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 .
Election/Restrictions
Applicant’s election of Invention I corresponding to claims 115-127 and 130 in the reply and the Species Group C filed on 07/16/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further search and consideration, the restriction election dated 06/09/2026 is withdrawn.
Claims 115-135 are pending and being examined on the merits.
Priority
The application is a 371 PCT of US2021/065386 filed 12/28/2021 which claims priority to application 63/131,528 filed 12/29/2020.
Information Disclosure Statement
The information disclosure statements filed 05/13/2026 and 06/02/2026 have been considered.
Claim Objections
Claims 115-120, 122, 128, and 131 are objected to because of the following informalities:
Claim 115, and 119-120 contains awkward phraseology by reciting “between at or about” or “of at or about”. Applicant may wish to amend the claim to recite “between about” or “between or about”; or “of or about” for improve claim language.
Claim 115 recites the lipid composition in terms of “moles versus moles od lipid”. While is is clear from the specification that the LNP comprises a molar ratio of about 30-70 moles of an ionizable lipid, to about 0.1 to about 20 moles of a phospholipid, about 20 to about 60 moles of cholesterol, and about 0.1 to about 5 .5 moles of PEGylated lipid. Applicant may wish to list the recited values as mole percent (mol%) or mole fraction relative to the total lipid composition for consistency with terminology ordinary used in the art.
Claims 116-118, the claim recite “the ratio…is at or about X” without identifying the ration convention. It would be remedial to recite about “(42:1 (w/w)” or equivalent language.
Claim 122 recites “the pka of the LNP” and lacks consistency with the antecedent limitation of claim 15, which recited the “liposomal pKa of the LPN”. It would be remedial to amend the claim to recite “the liposomal pKa of the LPM” for consistency.
Claim 128 is objected to because it improperly recited “The composition of claims 115”. It would be remedial to amend the claim to recite “The composition of claim 115”.
Claim 131 is objected to because the phrase “permitting the target cell to uptake the composition” is grammatically awkward. It would be remedial to amend the claim to recite “permitting the target cell to take up the composition” or “permitting uptake of the composition by the target cell”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 117 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 117 recites “the ratio of the total lipid weight to total RNA weight in the composition is between at or about 175 to 25”. As written, the claims recites a range having a higher lower endpoint than upper endpoint and therefore fails to clearly define the intended numerical range. It is unclear whether Applicant intended a ratio of about 17.5 to 25, 25 to 172, 175 to 25, or another range.
Claims 126-127, 130, 132-135 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The claims encompass RNAs encoding TERT having as little as 70% identity to SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40. The claims require that the TERT-mRNA LNP is in a cell and must be capable of functioning as a telomerase reverse transcriptase for treating diseases and disorders. Therefore, the claims require the provision of a genus of sequences between 70-100% identity to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 that are defined by the function of a transcriptase. While the specification teaches that the RNA encoding TERT comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 [0023], the specification only provides working examples with SEQ ID NOs: 39, 40, 1, 2, 31, 3, 5, and 4 at 100% identity [0074]. Therefore, the applicant has provided a limited genus of compositions comprising an RNA that comprises a sequence at least 70% identical to the recited sequences that is capable of functioning as a reverse transcriptase. Yamaguchi (Yamaguchi et al. New England Journal of Medicine 352.14 (2005): 1413-1424) teaches that telomerase activity TERT mutants with mutations in 5 specific codons was significantly reduced in comparison to wild type TERT. This teaches that 1 to 2 animo acid mutations in the TERT protein can affect activity. Therefore, Yamaguchi teaches that not all compositions comprising a sequence that is at least 70% identical to SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 is capable of functioning as a reverse transcriptase.
Additionally, claim 127 encompass a genus of TERT-encoding RNAs comprising one or more members selected from an extensive and chemically diverse collection of modified nucleotides. Although the specification contains working examples demonstrating delivery and biological activity of particular TERT-mRNAs, the working examples are not commensurate in scope with claim 127. This disclosure does not provide working examples demonstrating functional TERT-encoding RNAs incorporating the extensive and chemically diverse of modified nucleotides recited in claims 127. Rather the specification principally enumerated these modified nucleotides in Table 1B and identifies a small number of relevant modifications [0159], while the experimental examples demonstrate only particular TERT mRNA constructs and formulations. The unpredictability associated with the claimed genus is evidenced by Boo (Boo et al. Experimental & molecular medicine 52.3 (2020): 400-408). Boo teaches that approximately 170 different RNA modifications can affect multiple aspects of RNA behavior including translation, stability, and degradation [pg. 400, col. 2, para 2]. Boo further demonstrates that different modifications can product materially different and context-dependent effects. For example, m6A can either stabilize or destabilize and mRNA depending upon the particular reader proteins involved, whereas 8-oxoG can inhibit peptide-bond formation by more than 1000-fold, causing ribosome stalling, and result in rapid degradation of modified mRNA [pg. 402; pg. 404, col 2, para 2]. Boo additionally reports that pseudouridine may affect RNA secondary structure and protein-coding potential and may either stabilize or destabilize an RNA depending upon context [pg. 405, col 1, para 3].
Accordingly, in view of the limited amount of guidance provided by the specification and the art, and the unpredictability of the art, one of ordinary skill in the art would conclude that Applicant was not in possession of all compositions comprising an RNA that comprises a sequence of at least 70% identity to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 that is capable of functioning as a reverse transcriptase; and applicant was not in possession of the vast claimed RNA modifications.
Claims 126, 130, 132-135 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compositions and methods comprising a TERT mRNA wherein the RNA comprises SEQ ID NOs: 39, 40, 1, 2, 31, 3, 5, and 4, does not reasonably provide enablement for any compositions comprising a TERT mRNA wherein the RNA comprises a sequence at least 70% identical to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention
The claims encompass RNAs encoding TERT having as little as 70% identity to SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40. The claims require that the TERT-mRNA LNP is in a cell and must be capable of functioning as a telomerase reverse transcriptase for treating diseases and disorders.
Breadth of the claims
The claims require the provision of a genus of sequences between 70-100% identity to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 that are defined by the function of a transcriptase.
Guidance of the specification
While the specification teaches that the RNA encoding TERT comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to any one of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 [0023], the specification only provides working examples with SEQ ID NOs: 39, 40, 1, 2, 31, 3, 5, and 4 at 100% identity [0074]. Therefore, the applicant has provided a limited genus of compositions comprising an RNA that comprises a sequence at least 70% identical to the recited sequences that is capable of functioning as a reverse transcriptase.
Predictability and state of the art
Yamaguchi teaches that telomerase activity TERT mutants with mutations in 5 specific codons was significantly reduced in comparison to wild type TERT. This teaches that 1 to 2 animo acid mutations in the TERT protein can affect activity. Therefore, Yamaguchi teaches that not all compositions comprising a sequence that is at least 70% identical to SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 is capable of functioning as a reverse transcriptase.
Amount of experimentation necessary
A large amount of experimentation would be required to make and use the full scope of the claimed invention. One would be required to mutate every possible nucleotide, using single or multiple mutations, of SEQ ID NOS: 1-5, 7, 9, 14-17, 19, 21, 23, 25, 27, 29-31, 37-40 and measure their reverse transcriptase activity while making sure the mutants are at least 70% identical to SEQ ID NOs. This type of experimentation would require a large amount of inventive effort.
Thus, Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claims 132-135 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 132–135 encompass methods of treating or delaying the onset of a disease or disorder by administering the composition of claim 126 or the cell of claim 130. Claims 134 and 135 further encompass treatment of a broad genus of liver diseases including, inter alia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic hepatitis, liver cirrhosis, liver fibrosis, compensated cirrhosis, decompensated cirrhosis, acute-on-chronic liver failure, biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, chronic liver disease, hemochromatosis, Wilson’s disease, and ischemic hepatitis.
Although the specification identifies these diseases as embodiments, the disclosure does not reasonably convey to one of ordinary skill in the art that the inventors were in possession of methods effective for treating the full breadth of the claimed disease genus. The specification primarily provides experimental support directed to liver-targeted TERT mRNA delivery, telomerase activation, and liver fibrosis/cirrhosis-related models, but does not demonstrate representative treatment of the numerous diseases or mechanistically distinct liver diseases encompassed by the claims.
Claims 132-135 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compositions and methods comprising a TERT mRNA LNP for the treatment of liver cirrhosis and liver fibrosis related embodiments that demonstrate telomerase activation and biological benefit, does not reasonably provide enablement for any compositions comprising a TERT mRNA LNP for the treatment of any disease or any liver disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
Claims 132–135 encompass methods of treating or delaying the onset of a disease or disorder by administering the composition of claim 126 or the cell of claim 130. Claims 134 and 135 further encompass treatment of a broad genus of liver diseases including, inter alia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic hepatitis, liver cirrhosis, liver fibrosis, compensated cirrhosis, decompensated cirrhosis, acute-on-chronic liver failure, biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, chronic liver disease, hemochromatosis, Wilson’s disease, and ischemic hepatitis.
Breadth of the claims
The claims encompass methods of treating an extensive genus of diseases, including numerous liver diseases having substantially different etiologies, pathogenic mechanisms, and clinical manifestations.
Guidance of the Specification
While the specification demonstrates therapeutic effects in particular liver models using specific TERT mRNA/LNP formulations, it does not teach how to use the claimed compositions to successfully treat the entire scope of diseases encompassed by claims 132–135 without undue experimentation. The working examples are directed to specific embodiments and are not commensurate in scope with the breadth of the claims.
State of the Art
At the time of filing, liver disease therapeutics were recognized to be highly unpredictable. Henderson (Henderson et al. Nature 587.7835 (2020): 555-566) explain that fibrosis is a dynamic and heterogeneous process and that, despite significant advances in understanding fibrotic mechanisms, a substantial translational gap remains between identifying putative therapeutic targets and developing effective antifibrotic therapies.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to determine empirically, whether ever disease or liver disease can be treated with the TERT-mRNA LNP as claimed.
In view of the breadth of the claimed disease genus, the limited number of representative working examples, the absence of guidance demonstrating efficacy across the numerous recited liver diseases, and the unpredictable nature of liver disease therapeutics, a person of ordinary skill in the art would be required to engage in substantial experimentation to determine whether the claimed compositions are effective for each disease encompassed by the claims.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 115, 119-120, 122, 125-128, 130 and 131 are rejected under 35 U.S.C. 103 as being unpatentable over Ramunas (JP2016-514953A) in view of Nakai (US 2021/0023008 A1, PCT filed 3/25/2019) as evidenced by NM_198253.2 (NCBI Reference Sequence: NM_198253.2. Homo sapiens telomerase reverse transcriptase (TERT), transcript variant 1, mRNA. 1/13/2019).
Regarding claim 115 and 131, Ramunas teaches a composition for transient expression of exogenous telomerase activity in a cell and methods for extending a telomere, wherein the telomere extends in the cell, comprising administering a compound comprising a ribonucleic acid encoding telomerase reverse transcriptase (TERT) to a cell [abstract]. Ramunas teaches a compound for telomere extension, comprising a synthetic ribonucleic acid containing at least one modified nucleoside and encoding a telomerase reverse transcriptase, in a cell treated with the compound [pg. 2, para 9]. Ramunas teaches that the compounds and compositions further comprise a delivery carrier where the delivery carrier is a lipid nanoparticle [pg. 2, last paragraph; claim 19]. Ramunas teaches transiently increase telomerase activity upon transfection with a modified ribonucleic acid (modRNA) encoding TERT in MRC-5 cells [pg. 5, last paragraph].
Regarding claim 126, Ramunas teaches that the wild-type human TERT ORF used to create the DNA template for mRNA synthesis is identical to NCBI human TERT transcript variant 1 (reference sequence NM — 198253.2) [pg. 19, last paragraoh]. NM — 198253.2 comprises a sequence (nucleotides 92 to 3478) that is 82% identical to SEQ ID NO: 1.
Regarding claim 127, Ramunas teaches that the ribonucleic acid of the present invention is preferably a nucleoside modified RNA where the nucleoside is pseudouridine [pg. 9, para 10].
Regarding claim 128, Ramunas teaches that the composition further comprises a telomerase RNA component (TERC) [pg. 10, para 8].
Regarding claim 130, Ramunas teaches delivering the composition to liver cells [pg. 13, para 1].
Ramunas do not teach (a) a phospholipid at a molar ratio of between at or about 1 to 20 moles versus total moles of lipid in the LNP; (b) a PEGylated lipid at a molar ratio of between at or about 0.1 to 3 moles versus total moles of lipid in the LNP; (c) a cholesterol lipid at a molar ratio of between at or about 20 to 60 moles versus total moles of lipid in the LNP; and (d) an ionizable lipid comprising SS-OP or an SS-OP analog at a molar ratio of between at or about 30 to 70 moles versus total moles of lipid in the LNP; wherein the liposomal pKa of the LNP is between at or about 5.5 to 7.2.
Regarding claim 115, 120, 122, 125, and 131, Nakai teaches a cationic lipid that achieves further improvement of intracellular dynamics, which could not be achieved by the prior art, and can be used as a carrier for nucleic acid delivery, a lipid membrane structure using the cationic lipid, and a nucleic acid-introducing agent using the cationic lipid [0021]. Nakai teaches that the lipid membrane structure containing the novel cationic lipid shows high membrane fusion capacity in the endosomal environment, shows high endosomal escape efficiency, and thus can deliver nucleic acid efficiently into the cytoplasm [0023-0024]. Nakai teaches the cationic lipid represented by the formula (1) (i.e., a SS-OP)
PNG
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208
402
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where R1a and R1b are each independently an alkylene group having 1-6 carbon atoms, Xa and Xb are each independently a non-cyclic alkyl tertiary amino group having 1-6 carbon atoms and one tertiary amino group, or a cyclic alkylene tertiary amino group having 2-5 carbon atoms and 1-2 tertiary amino groups, R2a and R2b are each independently an alkylene group or an oxydialkylene group each having not more than 8 carbon atoms, Ya and Yb are each independently an ester bond, an amide bond, a carbamate bond, an ether bond or a urea bond, Za and Zb are each independently a divalent group derived from an aromatic compound having 3-16 carbon atoms and at least one aromatic ring, and optionally having a hetero atom, and R3a and R3b are each independently a residue derived from a reaction product of a liposoluble vitamin having a hydroxyl group, and succinic anhydride or glutaric anhydride, or a residue derived from a reaction product of a sterol derivative having a hydroxyl group, and succinic anhydride or glutaric anhydride, or an aliphatic hydrocarbon group having 12-22 carbon atoms [0025-0031]. Nakai teaches the preparation of mRNA-Encapsulated LNP of the cationic lipid lipid O-Ph-P4C2 (i.e., SS-OP) where the lipid composition comprises cationic lipid (i.e., ionizable lipid)/phospholipid/Chol/DMGPEG2k - 52.5/7.5/40/1.5 molar ratio [Table 14; 0299] or 60/10/30/3 [Table 5; 0260]. Nakai further teaches that the LNP possess a liposomal pKa of the cationic lipid 6.4 [Table 22].
Regarding claim 119, Nakai teachings of the lipid composition comprises cationic lipid (i.e., ionizable lipid)/phospholipid/Chol/DMGPEG2k - 52.5/7.5/40/1.5 molar ratio [Table 14; 0299] is a teaching where the the phospholipid is included in the LNP at a molar ratio of between at or about 4 to 6 moles versus total moles of lipid in the LNP; the PEGylated lipid is included in the LNP at a molar ratio of between at or about 1 to 2 moles versus total moles of lipid in the LNP; the cholesterol lipid is included in the LNP at a molar ratio of between at or about 35 to 45 moles versus total moles of lipid in the LNP; and the ionizable lipid is included in the LNP at a molar ratio of between at or about 50 to 60 moles versus total moles of lipid in the LNP since the specification teaches that "about" may refer to a range of values that fall within 25% or less in either direction (greater than or less than) of the stated reference value [0092].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to formulate the TERT mRNA composition of Ramunas using the LNP delivery system taught by Nakai because Nakai expressly teaches that cationic LNPs shows high membrane fusion capacity, promote endosomal escape efficiency, and achieves further improvement of intracellular dynamics. One of ordinary skill would reasonably expected Nakai’s improved mRNA delivery vehicle to increase intracellular delivery and translation of Ramunas’s TERT mRNA while maintaining the transient expression profile desired for telomere extension.
Claims 116-118, 121, and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Ramunas (JP2016-514953A) in view of Nakai (US 2021/0023008 A1, PCT filed 3/25/2019) as evidenced by NM_198253.2 (NCBI Reference Sequence: NM_198253.2. Homo sapiens telomerase reverse transcriptase (TERT), transcript variant 1, mRNA. 1/13/2019) as applied to claims 115 and further in view of Schwendt (WO 2020/128031, published 6/25/2020).
The teachings of Ramunas and Nakai are discussed above as applied to claim 115 and similarly apply to claims 116-118, 121 and 129.
Ramunas and Nakai do not teach where wherein the ratio of the total lipid weight to total RNA weight in the composition is between at or about 14 to 42 or where the ionizable lipid is included in the LNP at a molar ratio of between at or about 30 to 40 moles versus total moles of lipid in the LNP.
Schwendt teaches compositions and vaccines comprising said coding RNA in association with a polymeric carrier, a polycationic protein or peptide, or a lipid nanoparticle (LNP) [abstract]. Schwendt teaches the lipid nanoparticles (LNPs) comprise: (a) at least one coding RNA of the first aspect, (b) a cationic lipid, (c) an aggregation reducing agent (such as polyethylene glycol (PEG) lipid or PEG-modified lipid), (d) optionally a non-cationic lipid (such as a neutral lipid), and (e) optionally, a sterol; and that the ratio of cationic lipid to non-cationic lipid (i.e., ionizable lipid) to cholesterol-based lipid (i.e., phospholipid) to PEGylated lipid may be between about 30-60:20-35:20-30:1-15, or at a ratio of about 40:30:25:5, 50:25:20:5, 50:27:20:3, 40:30:20:10, 40:32:20:8, 40:32:25:3 or 40:33:25:2, or at a ratio of about 50:25:20:5, 50:20:25:5, 50:27:20:3, 40:30:20:10,40:30:25:5 or 40:32:20:8, 40:32:25:3 or 40:33:25:2, 50:10:38.5:1.5 or 47.4:10:40.9:1.7 respectively [pg. 129, para 1-2; pg. 157, para 1]. Schwendt teaches that a ratio of RNA to total lipid of 0.03-0.04 w/w which is analogous to a total lipid weight to total RNA weight ratio of 25 to 33.33 w/w [pg. 157, para 1]. Since the specification teaches that "about" may refer to a range of values that fall within 25% or less in either direction (greater than or less than) of the stated reference value [0092], this teaches wherein the ratio of the total lipid weight to total RNA weight in the composition is at or about 42. Schwendt teaches that the RNA-based composition has improved translation of coding RNA constructs [pg. 3, para 1].
Regarding claims 116-118 and 121, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to employ Schwendt’s established mRNA LNP formulations and weight ratios because Schwendt presents the lipid formulation as a generally suitable carrier for coding RNA, rather that as a structure that operates only with certain RNA. One of ordinary skill in the art would have a reasonable expectation of success since both Ramunas, Nakai and Schwendt each teach lipid enclosed RNAs and the combination would have predictably produced a TERT-mRNA LNP having overlapping lipid-component ranges.
Regarding claim 129, Schwendt teaches that the coding RNA of the first aspect may be an mRNA, a self-replicating RNA, a circular RNA, or a replicon RNA [pg. 45, para 4]. 28. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute the conventional modified TERT mRNA of Ramunas with a self-replicating or a circular RNA as taught by Schwendt with a reasonable expectation of success because Schwendt traches that these RNA formats are interchangeable coding RNA payloads for the same LNP delivery platform and identifies them as suitable alternatives for protein expression following LNP-mediated delivery.
Claims 123-124, and 132-135 are rejected under 35 U.S.C. 103 as being unpatentable over Ramunas (JP2016-514953A) in view of Nakai (US 2021/0023008 A1, PCT filed 3/25/2019) as evidenced by NM_198253.2 (NCBI Reference Sequence: NM_198253.2. Homo sapiens telomerase reverse transcriptase (TERT), transcript variant 1, mRNA. 1/13/2019) as applied to claims 115 and further in view of Coyle (US 2016/0324986 A1).
The teachings of Ramunas and Nakai are discussed above as applied to claim 115 and similarly apply to claims 123-124 and 132-135.
Ramunas and Nakai do not teach where the LPN formulated TERT further comprise a targeting moiety operably integrated in or attached to the LNP and where the TERT is adapted to interact with a liver cell for use in a method of treating liver cirrhosis.
Coyle teaches a method of treating a subject suffering from a disease associated with shortened telomeres comprising administering to the subject a liposome, wherein the liposome comprises a PEG-ylated lipid membrane having an external surface and defining an internal compartment, wherein: a) the external surface has attached thereto a targeting agent directed against a receptor on a target cell involved in receptor-mediated endocytosis or macropinocytosis; and b) the internal compartment contains a nucleic acid vector comprising an expression control sequence operative in the target cell and operatively linked to a nucleotide sequence encoding telomerase reverse transcriptase (TERT); wherein administration results in expression of active telomerase in target cells of the subject and wherein the active telomerase extends the length of telomeres in the target cells [0025-0027; claim 13]. Coyle teaches Coyle teaches that diesases associated with shortened telomeres include cryptogenic hepatic cirrhosis [Table I].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to attach Coyle’s known receptor-targeting ligand to the TERT-mRNA LNP as taught and suggested by Ramunas and Nakia. One of ordinary skill would be motivated to make the modification for the advantage of improving selective cellular uptake and reduce nonspecific delivery as taught by Coyle. It also would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to delivered the receptor-targeting ligand TERT-mRNA LNP as taught and suggested by Ramunas, Nakai, and Coyle to liver cells for use in a method of treating liver cirrhosis. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ramunas, Nakai and Coyle each teach lipid enclosed TERT, Ramunas teach the use of the TERT mRNA in methods for extending telomeres in liver cells, and Coyle teaches that diseases associated with shortened telomeres include liver cirrhosis.
Double Patenting
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 115-135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-9, 14, 19, 23-24, 30, 32, 35 and 37 of copending Application No. 18637899 in view of Ramunas (JP2016-514953A), Nakai (US 2021/0023008 A1, PCT filed 3/25/2019), Schwendt (WO 2020/128031, published 6/25/2020) and Coyle (US 2016/0324986 A1).
The copending claims teach all limitation of claim 115 except (a) a phospholipid at a molar ratio of between at or about 1 to 20 moles versus total moles of lipid in the LNP; (b) a PEGylated lipid at a molar ratio of between at or about 0.1 to 3 moles versus total moles of lipid in the LNP; (c) a cholesterol lipid at a molar ratio of between at or about 20 to 60 moles versus total moles of lipid in the LNP; and (d) an ionizable lipid comprising SS-OP or an SS-OP analog at a molar ratio of between at or about 30 to 70 moles versus total moles of lipid in the LNP; wherein the liposomal pKa of the LNP is between at or about 5.5 to 7.2. The teachings of Nakai are discussed above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to formulate the TERT mRNA composition of of the copending claims using the LNP delivery system taught by Nakai because Nakai expressly teaches that cationic LNPs shows high membrane fusion capacity, promote endosomal escape efficiency, and achieves further improvement of intracellular dynamics. One of ordinary skill would reasonably expected Nakai’s improved mRNA delivery vehicle to increase intracellular delivery and translation the TERT mRNA while maintaining the transient expression profile desired for telomere extension.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Raumnas, Nakai, Coyle, and Schwendt are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
This is a provisional nonstatutory double patenting rejection.
Claims 115-135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 11, 17, 18, 19-20, 25, 27, 29-32, 34, 36, 53, 66, and 98-109 of copending Application No. 17709108 in view of Ramunas (JP2016-514953A), Nakai (US 2021/0023008 A1, PCT filed 3/25/2019), Schwendt (WO 2020/128031, published 6/25/2020) and Coyle (US 2016/0324986 A1).
The copending claims teach all limitation of claim 115 except (a) a phospholipid at a molar ratio of between at or about 1 to 20 moles versus total moles of lipid in the LNP; (b) a PEGylated lipid at a molar ratio of between at or about 0.1 to 3 moles versus total moles of lipid in the LNP; (c) a cholesterol lipid at a molar ratio of between at or about 20 to 60 moles versus total moles of lipid in the LNP; and (d) an ionizable lipid comprising SS-OP or an SS-OP analog at a molar ratio of between at or about 30 to 70 moles versus total moles of lipid in the LNP; wherein the liposomal pKa of the LNP is between at or about 5.5 to 7.2. The teachings of Nakai are discussed above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to formulate the TERT mRNA composition of of the copending claims using the LNP delivery system taught by Nakai because Nakai expressly teaches that cationic LNPs shows high membrane fusion capacity, promote endosomal escape efficiency, and achieves further improvement of intracellular dynamics. One of ordinary skill would reasonably expected Nakai’s improved mRNA delivery vehicle to increase intracellular delivery and translation the TERT mRNA while maintaining the transient expression profile desired for telomere extension.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Raumnas, Nakai, Coyle, and Schwendt are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
This is a provisional nonstatutory double patenting rejection that has been issued a notice of allowance.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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