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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim interpretation
The term “about” is given its broadest possible interpretation in view of the specification and can be interpreted to encompass values
±
20
%
of the claimed value or range.
Preferable embodiments are not being given patentable weight as they are not required by the claim.
Claim 2 is directed to intended use of the composition recited in claim 1. However, the claim does not further limit the structure or composition of the claimed composition of claim 1.
WITHDRAWN REJECTIONS AND OBJECTIONS
Specification
The objection to the specification for not providing a descriptive title is withdrawn following amendment to provide a new title.
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.
Claims 8-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
The rejection due to lack of antecedent basis is withdrawn following claim amendments.
MAINTAINED REJECTIONS
Claim Rejections - 35 USC § 103
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.
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 3-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US8158601B2; published as Apr 17, 2012; hereinafter “Chen;” See PTO-892) in view of Santos et al (Biochim Biophys Acta. 2007 Jun; hereinafter “Santos;” See PTO-892).
Regarding claims 3, 4 and 6: Chen disclosed a lipid nanoparticle (LNP) comprising: 40-65% of cationic lipid, 5-10% of a neutral lipid, 25-40% of a sterol, and 0.5-10% of a PEG or PEG-modified lipid. (See Chen claim 3). Further claim 4 of Chen taught that the neutral lipid can be DSPC or DPPC, among other, which are phospholipids. Santos taught that “0.5 mol% of 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) modified with PEG having a mean molecular weight of 2000 (DSPE-PEG(2000)) substantially increased plasma circulation longevity of liposomes” (See Santos Abstract). It is noted that the liposomes used in Santos are made of DSPC (phospholipid) and are cholesterol free. However, one of ordinary skill in the art would have been motivated to use between 0.5%-2% PEG2K-DSPE in view of the advantages stated in Santos, such as improvement of longevity of the liposomes. As such it would be obvious to combine the teachings of Koker and Santos to arrive at the claimed liposome composition. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)
Claims 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US8158601B2; published as Apr 17, 2012; hereinafter “Chen;” See PTO-892) in view of Santos et al (Biochim Biophys Acta. 2007 Jun; hereinafter “Santos;” See PTO-892) and further in view of Narayanan et al (WO2018175783A1; published Sep 27, 2018; hereinafter “Narayanan;” See PTO-892) .
Regarding claim 5: As indicated above, Chen taught use of lipid nanoparticle comprising specific quantities of cationic, phospholipids, sterols and PEG-lipids. However, Chen did not teach the claimed ionizable lipids as required by the claim. However, Narayanan taught use of ionizable lipids comprising Dlin-MC3-DMA for making liposomes for use as mRNA-vaccine (See Narayanan p. 5, lines 20-25). As such it would have been obvious for a person of ordinary skill in the art to use the ionizable lipids for making mRNA vaccine. One of ordinary skill would recognize this as substituting one ionizable lipid for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12), i.e. making mRNA vaccines.
Regarding claim 7: Chen taught that the sterol can be cholesterol. (See Chen col.4, lines 23-27)
Response to Arguments: Applicant contends that the claimed compositions exhibit unexpectedly improved performance and relies on data in the Specification, including FIGs. 4A and 4B and Table 1, as well as examples describing immunogenic responses to various LNP formulations within the disclosed scope of PEG-lipid and lipid ratio variation, rather than a property uniquely attributable to the narrow claimed ranges. In particular the specification explicitly says that “Several mRNA-LNP-vaccines gave rise to over 50% of E7-specific CD8 T cell responses, whereas other mRNA-LNP-vaccines induced hardly any response (FIG. 4 a ). PEG-lipid chemistry and molar % of PEG-lipid were identified as critical parameters in relation to the magnitude of the E7-specific CD8 T-cell response. Low molar percentages of PEG-lipid were required to achieve a maximum T-cell response (FIG. 4 b ) DSG-PEG2000 based LNPs also the percentage of ionizable lipid had a significant impact on the immunogenicity.” (See [0282]).
Thus, the specification itself establishes that immunogenic performance is strongly dependent on routine formulation parameters, including PEG-lipid concentration, lipid ratios and PEG-lipid chemistry. This disclosure is consistent with the prior art teachings that LNP properties such as PEG content and lipid composition are known to be routinely optimized to achieve desired characteristics, including circulation, uptake and expression.
Accordingly, Applicants own data supports, rather than rebuts, the Examiner’s position that optimization of PEG-lipid molar percentage (including values below 1 mol%) and selection of Peg-lipid species such as C18-PEG2000 would have been a matter of routine experimentation within the scope of Chen’s overlapping ranges in view of Santos’ explicit teaching that low PEG-DSPE levels improve liposome performance.
With respect to Table 1 and FIG. 4A, while Applicant asserts that certain LNP formulations demonstrate improved immunogenicity, the data is not commensurate in scope with the claimed invention. The claims broadly encompass lipid nanoparticles defined by compositional ranges, whereas the data reflects a subset of specific experimental formulations under particular experimental conditions (including specific mRNA payloads and immunization protocols). Moreover, the specification indicates that a wide range of LNP compositions were tested, with variable outcomes., further supporting the conclusion that the results are attributable to general optimization of known formulation variables rather than a critical or unexpected property unique to the claimed ranges.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 103
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.
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Besin et al (WO2017099823A1; published Jun 15, 2017; hereinafter “Besin;” See PTO-892).
Regarding claim 1-2: Besin disclosed “In some embodiments, the molar lipid ratio is 50/10/35/4.5/0.5 (mol% cationic lipid/non-cationic lipid/structural lipid/PEG lipid).“ (See Besin, p. 90, lines 15-20). Besin disclosed that non-cationic lipids can be phospholipid and structural lipid can be a sterol. (See Besin, p. 90, lines 23-27). Further claim 33 of Besin taught that the lipid nanoparticle can be used for delivering nucleic acid such as mRNA. As such, Besin disclosed every aspect of the invention. Additionally, Besin additionally taught that suitable PEG lipids include Peg-DSPE, which is a C18 lipid. (See evidence in Ferillo Abstract). It would have been obvious to a person of ordinary skill in the art at the time of the invention to employ the specific lipid ratios taught by Besin, including 0.5 mol% PEG-DSPE in an mRNA comtaining lipid nanoparticle formulation as suitable for delivery of nucleic acids including mRNA. Selection of a value within an expressly disclosed prior-art range constitutes no more than routine optimization of a result-effective variable absent a showing of criticality or unexpected results associated with the claimed subrange.
Although the specification demonstrates improved immunogenicity for certain tested formulations comprising DSG-PEG2k at 0.5mol% the claim encompass numerous ionizable lipids, phospholipids, sterols, mRNA cargo and C18 PEG lipids throughout broad compositional ranges. The evidence is limited to particular formulations and therefore not commensurate in scope with the full-breadth of the claims.
It is further noted that Besin taught administration of LNP systemically or locally. (See p. 235, lines 20-30), as required by claim 2.
Claims 8-10, 16-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US8158601B2; published as Apr 17, 2012; hereinafter “Chen;” See PTO-892) in view of Santos et al (Biochim Biophys Acta. 2007 Jun; hereinafter “Santos;” See PTO-892).
Regarding claims 8-10; 16-18 and 20-21: The teachings of Chen in view of Santos are set forth above. Chen disclosed a lipid nanoparticle (LNP) comprising: 40-65% of cationic lipid, 5-10% of a neutral lipid, 25-40% of a sterol, and 0.5-10% of a PEG or PEG-modified lipid. (See Chen claim 3). Further claim 4 of Chen taught that the neutral lipid can be DSPC or DPPC, among other, which are phospholipids. Santos taught that “0.5 mol% of 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) modified with PEG having a mean molecular weight of 2000 (DSPE-PEG(2000)) substantially increased plasma circulation longevity of liposomes” (See Santos Abstract). It is noted that the liposomes used in Santos are made of DSPC (phospholipid) and are cholesterol free. However, one of ordinary skill in the art would have been motivated to use between 0.5%-2% PEG2K-DSPE in view of the advantages stated in Santos, such as improvement of longevity of the liposomes. As such it would be obvious to combine the teachings of Chen and Santos to arrive at the claimed liposome composition. It is noted that all the claimed compositions in the claims fall within the range taught by Chen in view of Santos. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)
Additionally, Chen taught a pharmaceutically acceptable formulation comprising the mRNA as required by claim 20 (claim 1 of Chen) and mRNA encoding Factor VII, an antigen as required by claim 18. It is noted that Chen taught that the pharmaceutical composition can be used to treat an infectious disease, as required by claim 21 (See Chen col. 83, lines 50-60).
Claims 19 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US8158601B2; published as Apr 17, 2012; hereinafter “Chen;” See PTO-892) in view of Santos et al (Biochim Biophys Acta. 2007 Jun; hereinafter “Santos;” See PTO-892) and further in view of Kowalski et al (Molecular Therapy, 2019; hereinafter “Kowalski;” See PTO-892).
The teachings of Chen in view of Santos are set forth above. It is noted that the claimed compositions did not teach an mRNA encoding CD40L, CD70 and caTLR4. It is however noted that these molecules are routinely delivered in mRNA liposomes. For example, Kowalski taught that “immunomodulatory molecules such as CD40L, CD70, OX40L, or granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., TriMix)” are encapsulated in mRNA-LNPs. As such the identity of the mRNA or the protein it encodes are deemed obvious absent showing of unexpected results. It would have been obvious to a person of ordinary skill in the art to encapsulate any one of the claimed mRNAs in the LNP taught by Chen in view of Santos, due to the teachings of Kowalski to enhance type I IFN activation.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US8158601B2; published as Apr 17, 2012; hereinafter “Chen;” See PTO-892) in view of Santos et al (Biochim Biophys Acta. 2007 Jun; hereinafter “Santos;” See PTO-892) and further in view of Akita et al (Molecular Therapy, 2019; hereinafter “Akita;” See PTO-892).
The teachings of Chen in view of Santos are set forth above. Chen or Santos did not teach or suggest the claimed ionizable lipid. However, it is noted that the claimed ionizable lipid was well known in the art. For example, Akita was directed to a lipid nanoparticle (LNP) composed of a series of SS-cleavable and pH-activated lipid-like materials (ssPalm) where a hepatocyte-targeting siRNA carrier by the molecular tuning
of the hydrophobic scaffold, and tertiary amine structures. The gene knockdown activity against a hepatocyte-specific marker (factor VII: FVII) was improved when a more fat-soluble vitamin (vitamin E) was employed as a hydrophobic scaffold. (See Akita Abstract). It would have been obvious to a person of ordinary skill in the art to combine the teachings of Chen in view of Santos with the teachings of Akita to arrive at a composition comprising the claimed ionizable lipid and C18 PEG-lipid, as the cited prior art are directed to delivery of gene therapy products. The person would have been further motivated to combine the prior art elements, as Akita clearly demonstrated enhanced targeting using the claimed ionizable lipid. [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M. Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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