DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of invention I in the reply filed on 2/19/25 is acknowledged.
Claims 21 and 24-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/19/25.
Claims 1-8 and 23. Claim 23 is newly presented.
Examiner’s Note
In applicant’s response, the following was stated in the first paragraph:“Applicant will cancel claim 23 after amended claim 1 has been examined.” It is unclear what applicants meant by this statement since claim 1 was previously examined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/15/26 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
(New Rejection Necessitated by Amendments) Claim 23 is rejected under pre-AlA 35 U.S.C. 102(e) as being anticipated by Geall et. al. (US PGPub. Nos. US 2013/0195968 A1, Priority 07/06/2010) as evidenced by Roldao et. al. (Roldao A, et. al. Expert Rev Vaccines. 2010).
Applicant’s submission of a statement under 35 USC 103(c)(1) is acknowledged pertaining to Geall et al. However, since this rejection is an anticipatory rejection, this statement is not sufficient to overcome the rejection (see MPEP 2146.03 for further guidance).
The claimed invention is drawn to an immunogenic composition comprising:
a first polypeptide antigen that is not associated with a viral replicon particle (VRP), and
a self-replicating RNA molecule that encodes a second polypeptide antigen, wherein the self- replicating RNA cannot induce production of infectious viral particles and is provided with a delivery system;
wherein said first and second antigens are antigens from different pathogens.
The Prior Art Geall teaches that nucleic acid immunization is achieved by delivering a self-replicating RNA encapsulated within a non-virion small particle (entire document; see abstract); the RNA encodes an immunogen of interest, and the particle may deliver this RNA by mimicking the delivery function of a natural RNA virus (entire document; see abstract). Geall teaches a non-virion particle for in vivo delivery of RNA to a vertebrate cell, wherein the particle comprises a delivery material encapsulating a self-RNA molecule which encodes an immunogen; these particles are useful as components in pharmaceutical compositions for immunizing subjects against various diseases (entire document; abstract). The self-replicating RNA may encode one or more immunogens, each within a separate open reading frame (ORF) ([0043]). The immunogens may be expressed as a single polypeptide (fusion 5 polypeptide) or as separate polypeptides under control of an IRES or promoter element (F[0054]). The condition of “one or more immunogens’” and the teachings of Geall can be interpreted broadly, in that the immunogen may be from the same protein or from different proteins from the same virus (4[0115]). The viral immunogens may be derived from cytomegalovirus (CMV)(q[0115]) or parvovirus (F[0112]), wherein “derived” from can broadly be interpreted as the entire protein itself or a fragment or variant thereof; and that soluble or full-length CMV glycoprotein H (gH; which is a glycoprotein that has a transmembrane anchoring domain) may be one of the heterologous proteins expressed (4[0285][0290][0292]). While the example where RNA replicons+liposomes and viral antigen delivered RSV F-protein, Geall clearly teaches that antigens may be derived from a variety of viruses, and would be easily substituted within this method of Geall. The composition may include viral glycoproteins or structural proteins, such as hepatitis B surface antigen (HBsAg) ([0105]) or influenza HA, NA, and matrix proteins ({[0095]) that are known to assemble into virus-like particles, as evidenced by Roldao (Table 1). The self-replicating RNA (derived from RNA viruses such as alphaviruses) does not encode structural proteins, so an alphavirus replicon may be formed within cells with helper plasmids expressing the missing structural proteins, wherein said resulting replicons can be delivered to other cells and can replicate within said cells but is not infectious, as said construct lacks the structural proteins within the self-replicating RNA to further generate virions (f[0040-0042]). Geall teaches that modified nucleotides may be utilized within the RNA (4[0049]). Geall teaches a composition comprising the self-replicating RNA of and a pharmaceutically acceptable vehicle (4[0121-0137]). Said self-replicating RNA can be delivered within cationic liposomes or cationic nanoemulsions ({[0197][0283]), and may comprise adjuvants such as MF59 (4[0357)).
Therefore, Geall et al. anticipates the instant invention.
Response to arguments:
Applicant’s response has been fully considered, but they are not persuasive.
The claim is drawn to an immunogenic composition comprising:
a first polypeptide antigen that is not associated with a viral replicon particle (VRP), and
a self-replicating RNA molecule that encodes a second polypeptide antigen, wherein the self- replicating RNA cannot induce production of infectious viral particles and is provided with a delivery system;
wherein said first and second antigens are antigens from different pathogens.
As stated above, Geall et al. teach combinations of immunogens that include proteins and nucleic acid sequences (self-replicating RNA) that encode proteins and the antigens are from different pathogens and can be combined into a composition. The pathogens can be viruses and depending on the viral protein, VLPs can be formed, as evidenced by Roldao et al. Therefore Geall et al. anticipate the invention as claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
(New Rejection Necessitated by Amendments) Claims 1, 6-8 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rappuoli et al. (US PGPub 2006/0257852) and Sah et al. (US PGPub 2011/0251262)
The claimed invention is drawn to an immunogenic composition comprising: a first component comprising a first polypeptide antigen, the first polypeptide antigen not being a virus-like particle or a viral replicon particle and
a second component comprising ribonucleic acid (RNA) molecules and liposomes; the liposomes encapsulating at least half the RNA molecules; the RNA molecules comprising a 5’ cap structure, a first segment, and a 3’ polyA tail. The liposomes comprise a PEG modified lipid, a cationic lipid, an antionic lipid or zwitterionic lipid, and a cholesterol. The cationic lipid comprising a tertiary amine; the first segment encoding a second polypeptide antigen, the RNA molecule being unable to induce production of infectious viral particles.
The first polypeptide antigen and the second polypeptide antigen are from different viruses.
The liposome comprises the zwitterionic lipid of 1,2-distearoyl-sn-glycero-3-phosphotidylcholine, which is also known as DSPC.
The RNA molecules comprise a modified nucleotide and the RNA molecules are self-replicating RNA molecules.
The claimed invention also requires an immunogenic composition comprising: (i) a first polypeptide antigen that is not associated with a viral replicon particle (VRP), and (ii) a self-replicating RNA molecule that encodes a second polypeptide antigen,
wherein the self- replicating RNA cannot induce production of infectious viral particles and is provided with a delivery system; wherein said first and second antigens are antigens from different pathogens.
The Prior Art
Rappuoli et al. teach the generation of combination vaccine formulations based on SARS polynucleotide sequences or proteins, such as the Spike protein. [see paragraph 9 and 559]
Rappuoli et al. also teach that the invention includes polynucleotides encoding for the SARS antigens of the invention. Rappuoli et al. teach that the term "polynucleotide", as known in the art, generally refers to a nucleic acid molecule. A "polynucleotide" can include both double- and single-stranded sequences and refers to, but is not limited to, cDNA from viral, prokaryotic or eukaryotic mRNA, genomic RNA and DNA sequences from viruses. [see paragraph 546] In addition, the invention includes polynucleotides which have been optimized for recombinant production (e.g. codon optimization) of the SARS antigens of the invention, including polynucleotides encoding for each of the SARS fusion constructs discussed above. [see paragraphs 760] Rappuoli et al. additionally teach the use of an "alphavirus RNA replicon vector", "RNA replicon vector", "replicon vector" or "replicon" refers to an RNA molecule that is capable of directing its own amplification or self-replication in vivo, within a target cell. To direct its own amplification, the RNA molecule should encode the polymerase(s) necessary to catalyze RNA amplification (e.g., alphavirus nonstructural proteins nsP1, nsP2, nsP3, nsP4) and also contain cis RNA sequences required for replication which are recognized and utilized by the encoded polymerase(s). The alphavirus RNA vector replicon also should contain a means to express one or more heterologous sequences. This RNA replicon also possesses a 5’ cap and a polyadenylate tract (or tail) [see paragraph 771] and RNA sequences can be stabilized from degredation by chemically modifying the 2’ location, such as by methylation. [see paragraphs 1086 and 1087] Rappuoli et al. also teach SARS proteins can be expressed by an alphavirus replicon and be co-administered with alphavirus replicons that express antigens from RSV. Additionally, DNA plasmids can be prepared that deliver DNA sequences for Spike proteins of SARS. [see paragraph 801] Rappuoli et al. also teach that liposomes can be used as a carrier for a composition of their invention. [see paragraphs 958 and 1122]
In addition, Rappuoli et al. also teach vaccine formulations comprising one or more SARS virus antigens and one or more other respiratory virus antigens. Additional respiratory virus antigens suitable for use in the invention include antigens from influenza virus, human rhinovirus (HRV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus, metapneumovirus, and rhinovirus. [see paragraph 10] Combinations of SARS Antigens and Other Respiratory Virus Antigens the invention further relates to vaccine formulations comprising one or more SARS virus antigens and one or more other respiratory virus antigens. Additional respiratory virus antigens suitable for use in the invention include antigens from influenza virus, human rhinovirus (HRV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus, metapneumovirus, and rhinovirus. [see paragraph 850] The invention may also comprise one or more bacterial or viral antigens in combination with the SARS viral antigen. Antigens may be used alone or in any combination. (See, e.g., WO 02/00249 describing the use of combinations of bacterial antigens). The combinations may include multiple antigens from the same pathogen, multiple antigens from different pathogens or multiple antigens from the same and from different pathogens. Thus, bacterial, viral, and/or other antigens may be included in the same composition or may be administered to the same subject separately. It is generally preferred that combinations of antigens be used to raise an immune response be used in combinations. [see paragraph 851]
However, Rappuoli et al. do not teach: that their liposome comprises a PEG modified lipid, a cationic lipid, an zwitterionic lipid (such as DSPC), and a cholesterol.
Sah et al. teach the generation of lipid nanoparticles that comprise cationic lipids (such as DLin-K-DMA or DLinDMA), DSPC, cholesterol and PEG modified lipid. [see paragraphs 145 and 147] DLinDMA is a cationic lipid with a tertiary amine. One intent behind Sah et al. is to deliver nucleic acids, such as RNA, to a cell using the liposomes, more specifically viral RNAs. [see paragraphs 143 and 100]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Rappuoli et al. in order to employ a liposome comprising a PEG modified lipid, a cationic lipid with a tertiary amine, DSPC, and a cholesterol for delivering nucleic acid sequences. One would have been motivated to do so, given the suggestion by Rappuoli et al. that the liposomes can be used for delivering nucleic acid sequences. There would have been a reasonable expectation of success, given the knowledge that liposomes comprising cationic lipids (such as DLin-K-DMA or DLinDMA, which comprise tertiary amines), DSPC, cholesterol and PEG modified lipid, as taught by Sah et al. Thus 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.
(New Rejection Necessitated by Amendments) Claims 2 and 3 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rappuoli et al. and Sah et al. as applied to claims 1, 6-8 and 23 above, and further in view of Singh et al. (Vaccine, 2007, Vol. 25, No. 33, pages 6211-6223).
The claimed invention also requires that the first polypeptide is RSV F antigen and the second polypeptide is a coronavirus antigen.
While Rappuoli et al. do teach the combination of antigen sequences of coronaviruses and RSV, they do not teach that the F protein of RSV is part of their immunogenic compositions. Sah et al. also fail to teach the F protein of RSV.
Singh et al. teach that recombinant RSV F protein compositions can be used as an immunogenic composition when administering the protein to mice. [see abstract] Singh et al. report both humoral and cell mediated immune responses in mice receiving the F protein composition [see sections 3.2 and 3.3]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Rappuoli et al. and Sah et al. to include the F protein of RSV as part of combination sequences from pathogens. One would have been motivated to do so, given the suggestion by Rappuoli et al. that the liposomes can be used for delivering nucleic acid sequences, which Sah teaches can be liposomes comprising cationic lipids (such as DLin-K-DMA or DLinDMA, which comprise tertiary amines), DSPC, cholesterol and PEG modified lipid and in view of the teachings by Rappuoli et al. that antigens or sequences encoding these antigens can be from coronaviruses and RSV. There would have been a reasonable expectation of success, given the knowledge that RSF F proteins can induce immune responses in mice, as taught by Singh et al. Thus 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.
(New Rejection Necessitated by Amendments) Claims 4 and 5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rappuoli et al. and Sah et al. as applied to claims 1, 6-8 and 23 above, and further in view of Kormelink (US PGPub 2011/0165226).
The 5’ cap structure comprises a triphosphate, a first 5’ ribonucleoside, and a 7-methylguanosine or a derivative thereof. The 7-methylguanosine or the derivative thereof is linked 5’ to the triphosphate and the triphosphate is linked 5’ to the first 5’ ribonucleoside, which comprises a 2’-methylated ribose.
The teachings of Rappuoli et al. and Sah et al. are summarized above, however, they do not teach that the RNA sequences comprise a 5’ cap structure comprises a triphosphate, a first 5’ ribonucleoside, and a 7-methylguanosine or a derivative thereof, wherein the 7-methylguanosine or the derivative thereof is linked 5’ to the triphosphate and the triphosphate is linked 5’ to the first 5’ ribonucleoside, which comprises a 2’methylated ribose.
Kormelink teach the generation of RNA sequences with 5’ capped ends that possess a 7-methylguanosine cap, 5’ linked to a triphosphate which is 5’ linked to a first 5’ ribonucleoside. The RNA sequences can that of a virus and this 5’ cap aids with mRNA transcription. [see paragraph 27] Kormelink also teach the formulation of liposomes, which can be used to deliver nucleic acid sequences. The liposomes can comprise a cationic lipid, an anionic lipid and a neutral lipid. [see paragraphs 44-45]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Rappuoli et al. and Sah et al. the RNA sequences comprise a 5’ cap structure comprises a triphosphate, a first 5’ ribonucleoside, and a 7-methylguanosine or a derivative thereof, wherein the 7-methylguanosine or the derivative thereof is linked 5’ to the triphosphate and the triphosphate is linked 5’ to the first 5’ ribonucleoside, which comprises a 2’methylated ribose. One would have been motivated to do so, given the suggestion by Rappuoli et al. that the liposomes can be used for delivering nucleic acid sequences, which Sah teaches can be liposomes comprising cationic lipids (such as DLin-K-DMA or DLinDMA, which comprise tertiary amines), DSPC, cholesterol and PEG modified lipid and in view of the teachings by Rappuoli et al. that RNA replicons possess a 5’ cap and a polyadenylate tract (or tail) and RNA sequences can be stabilized from degredation by chemically modifying the 2’ location, such as by methylation. There would have been a reasonable expectation of success, given the knowledge that RNA sequences with 5’ capped ends that possess a 7-methylguanosine cap, 5’ linked to a triphosphate which is 5’ linked to a first 5’ ribonucleoside and RNA sequences can that of a virus and this 5’ cap aids with mRNA transcription, as taught by Kormelink et al. Thus 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.
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.
(New Rejection Necessitated by Amendment) Claims 1 and 4-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,896,636 in view of Sah et al.(supra) and Kormelink (supra). The patented invention and the instant invention are drawn to similar inventions in that they are both drawn to an immunogenic composition comprising: a first component comprising a first polypeptide antigen, the first polypeptide antigen and
a second component comprising self-replicating ribonucleic acid (RNA) molecules and liposomes.
However, the patented invention does not require that the liposomes encapsulating at least half the RNA molecules; the RNA molecules comprising a 5’ cap structure, a first segment, and a 3’ polyA tail. The liposomes comprise a PEG modified lipid, a cationic lipid, an antionic lipid or zwitterionic lipid (DSPC), and a cholesterol. The cationic lipid comprising a tertiary amine; the first segment encoding a second polypeptide antigen, the RNA molecule being unable to induce production of infectious viral particles.
The teachings of Sah et al. and Kormelink are summarized above.
It would have been obvious to one of ordinary skill in the art to modify the compositions of the patented invention in view of Sah et al. and Kormelink to include liposomes comprising cationic lipids (such as DLin-K-DMA or DLinDMA, which comprise tertiary amines), DSPC, cholesterol and PEG modified lipid and RNA sequences comprise a 5’ cap structure comprises a triphosphate, a first 5’ ribonucleoside, and a 7-methylguanosine or a derivative thereof, wherein the 7-methylguanosine or the derivative thereof is linked 5’ to the triphosphate and the triphosphate is linked 5’ to the first 5’ ribonucleoside, which comprises a 2’methylated ribose. Thus 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.
Conclusion
No claims are 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 BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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