DETAILED ACTION
Claims 7-8, 11, 13-14, 17, 19-22, 24, 26, 28, 36, 39, 53, and 63-90 are pending. Of these, claims 19-21, 28, 63-73, 78-80, and 84 are withdrawn as directed to a nonelected invention. Therefore, claims 7-8, 11, 13-14, 17, 22, 24, 26, 36, 39, 53, 74-77, 81-83, and 85-90 are under consideration on the merits.
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 .
Status of the Rejections
The 112(b) rejection is withdrawn in view of the amendment.
The 103 rejection over Yu in view of Friedman is maintained and expanded to include additional claims in view of the amendment. The remaining 103 rejections are withdrawn in view of the amendment and replaced with new rejections over different combinations of references already of record, and which was necessitated by the amendment.
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 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90 are rejected under 35 U.S.C. 103 as unpatentable over Yu et al. (US Pat. 2019/0134184; published 5.9.2019) in view of Friedman et al. (US Pat. Pub. 2020/0276300; filed 8/17/2018).
As to claims 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90, Yu discloses vaccine formulations comprising a carrier, such as lipid nanoparticles encapsulating an antigen comprising a nucleic acid such as RNA, the nanoparticles comprising lipids (paragraphs 1, 83, 100, 106), wherein the RNA may be self-replicating mRNA (claim 88)(paragraph 12), the formulation further comprising an adjuvant such as an emulsion adjuvant comprising a squalene (paragraph 114), all as recited by base claims 7 and 8. Yu further teaches that the adjuvant may be administered separately in conjunction with the vaccine (paragraphs 103, 113), which reads on the language of claim 7 reciting a plurality of formulations comprising a first formulation comprising the lipid nanoparticle and mRNA and a second formulation comprising the squalene emulsion adjuvant.
Regarding claims 39 and 85-86, Yu teaches that the mRNA may comprise a chemical modification comprising an N1-methylpseudouridine (paragraph 81).
Regarding claim 87, Yi teaches that in certain embodiments, the mRNA may be replicating (paragraph 83), but Yu nowhere requires that the mRNA be replicating.
Regarding claim 90, ideally 100% of the RNA is encapsulated, which reads on the range recited by the claim (paragraph 106).
As to claims 13-14, 17, and 75-77, Yu teaches that the squalene adjuvant additionally may comprise a surfactant (claims 17 and 77) such as polysorbate 80 as recited by claims 13-14 and 75-76 as well as water (paragraph 102). The squalene may be used in the amount of 4.3 wt%, and the polysorbate 80 and sorbitan trioleate in the amount of 0.5% each (paragraph 104), which results in a ratio of squalene to total surfactant of 4.3 to 1, which is within the range of claims 17 and 77.
As to claims 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90, Yu does not further expressly disclose a specific embodiment wherein the nucleic acid is an mRNA and the carrier is a lipid nanoparticle as recited by base claims 7-8, nor that the lipid nanoparticle comprises a PEG-modified lipid, a noncationic lipid, a sterol, and an ionizable cationic lipid as recited by claims 7-8 and in the amounts recited by claims 53 and 89.
Friedman discloses MRNA vaccines comprising a modified mRNA encoding a herpes simplex virus glycoprotein antigen (paragraph 12), the vaccine comprising a lipid nanoparticle comprising the mRNA, the lipid nanoparticle comprising a pegylated lipid, a lipid that may be neutral (non-cationic), an ionizable cationic lipid, and a sterol (paragraphs 318 and 335). The cationic lipid is present in the amount of 30-95 mole % which overlaps the range of claims 53 and 89, and the non-cationic lipid is present in an amount such that the ratio of cationic lipid to the neutral lipid is from about 2:1 to about 8:1 (paragraph 331), and the sterol may be used in an amount such that there is a molar ratio of 2:1 to 1:1 cationic lipid to cholesterol (paragraph 333), and the PEGylated lipid may be used in an amount such that there is a molar ratio of 100:1 to 25:1 cationic lipid to PEGylated lipid. These molar ratios result in amounts that can be within the 5-25% non-cationic lipid and 25-55% sterol ranges of the claim. For example, the use of 50% cationic lipid and a 2:1 ratio of cationic to neutral lipid and a 2:1 ratio of cationic lipid to sterol and a 25:1 ratio of cationic lipid to PEGylated lipid would be within the ranges taught by Friedman, and would result in 25% non-cationic lipid and 25% sterol and 2% PEGylated lipid, which is within the ranges of claims 53 and 89.
As to claims 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to formulate the Yu composition as a formulation comprising a squalene emulsion adjuvant comprising a squalene and a lipid nanoparticle carrying mRNA, because Yu expressly teaches that its formulations may comprise mRNA as the type of nucleic acid, a lipid nanoparticle as the type of carrier for the nucleic acid, and a squalene emulsion adjuvant as the type of adjuvant. Such a modification is merely the combining of known elements of Yu’s disclosure according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143.
It further would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the Yu formulation comprising a lipid nanoparticle comprising mRNA by selecting a lipid nanoparticle that comprises cationic lipid, non-cationic lipid, sterol, and PEGylated lipid, and in amounts within the ranges of claims 53 and 89, because Yu does not expressly disclose the ingredients that make up the lipid nanoparticles which would have motivated the skilled artisan to search the art of lipid nanoparticle/mRNA formulations for information on how to formulate the lipid nanoparticles, which would have led to Friedman, which expressly teaches that a lipid nanoparticle comprising the ingredients recited by claims 7-8, 53, and 89 and in the recited amounts of claims 53 and 89 is suitable for use in formulations wherein the lipid nanoparticle is used as a carrier for mRNA, such that the skilled artisan reasonably would have expected that the Friedman nanoparticle could be used as the nanoparticle that carries the mRNA in the Yu formulation.
Claims 11 and 74 are rejected under 35 U.S.C. 103 as unpatentable over Yu et al. (US Pat. 2019/0134184) in view of Friedman et al. (US Pat. Pub. 2020/0276300) as applied to claims 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90 above, and further in view of Brito et al. (Molecular Therapy vol. 22, no. 12, 2118-2129 (2014); of record in IDS).
The teachings of Yu and Friedman are relied upon as discussed above, but they are silent regarding the droplet size of the squalene emulsion adjuvant as recited by claims 11 and 74.
Brito discloses mRNA vaccine formulations comprising an adjuvant comprising water, squalene, Span 85 (sorbitan trioleate), and Tween 80 (“polysorbate 80”), resulting in particles having a diameter of between 25 and 150nm, which overlaps the ranges of claims 11 and 74 (Abstract and 1st full paragraph of page 2119). Brito teaches that the formulation successfully elicited a potent immune response in animal models compared to a viral delivery technology (Abstract).
As to claims 11 and 74, it would have been prima facie obvious to select a squalene adjuvant comprising water, squalene, and sorbitan trioleate and polysorbate 80 surfactants and having a particle size range that is within the presently claimed range, because Yu is silent regarding the size of the squalene adjuvant such that the skilled artisan looking for guidance on the size of the squalene adjuvant droplets would look to Brito, which expressly teaches that such diameters are suitable for use in a squalene adjuvant for delivery of an RNA vaccine. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claims 22, 24, 26, and 81-83 are rejected under 35 U.S.C. 103 as unpatentable over Yu et al. (US Pat. 2019/0134184) in view of Friedman et al. (US Pat. Pub. 2020/0276300) as applied to claims 7-8, 13-14, 17-18, 39, 42, 44, 53, 57, 75-77, and 85-90 above, and further in view of Momin et al. (US Pat. Pub. 2007/0134268).
The teachings of Yu and Friedman are relied upon as discussed above, but they do not further expressly disclose that the squalene emulsion adjuvant further comprises a tocopherol as required by claims 22, 24, 26, and 81-83 and that is alpha-tocopherol (claims 26 and 83) and in an amount producing a squalene to tocopherol ratio of 20:1 or less as recited by claims 24 and 82.
Momin discloses a vaccine formulation comprising an emulsion adjuvant comprising water, squalene, alpha tocopherol, and Tween 80 (“polysorbate 80”)(paragraph 23), and discloses examples wherein the amounts of squalene and tocopherol are both 5%, which is a 1:1 ratio, which is within the range of claims 24 and 82. Momin teaches that the use of tocopherol in the adjuvant surprisingly has been found to enhance immune responses to a given antigen (paragraph 5).
As to claims 22, 24, 26, and 81-83, it would have been prima facie obvious to incorporate tocopherol in a 1:1 ratio with the squalene in the squalene emulsion adjuvant of Yu because Momin teaches that the use of tocopherol in such amounts in a squalene emulsion adjuvant advantageously enhances immune responses to the vaccine formulation.
Response to Applicant’s Arguments
Applicant argues that Yu discloses the use of a cationic nano-emulsion or a lipid nanoparticle as alternative embodiments for delivery of the nucleic acid, and fails to provide any motivation for using both delivery systems in combination. Applicant concludes that arriving at the claimed invention comprising both lipid nanoparticles and a squalene emulsion adjuvant is not merely the combining of known methods of Yu’s disclosure to yield predictable results.
In response, this argument is not persuasive because although Yu does teach a cationic nano-emulsion or a lipid nanoparticle as alternative embodiments for delivery of the nucleic acid as argued by Applicant, Yu also expressly teaches that any of the embodiments taught therein additionally may comprise the squalene-in-water emulsion as an adjuvant:
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Therefore, Yu teaches that the squalene emulsion can be used not only as a cationic nanoemulsion complexed with the mRNA as disclosed by Yu and discussed by Applicant, but also as an emulsion that may be incorporated into a composition that comprises any of the nucleic acid delivery systems taught therein, such as the lipid nanoparticles.
Applicant also argues that the claimed invention possesses unexpected effects because Figures 1-6 show that the addition of the squalene emulsion adjuvant increased IgG antibody titers against certain proteins from HSV-2 both when the mRNA was self-amplifying and when it was not self-replicating. Applicant concludes that this result must be unexpected because Yu describes the cationic nano-emulsion as a delivery system.
In response, Yu in fact describes the squalene emulsion as being an adjuvant as discussed above. In situations where the Applicants are relying upon unexpected results to rebut a prima facie case of obviousness, Applicants bear the burden to establish that the results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02(b).
Here, since Yu discloses that the squalene emulsion serves as an adjuvant in the compositions disclosed therein, the skilled artisan would have expected that its inclusion would enhance immune response to antigens upon administration, since that is the purpose of a vaccine adjuvant. Therefore, the IgG antibody titers disclosed by the specification are not unexpected based upon the evidence of record.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GAREN GOTFREDSON whose telephone number is (571)270-3468. The examiner can normally be reached on M-F 9AM-6PM.
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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/ Primary Examiner, Art Unit 1600
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