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 .
Rejections Necessitated by 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.
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.
Claim(s) 1-4, 8, 12-13, 19, 27-28, 32-33, 35-36, 38-40, 42-43, 45, 50 and 52-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Ciaramella (20190336595-cited by the IDS), Ciaramella (20180311336-see form 892), Baumhof et al (WO2018078053, from 3/4/2024 IDS) and Anderson (20160367686-see form 892).
Ciaramella (‘595) describes RNA vaccines comprising polynucleotides encoding one or more influenza antigens, including hemagglutinin antigens; see abstract. See para. 4 and 5 for describing a method of inducing an antigen specific immune response in a human subject, comprising administering a dose of 10-100 ug of a vaccine comprising an RNA polynucleotide having an open reading frame encoding a HA antigen formulated within a cationic lipid nanoparticle (LNP), wherein the HA antigen is HA7; see instant claims 8, 19, 45 and 54. Para. 126 and 252 teaches that the RNA polynucleotides comprise additional sequences, including a 5’ and 3’ UTR and a polyA tail; see instant claim 12, in part. Para. 128 teaches that the open reading frame is codon-optimized; see instant claim 57. Para. 128 also teaches that at least 80% of the uracil in the open reading frame have a chemical modification, including an N1-methyl pseudouridine; see instant claims 13 and 73-75.
See para. 129-130 teaching that the LNP comprises a cationic lipid, a PEG-modified lipid, a sterol (cholesterol lipid or cholesterol) and a non-cationic lipid, wherein the LNP has the molar ratio of about 20-60% cationic lipid, about 5-25% non-cationic lipid, about 25-55% sterol, and about 0.5-15% PEG-modified lipid, wherein the nanoparticles have a mean diameter of 50-200 nm; see instant claims 27, 28, 33, 52 in part, 58, 64 and 66. Para. 334 teaches that DOPE can be used as a non-cationic lipid; see claim 32, in part and para. 31 of the instant specification disclosing DOPE as a helper lipid. Para. 503 teaches the using PEG2000-DMG in an LNP; see instant claims 32 and 65. See para. 398 teaching administering the RNA vaccine via intradermal or intramuscular injection; see instant claims 40, 69 and 70. Para. 279 teaches that in order to protect against more than one influenza strain, a combination vaccine can be administered that includes RNA encoding at least one antigenic polypeptide of a first influenza and further includes RNA encoding at least one antigenic polypeptide of a second influenza, wherein the RNAs (mRNAs) can be co-formulated, for example, in a single LNP or can be formulated in separate LNPs destined for co-administration; see claims 38 and 39. See para. 151 and para. 315 which teaches administering a first and a second dose (booster) to a subject wherein the time of administration between the initial administration and booster includes 2 weeks, 3 weeks and 1 month; see claim 72. Para. 309 teaches compositions in kits for the prevention of influenza; see claim 50. See para. 163 which teaches that seasonal influenza consists of three principal strains, A/H1N1, A/H3N2 and B, which are covered by the annual vaccine; see claim 71, in part. Also see para. 2 and 3 for teaching that H7N9 and H10N8 strains have a high potential to be pandemic.
Ciaramella does not explicitly express a composition comprising eight mRNA wherein each mRNA encodes for H3, N2, H1, N1, an HA and an NA from the influenza B/Victoria (see claims 1-4); wherein the cationic lipid is selected from the group provided by claims 32, 52 and 63 (e.g. OF-02, etc.); wherein the composition comprises between 1mg/mL to 10mg/mL of the LNP (claims 35 and 68); wherein the LNP comprises between 1 and 20, 5-10 or 6-8 mRNA molecules (claim 36); and, wherein the cationic lipid is biodegradable, not biodegradable, cleavable or not cleavable (claims 59-62). Ciaramella does not teach the claimed molar ratio of each component in the LNP; see instant claims 28, 32 and 52.
BAUMHOF teach mRNA vaccine combinations that can have 8 mRNAs that code for proteins (page 20 line 29) and “Of note: No differences were detected between the immune responses detected in mice vaccinated with tetravalent HA mRNA vaccine, showing that the addition of further mRNA constructs encoding NA antigens did not reduce the effectiveness of the septavalent mRNA vaccine. … Of note: No differences were detected between the immune responses detected in mice vaccinated with trivalent NA mRNA vaccine, showing that the addition of further mRNA constructs encoding HA antigens did not reduce the effectiveness of the septavalent mRNA vaccine” (from example 25).
Ciaramella (‘336) for amended claim 1 teach mRNAs formulated with LNP wherein the mRNAs encode an antigen from B/Yamagata (HA and NA) (para 589) and teach influenza RNA vaccines, comprising an RNA having an open reading frame which encodes an influenza HA antigen, and another RNA having an open reading frame which encodes an influenza NA antigen (neuraminidase); see para. 15. See para. 416 for teaching the improvement of LNP formulations by replacing the cationic lipid with a biodegradable cationic lipid which is known as a rapidly eliminated nanoparticle. The inventor also teaches the inclusion of an enzymatically degraded ester linkage to improve the degradation profile of the cationic component, while still maintaining the activity of the LNP formulation; see para. 416. See para. 589 for teaching mRNAs formulated with LNP wherein the mRNAs encode an antigen from B/Yamagata (HA and NA).
Anderson describes lipid nanoparticles comprising OF-02, wherein the LNP comprise mRNA; see para. 298-304. See para. 299 describing OF-02 LNP as a potent mRNA delivery vehicle compared to other LNPs.
It would have been obvious for one of ordinary skill in the art at the time of the invention to combine the teachings and prepare an RNA vaccine comprising eight different mRNAs, wherein each mRNA encodes an H3, an N2, an H1, an N1, as well as an HA and an NA from the influenza B/Victoria. One would have been motivated to do so because Ciaramella teaches that seasonal influenza consists of three principal strains, A/H1N1, A/H3N2 and B, which would be covered by the RNA vaccine. Also, noted is that Ciaramella (‘336) describes influenza RNA vaccines wherein an RNA encodes an antigen different than the HA antigen, such as NA.
Further, it would have been obvious for one of ordinary skill in the art at the time of the invention to further incorporate in the composition an RNA encoding an HA and an RNA encoding an NA from a different influenza strain in the event of a pandemic caused by such strain. For example, it would be beneficial to further incorporate an mRNA encoding an HA and an mRNA encoding an NA of B/Yamagata or H7N9 in the event of a pandemic caused by B/Yamagata or H7N9.
It would have been obvious for one of ordinary skill in the art at the time of the invention to use OF-02 as a cationic lipid in an LNP of the RNA vaccine. One would have been motivated to do so because Anderson describes the OF-02 LNP as a potent mRNA delivery vehicle.
It would have been obvious for one of ordinary skill in the art at the time of the invention to incorporate a cationic lipid that is biodegradable or not, or cleavable or not. One would have been motivated to do so because a biodegradable cationic lipid is known as a rapidly eliminated nanoparticle and the inclusion of an enzymatically degraded ester linkage improves the degradation profile of the cationic component.
It would have been obvious for one of ordinary skill in the art at the time of the invention to optimize the RNA vaccine in view of the LNP amount, or the number of mRNA molecules in an LNP or the molar ratio of each component in the LNP. One would have been motivated to do so for the gain of increasing the efficacy of the vaccine; for example, decreasing the LNP or the mRNA molecule in an LNP in order to attenuate an immune response in a subject; or modification of the molar ratio of each component in an LNP to stabilize its degradation profile.
There would have been a reasonable expectation of success given the underlying materials and methods are widely known, commonly used and successfully demonstrated; for example, OF-02 as a cationic lipid in an LNP for RNA delivery has been characterized, preparing an RNA encoding an influenza antigen is well-understood, and routine experimentation for optimization is commonly practiced in the arts.
The invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Applicant argues that reference alone or in combination do not teach an octavalent vaccine and each mRNA is at a 1:1 ratio as recited in claim 1, that applicant has discovered a robust immune response pointing to data points in Figures 32 and 33, and that both Ciaramella references do not teach the instantly claimed invention. Applicant argues that Baumhof does not teach 8 mRNAs and points to page 20, and finally, that none of the referencesx alone or in combination teach the claimed invention.
Applicant’s arguments have been fully considered and not found persuasive.
The rejection has been amended as the result of the amendment to include a reference that that includes an octavalent vaccine and that in a septivalent influenza mRNA vaccine, the immune response was not diminished as compared to the quadrivalent vaccine (Baumhof Ex 25 as noted in the body of the rejection). Thus, there is an expectation that the titers of an octavalent vaccine would have similar titers compared to quadrivalent as required by the claims.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
As for the robust results, the “data points” referred to are groups and the groups have multiple data entries. Not all are robustly higher especially when considering the error bars. It is not clear if the results are surprising or if it just argument from counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulz, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).
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 1-4, 8, 12, 13, 19, 27, 28, 32, 33, 35, 36, 38-40, 42, 43, 45, 50 and 52-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 and 28-33 of U.S. Patent No. 11771652 in view Baumhof et al (WO2018078053)
This rejection has been updated in view of the recently patented claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a composition comprising an LNP and influenza mRNAs comprising an ORF encoding a different influenza antigen; see patented claims 1 and 4. The new limitation of 8 influenza mRNAs is met by patent claim 22. The two sets of claims differ in the dependency of the claims; for example, the instant independent claim 1 is directed to an influenza vaccine composition comprising eight mRNAs, wherein each mRNA encodes a different influenza antigen; whereas patented claim 1 is directed to an LNP comprising cKK-E10, DMG-PEG2000, cholesterol, DOPE. However, the dependent claims of both sets lead to a composition comprising both the LNP and influenza mRNAs comprising an ORF encoding a different influenza antigen. For example, see instant claims 19 and 32 directed to an LNP wherein the LNP comprises cKK-E10, DMG-PEG2000, cholesterol and DOPE; also see independent claim 1 of the instant application directed to an influenza vaccine composition comprising eight mRNA wherein one mRNA encodes an H3 HA antigen, one mRNA encodes an N2 NA antigen, one mRNA encodes an H1 HA antigen, one mRNA encodes an N1 NA antigen, one mRNA encodes an HA antigen from the Victoria lineage and one mRNA encodes an NA antigen from the Victoria lineage. Patented claim 24 (directed to 8 mRNAs) depends on claims 9, 6, 5, 4 and 1, anticipates the composition of instant claims 1-4, 9, 10, 19, 27, 28, 32, 36, 38, 39, 40, 42, 43, 51-56, 58 and 63-67; patent claim 24 is directed to a composition comprising eight mRNAs, including those mRNAs of instant claim 1, and an LNP as defined above.
See patented claim 1 is directed to an LNP comprising (in molar ratio): 40% cKK-E10, 1.5% DMG-PEG2000, 28.5% cholesterol, and 30% of a helper lipid or DOPE; see instant claim 32. Patented claim 4 is directed to the mRNA molecule comprising an ORF encoding an antigen derived from influenza virus; see instant claim 1. Patented claims 19 and 20 are directed to HA and NA antigens of influenza A; see instant claims 2 and 3 and 54 and 55. Patented claims 8 and 24 are directed to the LNP composition of claim 7 comprising 8 mRNA molecules; see instant claim 1.
See claim 77 of the ‘200 application which is directed to mRNA molecules encoding HA and NA antigens selected form H1N1, H3N2, H2N2, H5N1, etc. in the LNP claimed; this claim meets the limitations of instant claim 8.
See claim 70 of the ‘200 application which is directed to an mRNA molecule in the LNP comprising at least one 5’ UTR, at least one 3’ UTR and at least one poly(A) sequence; this meets the claim limitations of instant claim 12. The ‘200 application teaches that incorporation of sequences, including that of a 5’ UTR, a 3’ UTR and a poly(A) sequence, improves the stability of an mRNA molecule. This provides one of ordinary skill in the art motivation to incorporate such sequences in mRNA molecules, including those which encode an influenza antigen.
Patented claims 16-18 are directed to a mRNA molecule which comprises at least one modification, including those listed in claim 18. The claims meet the claim limitations of instant claim 13, 74 and 75.
Patent claim 3 is directed to the LNP with an average diameter of 30-200 nm or 80-150 nm; this meets the claim limitation of instant claim 33.
Patent claim 13 is directed to a composition comprising 1-10 mg/mL of the LNP; this meets the limitation of instant claim 35.
Patent claim 10 is directed to an ORF which is codon-optimized; this meets the limitations of instant claim 57.
Patent claim 14 is directed to an LNP comprising 1-20 nucleic molecules; this meets the limitation of instant claim 68.
Patent claim 12 is directed to a composition formulated for intramuscular injection; this claim meets the limitation of instant claims 69 and 70.
Patent claim 17 is which is directed to various percentages, from 20% to 100%, of uracil nucleotides in the mRNA or the ORF which are chemically modified; this meets the limitations of instant claim 73.
The patent claims differ in that the instant claims in that they do not recite 1:1 ratio.
Baumhof et al. teach using multiple mRNA lipid nanoparticles together with different influenza antigens and use a 1:1 ratio. See Examples 15 and 25.
Applicant argues that the patent does not teach 8 mRNA segments and not 1:1 ratio of mRNAs..
The arguments are not found persuasive.
The patent does claim 8 mRNAs as recited in claim 22 and includes the same individual influenza antigens in patent claim 22 with the same antigens in the group listed in claim 23 as recited in pending claims 1. The 1:1 ratio is known in the art as evidenced by Baumhof et al (WO2018078053).
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 MYRON G HILL whose telephone number is (571)272-0901. The examiner can normally be reached Mon-Fri.
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MYRON G. HILL
Examiner
Art Unit 1671
/M.G.H/ Examiner, Art Unit 1671
/Shanon A. Foley/ Primary Examiner, Art Unit 1671