, third paragraph).
Regarding claim 66, Schlake teaches that the modification of RNA can comprise N1-methyl pseudouridine (page 142, second paragraph).
Regarding claim 67, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 68, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 69, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 70, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 71, Thess teaches that genetic vaccines can comprise pathogen fragments from viruses (page 2 final paragraph and page 20, second paragraph). Furthermore, Schlake teaches that pathogenic antigens can be derived from influenza (page 145, line 17).
Regarding claim 72, Schlake teaches that the 5’-CAP structure can be cap1 (page 143, final paragraph).
Regarding claim 73, Ciaramella teaches that the LNPs comprise at least one cationic lipid, a neutral lipid comprising DSPC, cholesterol, and PEG-lipid (page 876, fifth paragraph).
Regarding claim 74, Ciaramella teaches that the ratio of cationic lipid, neutral lipid, sterol, and PEG-lipid was 20-60%, 5-25%, 25-55%, and 0.5-15% (page 876, fifth paragraph).
Regarding claim 75, Thess teaches SEQ ID NO: 1415, which is 100% identical to SEQ ID NO:1 of the present application. Note that presently recited SEQ ID NO:2, as recited in claim 58, is simply the RNA equivalent of SEQ ID NO: 1 of the present application. Given that Thess teaches SEQ ID 1415 which is equivalent to instant SEQ ID NO:1, and further that Thess also teaches that their constructs can be RNA, Thess inherently teaches the RNA equivalent of instantly recited SEQ ID NO:2, which is 100% identical to SEQ ID NO 2 (Thess, SEQ ID NO 1415 RNA equivalent, and page 3, third paragraph).
Regarding claim 76, Schlake teaches SEQ ID NO 164. SEQ ID NO 164 of Schlake is a 100% match to SEQ ID NO: 23 of the instant application; note that presently recited SEQ ID NO: 24 is simply the RNA equivalent of SEQ ID NO 23. Schlake teaches that their constructs can be mRNAs, and therefore inherently teaches the RNA equivalent of their SEQ ID NO: 164 with 100% match (i.e., instantly recited SEQ ID NO: 24).
Regarding claim 77, Thess teaches that the molecule can comprise a histone stem-loop (page 62, lines 27-29).
Response to Arguments
As an initial matter, all arguments relating to the traversal of the rejections of claim 59 are moot because the Applicant has canceled claim 59. Thus, the absence of the rejections of claim 59 are not a concession of the Applicant’s arguments but are rather not included in this rejection because the Applicant has cancelled claim 59.
Regarding the Applicant’s arguments concerning the double patenting rejection with respect to ‘518, the Applicant argues that they have made amendments to ‘518 which render the rejection moot. This argument is not persuasive because the Applicant has not made amendments to ‘518 since the issuance of the previous office action, and the claims of ‘518 still warrant the double patenting rejection as outlined above.
The Applicant argues that the double patenting rejection with regards to ‘182 should withdraw because it is the only outstanding rejection. This argument is not persuasive because it is not the only outstanding rejection (see 103 and double patenting rejections, above).
Conclusion
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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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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