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 .
Claim Status
Amended claims 1, 4, 6-17, 19-23, 25-31, 104-112 are pending and new claims 113-114.
Claims 1, 4, 6-8, 13-14, 19, 22-23, 108-114 and the elected species of coding RNA, DMSO, lipid, and ionizable lipid are under consideration. Claims 9-12, 15-17, 20-21, 25-31, 104-107 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/19/2023.
Priority
Applicant’s claim of domestic benefit of U.S. Provisional Application 63/116602, filed on 11/20/2020 is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 63/116,602 (referred as ‘602), fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claims have been amended and recite “an aqueous solution” and “one polar aprotic fluid” (cl. 1), which were not limitations in prior examined version of the claims. ‘602 does not disclose the sub-genus of “polar aprotic fluid.” ‘602 discloses the genus of aprotic fluid, which comprises non-polar aprotic fluids and polar-aprotic fluids, and the species of DMSO. Thus, all the claims, except claim 6, enjoy the benefit of instant non-provisional application (11/19/2021); claim 6 enjoys the benefit of ‘602, 11/20/2020.
Claim Interpretation
Claim 1 in element a) recites “at least one polar aprotic fluid” and then element b) recites “all polar aprotic fluids,” (underline added for emphasis); claim 1 is interpreted that there can be more than one type of polar aprotic fluid in the composition.
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 112-114 are 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 112 recites the following: “c) said kit is provided to produce a composition.” The claim attempts to recite a method of use step of said kit to produce a composition, i.e. claims both an apparatus and the methods of using the apparatus is indefinite (see MPEP 2173.05(p)(II)). The claim is a mixed statutory claim. Further, it is unclear if the claim requires that the “said solution” and “coding RNA substance” are separate, since the “kit comprising a solution for storing” claimed RNA substance, which implies that it does not comprise RNA substance. Dependent claims 113-114 fail to overcome the indefiniteness, thus are rejected.
In the interest of compact prosecution, claim 112 will be interpreted as a kit comprising a solution of water and one polar aprotic fluid for storing at least one extracellular coding RNA substance, and all polar aprotic fluids has a total weight of at least 50% and is provided in a sealed chamber with an access port, thus said kit comprises said solution and said at least one extracellular coding RNA substance, which contacts said one polar aprotic fluid.
Claim Rejections - 35 USC § 103
Rejection of amended claims 1, 4, 6-8, 13, 19, 22-23, 108-111 is maintained, and the amended/new claims 112-114 are rejected as noted below.
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, 4, 6-8, 13, 19, 22-23, 108-111 are rejected under 35 U.S.C. 103 as being unpatentable over Baker et al. (WO 2009131995 A1, pub. 10/29/2009, of record, referred as Baker) and Brito et al. (2014, Mol. Ther., 22, 2118-2129, referred as Brito).
Baker discloses a nanoemulsion influenza vaccine, which comprises an aqueous phase, at least one oil, at least one surfactant, at least one organic solvent and one influenza immunogen (pg. 1). Influenza disease is caused by an RNA virus (pg. 1), and one immunogen is a partially inactivated influenza virus, such as FluMist® (cl. 9), which inherently encodes a protein immunogen and therefore comprises an extracellular coding RNA (pg. 20 and cl. 9); one organic solvent is a DMSO, which is a polar aprotic fluid and discloses that the aqueous phase can be distilled water (pg. 24, relevant to instant cl. 1); further it is known that oil is a type of lipid and Baker indicates various lipid structures that can form following mixtures of the aqueous, oil and organic solvents, including DMSO or combinations thereof (pg. 24, relevant to instant cl. 1, 4, 6, 7, 13); discloses nanoemulsion vaccine of the invention may be formulated into pharmaceutical composition in a therapeutically effective amount (pg. 38, relevant to cl. 22, 23, 111); Table 21 discloses the pH of solution at range of 5.2 and the DMSO is still aprotic (pg. 73, relevant to cl. 8); discloses intranasal administration by nasal drop/spray (pg. 41, relevant to cl. 108). Baker discloses a range of 0.1% to about 50% of organic solvent (pg. 13), with “about” meaning to be “plus or minus 10% of the particular term” (pg. 16, relevant to instant cl. 1). Further Baker discloses the need for improved storage stability, including recall of Fluvirin® in 2006 due to improper storage temperature creating a shortage (pg. 2); storage stability is a characteristics of the disclosed nanoemulsion vaccine (pg. 3, 4).
Baker does not disclose an extracellular coding RNA substance (cl. 1) and self-amplifying RNA (cl. 19).
Use of mRNA as an immunogen for vaccination purposes is known in the art. Brito discloses a cationic nanoemulsion (CNE) delivery system developed to deliver a 9kb self-amplifying mRNA (SAM) vaccine that elicits a “potent immune response in mice, rats, rabbits and nonhuman primates comparable to viral delivery technology, and demonstrate[s] that, relatively low doses (75 ug) induce antibody and T-cell responses in primates” (abstract, relevant to instant cl. 1 and 19). The RNA was transcribed and purified and complexed to CNE (pg. 2126). Brito discloses administering the SAM/CNE complex via i.m. injections to the animals (pg. 2121, relevant to instant cl. 108); if an injection is used, then it is inherent that the drug was in an injection, i.e. a sealed chamber). Brito concludes “[g]iven the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology” (abstract). Brito discloses advantages of a self-amplifying RNA over both organismal-based vaccines, including viral replicon particles (VRPs), and plasmid DNA (pDNA) vaccines (pg. 2118), in that its ability to amplify in the cytoplasm leads to greater immune responses than conventional RNAs and have a lesser risk than pDNA of integrating into host genome (pg. 2118-2119). Brito discloses the use of squalene as a solvent in the nanoemulsion composition (see Fig. 1a, excerpt below, noting there is contact between oligonucleotide and the squalene).
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One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the viral immunogen of Baker in view of Brito and arrive at the claimed invention with a reasonable expectation of success. Based on Baker’s disclosure in designing nanoemulsion particles with DMSO as an organic solvent, and Brito demonstrating using a nanoemulsion particle to deliver a self-amplifying RNA as a safer immunogen due to its translation in the cytoplasm, a skilled artisan would reasonably expect success in substituting Baker’s viral immunogen with a self-amplifying mRNA of Brito for an improved/similar potency and safer in-vivo antigen response. Thus, claims 1, 4, 6, 7, 8, 13, 19, 22, 23, 108, 111 are obvious.
Regarding instant claim 109, Baker’s Tables 1 and 2 disclose the use of soybean oil, as the hydrophobic oil core, and dehydrated ethanol, as the organic solvent, and the total of both is ~41% (pg. 40). Baker discloses that the hydrophobic oil range can vary from 1% to 80% and organic solvent’s range is 0.1% to about 50% (pg. 12). One of skilled in the art recognizes that lipid is a broad genus, comprising of oil as a sub-genus. Although the exemplary total weight does not meet the 55% limitation of the claim, a) the adjustment of weight of each oil core and ethanol can be optimized through routine optimization with the range of oil and organic solvent provided, as provided under MPEP 2144.05(II)(A), or are relatively close enough that a prima facie case of obviousness is established; or the claimed 55% would lie within the range disclosed, thus also establishes prima facie obviousness.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted one organic solvent of Baker with the other organic solvent of Baker and arrive at the claimed invention with a reasonable expectation of success. Both ethanol and DMSO are provided as suitable organic solvents, thus a skilled artisan would expect substituting DMSO for ethanol at a similar or same weight percentage would successfully result in similar function in producing the nanoemulsion vaccine. Thus claim 109 is obvious.
Regarding instant cl. 110, Baker discloses a range of 0.1% to about 50% of organic solvent (pg. 13), with “about” meaning to be “plus or minus 10% of the particular term” (pg. 16). Thus, Baker discloses at least a range of up to 60%. Instant cl. 110 is directed to a polar aprotic fluid comprises at least 60%. Under MPEP 2144.05 a prima facie case of obviousness exists where the claimed ranges overlap with the prior art; here the ranges overlap at 60% of organic solvent. Thus, claim 110 is prima facie obvious.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Baker et al. (WO 2009131995 A1, pub. 10/29/2009, of record, referred as Baker) and Brito et al. (2014, Mol. Ther., 22, 2118-2129, referred as Baker) as applied to claims 1, 2, 4, 6, 7, 8, 13, 19, 22, 23, 108-112 above, and further in view of Anderluzzi et al. (2020, Vaccines, 8, 212, pg. 1-22).
Rejection of claims 1, 2, 4, 6, 7, 8, 13, 19, 22, 23, 108-111 is noted above.
Baker and Brito do not disclose ionizable lipid.
Anderluzzi discloses that various lipid nanoparticles aid in delivering self-amplifying mRNA (SAM) (pg. 1-2), and these lipid nanoparticles may comprise of amino lipids that are either non-ionizable lipids or ionizable lipids, which have “low toxicity profiles and are among the most promising” and have been approved by the FDA for therapeutic purposes (pg. 2). Anderluzzi suggests that either ionizable or non-ionizable lipids can be used to formulate any of the four non-viral vectors studies, liposomes, solid lipid nanoparticles (SLNs), polymeric nanoparticles (NPs), and emulsions (pg. 2) and only used non-ionizable lipids to test the four vector delivery vehicle for cost-effective purposes.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted one type of oil/lipid of Baker or the cationic lipid of Brito with ionizable lipid of Anderluzzi and arrive at the claimed invention with a reasonable expectation of success. Because Anderluzzi suggests that nanoemulsion comprising of lipid nanoparticles composed of various lipids, one being ionizable lipid, which has a low toxicity profile and is FDA approved for therapeutic use, and Baker uses nanoemulsion comprising oil phase, comprising lipids, and Brito demonstrates use of nanoemulsion comprising cationic lipid, that a skilled artisan would have expected reasonable success in incorporating ionizable lipid based particles in Baker’s nanoemulsion. Thus claim 14 is obvious.
Claims 112-114 is rejected under 35 U.S.C. 103 as being unpatentable over Baker et al. (WO 2009131995 A1, pub. 10/29/2009, of record, referred as Baker) and Brito et al. (2014, Mol. Ther., 22, 2118-2129, referred as Brito) as applied to claims 1, 4, 6, 7, 8, 13, 19, 22, 23, 108 - 111 above, and further in view of Ingle and Agarwal (2014, Expert Opin. Drug Deliv., 11, 1391-1399, “Ingle”).
The disclosure of rejection of claims 1, 4, 6, 7, 8, 13, 19, 22, 23, 108 – 111 is noted above. Baker discloses nanoemulsion-containing containers can further be packaged as a kit and discloses that nanoemulsions can be delivered in any suitable container (relevant to instant cl. 112, pg. 42). Baker discloses a range of DMSO solvent, see above (relevant to instant cl. 113-114).
Baker nor Brito disclose a sealed chamber with an access port.
Ingle discloses that prefilled syringe (PFSs) are predicted to increase their usage from 2 billion PFSs sold in 2009 to 6.83 billion units in 2025 (pg. 1392). The PFSs have many advantages, including performing dual function of storage as well as delivery of the drug (pg.1392), sterility, and, more importantly, for patient safety, PFSs come in accurate dosage without requiring mixing and thus avoiding errors (pg. 1392, 1393). The PFS with Luer lock assembly, as opposed to needle glued to the barrel, have greater flexibility since fill volume can have a broader range from 1 to 50 ml and gives the administrator the flexibility to choose a type of needle depending on the site of administration (pg. 1392). Luer lock syringe is a sealed chamber with an access port (relevant to instant cl. 112).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted a container of Baker in view of Ingle and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute a container of Baker with a PFS with Luer-lock assembly of Ingle for advantages disclosed for PFSs, including to allow the administrator (i.e. a subject or medical provider) full flexibility of choosing a needle depending on route of administration. Thus, cl. 112-114 are obvious.
Response to Arguments
Applicant's arguments filed 03/23/26 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks of 03/23/26 argue the following:
The references do not satisfy the contact element: Neither Baker nor Brito discloses a polar aprotic fluid contacting a coding RNA (maintains viral immunogen is non-coding RNA and is sequestered at the center of viral particle; Brito is sequestered via electrostatic interaction, on the hydrophilic surface of the particle away from hydrophobic squalene core).
The Remarks argue that "Brito clearly depicts squalene (yellow) in the center of the lipid particle forming a hydrophobic core and the RNA oligonucleotide decorating the hydrophilic surface of the lipid particle" (pg. 10-11).
Baker does not disclose or suggest the concentration element: Baker only uses ethanol (i.e. one species) and highest concentration of ethanol demonstrated is 4.04%. Alternatively, the recited DMSO at 50% would dissolve the lipid membrane that is essential to the stable nanoemulsion. The proposed combination would not yield the concentration component (pg. 8).
Then the Remarks argue that the combinations of the references are improper and would not be successful since it would require undue experimentation, i.e. the combination would result in unenabled product (pg. 22). POSITA would not reasonably expect to maintain a stable lipid structures when stored in a composition comprising at least 50% DMSO (pg. 13), due to “presence of DMSO above a critical concentration results in loss of membrane integrity and destabilization of the lipid membrane” (pg. 17). Even if the viral immunogen of Baker is replaced with the SAM of Brito, the references do not teach the limitation of amended claims (greater than 50% of polar aprotic fluid, pg. 12 and 50-80% have better stability than 30-40% (pg. 5). Baker NE vaccine requires stable lipid structures with an average diameter of less than 1000 nm (pg. 13).
The Remarks cite various references (Gurtovenko, Menorval) arguing that the “presence of DMSO above a critical concentration [~ 10 mole%]results in loss of membrane integrity and destabilization of the lipid membrane” (pg. 17). Thus the Remarks conclude: “Therefore, a POSITA would not expect success by simply replacing a single component or organic solvent at a given concentration in the nanoemulsion described by Baker with a substantially higher concentration than those directly tested by Baker and expect success” (pg. 17).
The Remarks distinguishes various organic solvents: squalene and ethanol are not polar aprotic fluids as recited in claim 1, so “substituting a polar aprotic fluid with different properties than a nonpolar aprotic fluid (squalene) or a polar protic fluid (ethanol) would not necessarily yield predictable results (pg. 17-18).
Then Remarks contend that Baker even warns that a) embodiments need to be tested since it is possible the nanoemulsion cannot be formed (pg. 18-19) and “does not demonstrate that a stable nanoemulsion vaccine can be formed in at least 50% DMSO or in any polar aprotic solvent for that matter” and is silent regarding the success of forming other nanoemulsions at higher ethanol (above 4.04% tested) concentrations or with other solvents (pg. 19-20).
The Remarks identify undue experiments that would need to be conducted for enablement (pg. 21-22).
The Remarks argue that combining the references is improper since the combination renders the primary reference inoperative for its intended purpose (pg. X, pg. 30): Brito and Baker improper since Brito provides that MF59 (nanoemulsion adjuvant for RNA delivery does not yield predictable results in antibody titers, so combining Brito's RNA with Bake's nanoemulsion vaccine adjuvant is directly refuted with experimental data in Brito paper (pg. 25).
The Remarks add that replacing squalene with a polar aprotic solvent, such as DMSO that is miscible in water (squalene in Brito is immiscible in water), would not yield predictable results as DMSO would not necessarily form a stable hydrophobic core.
Brito teaches away from simply substituting any nanoemulsion or single component of the CNE used to deliver SAM RNA since the MF59 tested by Brito was “shown to be less effective at stimulating antibody titers is also a nanoemulsion vaccine adjuvant” noting that “using the substitute MF59 nanoemulsion vaccine adjuvant for delivery of the RNA-based vaccine did not produce predictable results and resulted in lower antibody titers than not just the CNE, but even worse than RNA in buffer alone without any nanoemulsion” (pg. 24-25).
Similarly, warning against a simple substitution noted in the obviousness in the action, the Remarks note that “Brito stresses that delivering an RNA vaccine requires a specific balance of immune stimulation, adjuvant properties, and proper particle formation for induction of a potent immune response and optimal non-viral delivery of RNA vaccines” (pg. 26).
The Remarks add that “[d]elivery of an RNA-based vaccine is complex and not obvious” (pg. 27).
The Remarks note that the SAM RNA-based vaccines must evade clearance by the body and reach target tissues, and then after cell-entry, the RNA needs to escape the endosome to reach the cytoplasm to produce the vaccine antigen (pg. 27-28).
Then the Remarks argue Brito is silent regarding protection of RNA from RNase-mediated degradation in nanoemulsion vaccine (pg. 27) and Brito is silent regarding endosomal escape of RNA into the cytoplasm of a cell (pg. 29).
The Remarks add that the specification demonstrates the criticality of the at least 50% concentration set forth in the concentration element (pg. 30) and point to a “portion of Fig. 4,” i.e. the black and white panel at 60oC stability at 72 hrs. of incubation. Thus, the “specification clearly distinguishes between the efficacy of samples having concentration of 50% and greater and that of samples having a concentration of less than 50% in relation to RNA degradation over time” (pg. 31).
Regarding rejection of cl. 14, the Remarks rely on the arguments against Brito, Baker and adds that Anderluzzi does not teach comprising at least 50% polar aprotic fluid and does not cure Brito’s and Baker’s deficits (pg. 33-34).
The argument is not persuasive.
Addressing that the references do not disclose the contact element, the argument is not persuasive. In response to the Remarks 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). Here, the obviousness rejection is based on the combination of references. Brito clearly states that “Figure 1a shows a pictorial representation of the emulsion bound to RNA,” (pg. 2119). The Remarks also note that “SAM RNA bound to CNE was protected, despite being adsorbed to the surface of the delivery particle where it may be accessible to the RNAse” (pg. 11). The statements by the Remarks lack evidence that clearly indicates that it is not in contact. Even electrostatic interaction would be considered contact, as indicated that the SAM RNA is protected from the RNAse.
Further, the Remarks focus on the narrower dependent claims. Under BRI, the specification defines polar aprotic substance “is an aprotic substance comprised of at least one oxygen atom or at least one nitrogen atom” (pg. 11, lines 8-9). Thus, here, under BRI, ethanol contains at least one oxygen atom and would fall under the category of polar aprotic as defined by the specification.
Regarding the argument that Baker does not disclose or suggest the concentration element, the argument is not persuasive. As long as some concentration range is tested, the complete concentration range does not need to be taught. Here, as noted in the action, Baker discloses the overlapping higher concentration limit of similar organic solvent. Baker teaches suitable organic solvents for the nanoemulsion, and teaches one species, i.e. ethanol, of the organic solvent, and DMSO’s cryoprotective nature is known in the art, i.e. it is used in composition to freeze cells.
Next, addressing the improper combination of references, it should be noted that the instant specification discloses the use of lipid nanoparticles, lipid micelle, lipid bilayer or membrane vesicles as a few examples of cellular uptake agents that may be suitable for use with the RNA stabilizing substances, i.e. DMSO (pg. 78, line 10-13; 49, and see pg. 74). The lipid cited from Baker is the soybean oil used as an example, and is combined with the SAM of Brito. Further, the claims also broadly recite cellular uptake agent (cl. 4), comprising either a lipid or ionizable lipid (cl. 12, 14, respectively). The cationic nanoemulsion has man-made lipids (DOTAP of Brito, ionizable lipid of Anderluzzi) that are distinct from natural cellular membranes. The evidentiary support provided are of natural cellular membrane (Gurtovenko title refers to cell membranes; Posokhov tests acetone, also a polar aprotic fluid, on phosphocholine bilayer; Menorval also uses natural membrane with cholesterol). Gurtovenko, Posokhov and Menorval is silent on tests with cationic lipid, ionizable lipids, and nanoemulsions generally. And as noted above, the instant specification and claims both indicate that cellular uptake agent may be suitable for use with RNA stabilizing substances, which include DMSO.
Further, regarding undue experimentation, here mixing RNA with various organic solutions and exposing the solution in varying conditions to determine RNA’s integrity would not require undue experimentation.
The discussion of MF59, which the Remarks note did not “produce predictable results” is not convincing. Brito used MF59 as the adjuvant since it was a standard and used in many clinical trials (see pg. 2119), but the antigen differed and Brito added a cationic lipid, DOTAP, to formulate a cationic nanoemulsion (CNE). Thus the differences or “unpredictability” is not because of MF59 but the antigen type used, along with the type of cationic lipid used. Brito notes that “strong cellular infiltrate alone does not improve immune responses and that adsorption of the RNA to the surface of the particle by interaction with a cationic lipid is required for efficient cellular transfection and subsequent immune responses” (pg. 2125) following comparison of CNE and MF59 with SAM.
Brito tested various types of antigens: protein/peptide antigen, SAM, mRNA, virus replicon particles (VRP) and pDNA. But Brito indicates “[b]oth the humoral and cellular responses elicited by CNE SAM vaccine were comparable to other experimental CMV vaccines including a pDNA prime/modified vaccinia virus boost in non-human primates . . . and an MF59 adjuvanted subunit vaccine in phase 2 trials . . . The CNE-delivered SAM vaccine had the protein expression profile of VRP-delivered SAM RNA, but elicited a cellular infiltrate at the site of injection comparable in magnitude to that elicited by the emulsion adjuvant, MF59” (pg. 2124). Thus, overall the results are similar between CNE-SAM and MF59 SAM, and only one difference in a study does not make a formulation without cationic lipid unpredictable, thus combining SAM with Baker’s formulation would reasonably result in either a comparable or improved outcome.
Here, the argument that RNA-based vaccine is complex and not obvious is not convincing, at least in terms of not being obvious, since Anderluzzi’s ionizable lipid would serve a similar purpose as cationic lipid of Brito’s to protect the RNA. Further, Brito does not indicate that MF59 studies with SAM did not induce an immune reaction (which would point to not obviousness), since Brito does indicate “[m]ice immunized with MF59 -/+ SAM RNA and CNE -/+ SAM RNA showed a strong cellular infiltrate of CD11b+ cells” (pg. 2122). Thus, it would be obvious that even with MF59, i.e. which does not contain the cationic lipid is still able to generate an immune response.
Addressing that the present specification demonstrates the criticality of the at least 50% concentration, the results are not in commensurate with the scope of the claims. The claimed subject matter is not limited to the temperatures and time points of the panel, but under BRI would be encompass multiple times and temperatures. The Remarks point to one panel of Fig. 4 illustrating improved stability at exposing the solution at 600C for 72 hrs. in DMSO concentration greater than 50% DMSO (lanes 3-5). However, other panels of Fig. 4 show RNA stability for the lowest concentration of 30% DMSO for time period of 24 hrs. and 48 hrs. Further, the range of 30-60% DMSO is within the range disclosed by Baker. Another issue is that the panel provided by the Remarks of 600C for 72 hrs. demonstrate that 90% DMSO (lane 2, pg. 31 of Remarks) has similar RNA degradation as lower concentration of 30-40% DMSO (lanes 7-8).
Thus, the rejection is maintained.
Allowable Subject Matter
No claim allowed.
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 KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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