Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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 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.
DETAILED ACTION
Claim status
Claims 15-36 are pending
Claims 15-36 are under examination
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/14/2023, 11/06/2024, 11/21/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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 negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
Claims 15 and 24 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023)
Based upon the earlier effective U.S. filing date of the applied references of Guild et al., and Hope et al., constitutes prior art under pre-AIA 35 U.S.C. 102(e). This rejection under pre-AIA 35 U.S.C. 103(a) might be overcome by showing that the reference is disqualified under pre-AIA 35 U.S.C. 103(c) as prior art in a rejection under pre-AIA 35 U.S.C. 103(a). See MPEP § 706.02(l)(1) and § 706.02(l)(2).
In regard to claim 15, MacLachlan teaches compositions comprising RNA and liposomes comprising a cationic lipid, PEG-lipid, and cholesterol [0109-0150, 0163-0169].
In regard to the RNA of claim 15, MacLachlan discloses a genus of RNA based-cationic lipid liposomes, which are termed SPLPs and SNALPs (p.2, Summary of Invention and p. 7, Definitions, [0034]). These RNA based nucleic acids include not only siRNA, but longer RNA molecules such as mRNA ([0010], [0034, 0046]). Furthermore, in regard to the RNA being immunogenic, MacLachlan suggests said RNA liposomes to "generate an immune response against the polypeptide expressed by the gene" (p.23, [0084], lines15-18), thereby producing a recombinant immunogen in vivo. Clearly MacLachlan contemplates that “liposomes containing the cationic lipids of the present invention (are) for immunization purposes” (p.50, [0174], lines 14-15), and are “particularly useful as carriers for vaccines that will be targeted to the appropriate lymphoid organs to stimulate an immune response” ([0175], lines 17-18). Thus, MacLachlan suggests a population of cationic liposomes comprising an immunogen-encoding RNA suitable for in vivo delivery and capable of eliciting a protective immune response. In regard to the nature of the immune response, as stated supra, MacLachlan teaches that the liposomes are for “immunization purposes” and “stimulate an immune response”, such as the “proliferation of B cells displaying surface antibodies” (p. 50, [00177]). Thus, the composition of MacLachlan et al. appears to be able to generate antibodies.
However, MacLachlan et al. are silent with respect to a self-replicating RNA encoding an immunogen.
Perrie teaches of nucleic acid encoded vaccines comprising encapsulated RNA. With respect to claim 15, Perri teaches that the vector for the RNA specifically comprises a RNA-dependent RNA polymerase such as members of the self-replicating alphavirus replicase proteins nsP1, nsP2, nsP3, and nsP4 [0072-0073, 0083], which lead to immunogen production. Specifically, Perri teaches the inclusion of the coding sequences for said replicase complex [0114-0115] and teaches the vector “may be used directly for administration in vivo as RNA, (…) for in vivo vaccine and therapeutic applications” (p. 12, [0101]).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate mRNA encapsulated in cationic lipid liposome comprising a tertiary amine such as DLinDMA for vaccination purposes as suggested by Maclachlan et al., and use a self-replicating RNA encoding an immunogen and an alphavirus replicase as taught by Perri with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, Perri cites the review of Schlesinger & Dubensky (1999, Curr Opin Biotech, 10:434-439) in order to teach that the use of the self-amplifying “replicon” RNA vectors were well known as being advantageous for stimulating immune responses (see [0099] of Perri). Specifically, Schlesinger teaches that the advantages of self-amplifying RNA vectors include both increased expression levels (i.e., sustained copy number from self-amplification) and increased cytokine production due to the presence of alphavirus replicon RNA (p. 437, 1st para of Schlesinger).
In regard to the reasonable expectation of success of combining a self-replicating RNA with an alphavirus replicase encoding an immunogen in a cationic liposome as suggested by MacLachlan et al., in further view of Perri et al., the prior art of Dubensky et al., (US 6,015,686), who is the same corresponding author as Schlesinger & Dubensky (1999), demonstrate that the alphavirus RNA over 10 kb in length formulated in cationic liposomes (e.g., Lipofectamine or Lipofectin) can successfully be used to transfect mammalian cells (Example 1, col 52, last para, see also Example 3, col 59, 1st & 2nd para., Fig. 6, col 66, 3rd para.. col 67 5th para.). Importantly, Dubensky teaches that “abundant reporter gene expression follows transfection” (col 59, 2nd para., Fig. 6, but see also Figs. 9 & 23 demonstrating robust luciferase reporter expression in mammalian cells). Thus, Dubensky teaches that the self-replicating RNA formulated into a cationic liposome can be translated in cyto, which would have provided a reasonable expectation of success that the self-replicating RNA can be translated when formulated in the cationic liposomes of MacLachlan et al.
[AltContent: textbox ([img-media_image1.png])]In regard to the tertiary amino group of the cationic lipid of claim 15(a), as stated supra, MacLachlan discloses a genus of cationic lipids with tertiary amino groups, and specifically teaches the cationic lipid of DLinDMA ([0015-0016, 0022-0028, 0138, 0213], Fig. 2 see adjacent, Figs. 4-12, see Examples 3-13).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising a tertiary amine cationic lipid such as DLinDMA as suggested by MacLachlan et al., with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, as stated supra, MacLachlan explicitly suggests DLinDMA. Second, Hope (WO2010) teaches that unlike cationic lipids with tertiary amines, those lipids with quaternary amino groups are permanently positively charged and showed reduced activity and increased toxicity (p. 123, 2nd para., p. 130, 1st para.). Generally, Hope teaches that ionizable cationic lipids with ionizable tertiary amine headgroups are advantageous because their pKa allows these lipids to be neutral at physiological pH so as to have favorable plasma protein adsorption, blood clearance and tissue distribution, while being positively charged at an acidic pH so as to favor endosomal escape (p. 123, 1st para., p. 136, 1st para.). Specifically, Hope (WO 2010) teaches that cationic lipids such as DLinDMA with pKa of about 6.4 have a neutral charge in circulation but will become positively charged upon uptake by endosomes (p. 123, 1st para., p. 137, 1st para., and Table 11). Thus, it would have been obvious to choose the tertiary amine based cationic lipid of DLinDMA when making the liposome of MacLachlan et al.
In regard to encapsulation of the RNA as per claim 15, Martinon et al., (1993) reduces to practice an RNA based vaccine comprising a zwitterionic liposome and a RNA encoding a polypeptide immunogen (p. 1719, Title, Abstract, Materials and Methods, Section 2.1). Martinon demonstrates that the mRNA delivered by the liposome is translated in vivo and that the translated protein enters the intracellular antigen processing pathway in order to generate a humoral immune response (p. 1720, last para., p. 1722, last para.). Furthermore, Martinon teaches that the mRNA must be encapsulated in order to induce a T cell response (p. 1721, 3rd para.).
Thus, it would have been obvious to optimize encapsulation efficiency to at least 50 % of the RNA within the cationic lipid particle of MacLachlan in order to induce an immune response. In regard to the reasonable expectation of success of doing so, MacLachlan provides a working example with a SNALP formulation, wherein DLinDMA generated liposomes with about an 84% encapsulation rate (p. 61, [0211], Table 1), albeit with smaller siRNA. Nevertheless, Hope (WO 2010) teaches that when using ionizable cationic lipids with a tertiary amine head group, the loading of nucleic acids is first accomplished at a lower pH so that the tertiary amine is protonated and electrostatically binds the negatively charged nucleic acid to allow efficient encapsulation and any external nucleic acids to be removed (p. 69, last para., p. 70, first para.). Thus, Hope provides a scientific rationale for the extrapolation of MacLachlan’s encapsulation efficiencies of liposomes comprising the tertiary amine cationic lipid DLinDMA with siRNA to similar negatively charged nucleic acids but much larger RNA such as mRNA and/or self-replicating RNA. Accordingly, MacLachlan et al. make obvious that at least half of the RNA molecules are encapsulated in the liposomes.
Finally, in regard to the diameter of the lipid particles encapsulating the RNA as per claim 15, Guild et al. teaches a mRNA encapsulated in a lipid particle, wherein the lipid particle comprises a tertiary amine (i.e., DODAP), wherein the majority of the lipid particles exhibit a relatively well-defined size distribution of about 100 nm in diameter (p. 18, last para., Example 1, p. 29, 1st and 2nd para. of priority document).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising a tertiary amine cationic lipid such as suggested by MacLachlan et al., and to have a relatively well-defined sized distribution of around 100 nm as taught by Guild with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so at taught by Guild because of uptake into the target cell or tissue (p. 19, 3rd para.). Furthermore, MacLachlan teaches that nucleic acid-lipid particles should typically have a mean diameter of about 100 nm in order to be nontoxic [0052], In regard to the relatively well-defined sized destruction being at least 80% of the lipid particles, Guild teaches the particles can be cycled through sizing membranes several times to reach the desired size (p.19, 1st para.), and therefore it would have been obvious to one having ordinary skill in the art at the time the invention was made to have at least 80% of the lipid particles about 100 nm in diameter, since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233.
In regard to claim 24, as stated supra, MacLachlan the liposome comprises not only a cationic lipid, but also a phospholipid such as DSPC (see Example 1 [0196], Example 7, [0216]).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 16-21, 23 and 25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023), as applied to claim 15, in further view Thalhamer et al., (WO 2009/040443, filed 9/29/2008, published 4/02/2009)
As stated supra, MacLachlan et al. suggest a formulation comprising a self-replicating RNA that encodes a polypeptide immunogen encapsulated in a liposome comprising a tertiary amine cationic lipid DLinDMA.
However, in regard to claims 16-17, MacLachlan et al. are silent with respect to the mRNA comprising a 5’ guanosine cap linked 5’ to 5’ to the first 5’ nucleotide (i.e. cap0) structure, as well as where the guanosine ribonucleotide comprises a 2’-methylated ribose (i.e., cap1) structure.
Nevertheless, Perri appears to disclose that the self-replicating RNA comprises a “m7G” cap (see adjacent excerpt of Figure 1):
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Furthermore, Thalhamer teaches a formulation comprising a RNA vaccine (Abstract, p. 3, 2nd and 3rd para.), wherein the RNA is formulated in a cationic liposome (p. 13, last para., p.14, 1st para.). Specifically, Thalhamer teaches the RNA comprises either a 5’ 7meGpppG (i.e. cap0) structure or a 5’ 7meGpppGme (i.e., cap1) structure, wherein the guanosine ribonucleotide comprises a 2’-methylated ribose (p. 9, 5th para., p. 10, 1st para., p. 12, 5th & 6th para., p. 16, 3rd & 6th para., see Claim 8 of Thalhamer).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate mRNA encapsulated in cationic lipid liposome as suggested by MacLachlan et al., and to combine a 5’ cap0 or 5’cap1 structure with the mRNA as taught by Thalhamer with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Thalhamer because 5’ cap0 mRNA is important for binding translation initiation factors and contributed to mRNA stability, while the 5’ cap1 structure further increases translation efficiency (p. 18, last para., p. 10, first para.).
In regard to claim 18, as stated supra, MacLachlan suggests said RNA liposomes to generate an immune response against the polypeptide expressed by the gene. Specifically, MacLachlan teaches the vaccine comprises viral antigens capable of treating a pathogenic infection [0084, 0174]. Furthermore, Martinon reduces to practice a mRNA based influenza A vaccine, which is taught be safer than alternative vaccines using non-recombinant viral material (p. 1719, Introduction). Thus, choosing a influenza A immunogen would have been predictably obvious for the vaccine of MacLachlan.
In regard to claims 19-21, and 25, as stated supra, MacLachlan the liposome comprises not only a cationic lipid, but also a phospholipid such as DSPC, a sterol such as cholesterol at 48%, and a pegylated lipid at 2% (see Example 1 [0196], Example 7, [0216]). Specifically, MacLachlan suggests that the liposome comprises up to about 60% of the cationic lipid, and specifically recites about 40% (p. 12, [0051]), which is about the molar percent range used in working Examples 1 and 8-12). Furthermore, MacLachlan demonstrates that about 40% of DLinDMA exhibit the best activity for siRNA (p. 63, last para, see Fig. 6). Moreover, Guild et al. disclose examples of mRNA liposomes comprising the tertiary amine cationic lipid DODAP, together with DSPC, cholesterol, and a pegylated lipid wherein the cholesterol is at about 40% and the PEG-lipid is at about 4 mol% (Examples 2, 4 & 5, pgs. 28-33 of 61/265,653 priority document).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising about 40-60% of the tertiary amine cationic lipid DLinDMA, together with DSPC, cholesterol between 40-50 mol%, and a pegylated lipids between 2-4% as suggested by MacLachlan et al., with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Furthermore, in regard to claim 23, as stated supra, Martinon teaches the RNA based vaccines against the influenza A immunogen induce a CTL mediated immune response. Thus, the composition of MacLachlan et al. would have been able to induce both humoral and cell-mediated responses (see also p. 1722, last para. of Martinon). Applicant is reminded that limitations reciting an immunogenic response in vivo are directed to the intended use of the claimed composition.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 22 is rejected under 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023) and Thalhamer et al., (WO 2009/040443, filed 9/29/2008, published 4/02/2009, see IDS filed 11/14/2023), as applied to claims 15-21, in further view of Manoharan et al., (WO2009/132131, filed 4/22/2009, published 10/29/2009, see IDS filed 11/14/2023).
As stated supra, MacLachlan et al. suggest a formulation comprising a self-replicating RNA that encodes a polypeptide immunogen encapsulated in a liposome comprising a tertiary amine cationic lipid DLinDMA.
In regard to claim 22, as stated supra, MacLachlan teaches that the formulation comprises not only the tertiary amine cationic lipid, but also other lipids such as PEG conjugated lipids (see Example 1 [0196]). However, although MacLachlan teaches methoxyPEG conjugated lipids [0058-0059, 0069, 0195], and generally suggests the PEG conjugated lipid is dimyristoyl C14 chain [0066-0068, 0072], they are silent to a methoxyPEG conjugated DMG.
Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as taught by MacLachlan and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 26 and 35 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023), Hofmann et al., (J Lip Res, 1984, 25:1477-1489, see IDS filed 11/14/2023), Hope (WO 2011/075656, filed 12/17/2010, with priority to provisional 61/287,995 filed 12/18/2009, see IDS filed 11/14/2023), Kazuya (JP2010025644, published 2/04/2010, see IDS filed 11/14/2023), and Sasaki et a. (US 6,048,546, patented 4/11/2000, see IDS filed 11/14/2023), Bailey and Cullis (Biochem, 1994, 33:12573-12580, see IDS filed 11/14/2023), McGown (BioTechniques, 2000, 28:60-64, see IDS filed 11/14/2023), Schedin-Weiss et al. (Biochemistry, 2008, 47:13610-13619, see IDS filed 11/14/2023), and Qa’Dan et al. (Infect & Immun, 2000, 68:2470-2474, see IDS filed 11/14/2023)
In regard to claim 26, MacLachlan teaches compositions comprising RNA and liposomes comprising a cationic lipid, PEG-lipid, and cholesterol [0109-0150, 0163-0169].
In regard to the RNA of claim 26, MacLachlan discloses a genus of RNA based-cationic lipid liposomes, which are termed SPLPs and SNALPs (p.2, Summary of Invention and p. 7, Definitions, [0034]). These RNA based nucleic acids include not only siRNA, but longer RNA molecules such as mRNA ([0010], [0034, 0046]). Furthermore, in regard to the RNA being immunogenic, MacLachlan suggests said RNA liposomes to "generate an immune response against the polypeptide expressed by the gene" (p.23, [0084], lines15-18), thereby producing a recombinant immunogen in vivo. Clearly MacLachlan contemplates that “liposomes containing the cationic lipids of the present invention (are) for immunization purposes” (p.50, [0174], lines 14-15), and are “particularly useful as carriers for vaccines that will be targeted to the appropriate lymphoid organs to stimulate an immune response” ([0175], lines 17-18). Thus, MacLachlan suggests a population of cationic liposomes comprising an immunogen-encoding RNA suitable for in vivo delivery and capable of eliciting a protective immune response. In regard to the nature of the immune response, as stated supra, MacLachlan teaches that the liposomes are for “immunization purposes” and “stimulate an immune response”, such as the “proliferation of B cells displaying surface antibodies” (p. 50, [00177]). Thus, the composition of MacLachlan et al. appears to be able to generate antibodies.
However, MacLachlan et al. are silent with respect to a self-replicating RNA encoding an immunogen.
Perrie teaches of nucleic acid encoded vaccines comprising encapsulated RNA. With respect to claim 26, Perri teaches that the vector for the RNA specifically comprises a RNA-dependent RNA polymerase such as members of the self-replicating alphavirus replicase proteins nsP1, nsP2, nsP3, and nsP4 [0072-0073, 0083], which lead to immunogen production. Specifically, Perri teaches the inclusion of the coding sequences for said replicase complex [0114-0115] and teaches the vector “may be used directly for administration in vivo as RNA, (…) for in vivo vaccine and therapeutic applications” (p. 12, [0101]).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate mRNA encapsulated in cationic lipid liposome comprising a tertiary amine such as DLinDMA for vaccination purposes as suggested by Maclachlan et al., and use a self-replicating RNA encoding an immunogen and an alphavirus replicase as taught by Perri with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, Perri cites the review of Schlesinger & Dubensky (1999, Curr Opin Biotech, 10:434-439) in order to teach that the use of the self-amplifying “replicon” RNA vectors were well known as being advantageous for stimulating immune responses (see [0099] of Perri). Specifically, Schlesinger teaches that the advantages of self-amplifying RNA vectors include both increased expression levels (i.e., sustained copy number from self-amplification) and increased cytokine production due to the presence of alphavirus replicon RNA (p. 437, 1st para of Schlesinger).
In regard to the reasonable expectation of success of combining a self-replicating RNA with an alphavirus replicase encoding an immunogen in a cationic liposome as suggested by MacLachlan et al., in further view of Perri et al., the prior art of Dubensky et al., (US 6,015,686), who is the same corresponding author as Schlesinger & Dubensky (1999), demonstrate that the alphavirus RNA over 10 kb in length formulated in cationic liposomes (e.g., Lipofectamine or Lipofectin) can successfully be used to transfect mammalian cells (Example 1, col 52, last para, see also Example 3, col 59, 1st & 2nd para., Fig. 6, col 66, 3rd para.. col 67 5th para.). Importantly, Dubensky teaches that “abundant reporter gene expression follows transfection” (col 59, 2nd para., Fig. 6, but see also Figs. 9 & 23 demonstrating robust luciferase reporter expression in mammalian cells). Thus, Dubensky teaches that the self-replicating RNA formulated into a cationic liposome can be translated in cyto, which would have provided a reasonable expectation of success that the self-replicating RNA can be translated when formulated in the cationic liposomes of MacLachlan et al.
[AltContent: textbox ([img-media_image1.png])]In regard to the tertiary amino group of the cationic lipid of claim 26a), as stated supra, MacLachlan discloses a genus of cationic lipids with tertiary amino groups, and specifically teaches the cationic lipid of DLinDMA ([0015-0016, 0022-0028, 0138, 0213], Fig. 2 see adjacent, Figs. 4-12, see Examples 3-13).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising a tertiary amine cationic lipid such as DLinDMA as suggested by MacLachlan et al., with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, as stated supra, MacLachlan explicitly suggests DLinDMA. Second, Hope (WO2010) teaches that unlike cationic lipids with tertiary amines, those lipids with quaternary amino groups are permanently positively charged and showed reduced activity and increased toxicity (p. 123, 2nd para., p. 130, 1st para.). Generally, Hope teaches that ionizable cationic lipids with ionizable tertiary amine headgroups are advantageous because their pKa allows these lipids to be neutral at physiological pH so as to have favorable plasma protein adsorption, blood clearance and tissue distribution, while being positively charged at an acidic pH so as to favor endosomal escape (p. 123, 1st para., p. 136, 1st para.). Specifically, Hope (WO 2010) teaches that cationic lipids such as DLinDMA with pKa of about 6.4 have a neutral charge in circulation but will become positively charged upon uptake by endosomes (p. 123, 1st para., p. 137, 1st para., and Table 11). Thus, it would have been obvious to choose the tertiary amine based cationic lipid of DLinDMA when making the liposome of MacLachlan et al.
In regard to encapsulation of the RNA as per claim 26, Martinon et al., (1993) reduces to practice an RNA based vaccine comprising a zwitterionic liposome and a RNA encoding a polypeptide immunogen (p. 1719, Title, Abstract, Materials and Methods, Section 2.1). Martinon demonstrates that the mRNA delivered by the liposome is translated in vivo and that the translated protein enters the intracellular antigen processing pathway in order to generate a humoral immune response (p. 1720, last para., p. 1722, last para.). Furthermore, Martinon teaches that the mRNA must be encapsulated in order to induce a T cell response (p. 1721, 3rd para.).
Thus, it would have been obvious to optimize encapsulation efficiency to at least 50 % of the RNA within the cationic lipid particle of MacLachlan in order to induce an immune response. In regard to the reasonable expectation of success of doing so, MacLachlan provides a working example with a SNALP formulation, wherein DLinDMA generated liposomes with about an 84% encapsulation rate (p. 61, [0211], Table 1), albeit with smaller siRNA. Nevertheless, Hope (WO 2010) teaches that when using ionizable cationic lipids with a tertiary amine head group, the loading of nucleic acids is first accomplished at a lower pH so that the tertiary amine is protonated and electrostatically binds the negatively charged nucleic acid to allow efficient encapsulation and any external nucleic acids to be removed (p. 69, last para., p. 70, first para.). Thus, Hope provides a scientific rationale for the extrapolation of MacLachlan’s encapsulation efficiencies of liposomes comprising the tertiary amine cationic lipid DLinDMA with siRNA to similar negatively charged nucleic acids but much larger RNA such as mRNA and/or self-replicating RNA. Accordingly, MacLachlan et al. make obvious that at least half of the RNA molecules are encapsulated in the liposomes.
Finally, in regard to the diameter of the lipid particles encapsulating the RNA as per claim 26, Guild et al. teaches a mRNA encapsulated in a lipid particle, wherein the lipid particle comprises a tertiary amine (i.e., DODAP), wherein the majority of the lipid particles exhibit a relatively well-defined size distribution of about 100 nm in diameter (p. 18, last para., Example 1, p. 29, 1st and 2nd para. of priority document).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising a tertiary amine cationic lipid such as suggested by MacLachlan et al., and to have a relatively well-defined sized distribution of around 100 nm as taught by Guild with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so at taught by Guild because of uptake into the target cell or tissue (p. 19, 3rd para.). Furthermore, MacLachlan teaches that nucleic acid-lipid particles should typically have a mean diameter of about 100 nm in order to be nontoxic [0052], In regard to the relatively well-defined sized destruction being at least 80% of the lipid particles, Guild teaches the particles can be cycled through sizing membranes several times to reach the desired size (p.19, 1st para.), and therefore it would have been obvious to one having ordinary skill in the art at the time the invention was made to have at least 80% of the lipid particles about 100 nm in diameter, since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233.
However, in regard to the method by which the pKa of DLinDMA was determined as per claim 26, as stated supra, Hope (WO 2010) teaches that cationic lipid DLinDMA has a pKa of about 6.4, and it is noted that even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production (or in this case, the method of determination). If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made/determined by a different process.
Nevertheless, in regard to pKa determination steps of claim 26, although MacLachlan et al. teach general method steps for determining the pKa of the SNALP lipid, they are silent to every of the claimed 14 method steps. Specifically, MacLachlan teaches the following steps for determining the pKa of the SNALP lipid (Example 1, pgs. 56-57, [0197], see also Example 5, pgs. 61-62, [0212-0213]):
Step (1) Admixing the SNALP lipid with fluorescent TNS probe, thereby obtaining a lipid/TNS mixture;
Steps (2-9) Forming various sodium salt mixtures comprising a 20 mM sodium phosphate, 25 mM citrate, 20 mM ammonium acetate, and 150 mM sodium chloride, wherein the mixtures have a range of pH from 4.5 to 9.5, thereby obtaining a plurality of pH varied lipid/TNS mixtures. Note that MacLachlan also discloses sodium citrate and sodium acetate salts [0155, 0189, 0198], which would have been considered obvious salts to use with nearly equivalent efficacy;
Step (10) Measuring absolute fluorescence emissions at 431 nm with a 322 nm excitation of the plurality of pH varied lipid/TNS mixtures, thereby obtaining the absolute fluorescence of the plurality of pH varied lipid/TNS mixtures;
Step (12) Normalizing each of the fluorescence emissions of the plurality of pH varied lipid/TNS mixtures with a sodium salt buffer having the lowest pH of the first sodium salt buffers (i.e., pH 4.5), thereby obtaining a relative fluorescence for each of the plurality of the pH varied lipid/TNS mixtures;
Step (13) Obtaining a line of best fit of pH versus relative fluorescence of the plurality of pH varied lipid/TNS mixtures (see Fig. 4 of MacLachlan);
Step (14) Defining the pKa as the pH at which a relative fluorescence of 0.5 is obtained (i.e., 50% of the molecules are charged).
In regard to the deficiencies of the pKa determination method taught by MacLachlan, in step (1) of the pKa determination method, MacLachlan is silent with respect to measuring the pKa of the tertiary amine cationic lipid in a 100% ethanol solution.
Nevertheless, in regard to step (1), Guild et al. teaches that 100% (i.e. absolute) ethanol was used to dissolve the taught cationic lipids (p. 28, Example 1 of 61/265,653 priority document).
Furthermore, in regard to step (1), Hofmann reviews methods for the determination of pKa of ionizable lipids with alkyl side chains (Abstract). Specifically, Hofmann teaches the method step of first admixing the lipid with ethanol before determining the pKa (p. 1481, 3rd para.)
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a SNALP lipid in a TNS assay as suggested by MacLachlan et al., and to substitute the method step preparing a first 100% ethanol mixture of the tertiary amine lipid with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, Hofmann teaches that because of the poor solubility of ionizable lipids with long alkyl chains (such as DLinDMA of MacLachlan), the isolated lipid must first be mixed with ethanol (p. 1481, 3rd para., p. 1482, 2nd para.), and Guild discloses that 100% ethanol would have been an option for doing so with a reasonable expectation of success since it was able to dissolve the tertiary amine cation lipid in a mixture. In regard to determining the pKa of the tertiary amine lipid as opposed to the SNALP lipid, Hope (WO2011) teaches that because using the TNS fluorescence assay yields an empirical pKa, the method determines the combined pKa values of individual lipids in a mixture (pg. 141, last para., p.142, first two para. of provisional 61/287,995). As stated supra, MacLachlan teaches that the prepared RNA liposomes comprise not only the cationic lipid comprising the tertiary amine, but other lipids with ionizable groups at varying molar percentages that would affect the empirical pKa. Thus, knowing a priori the pKa of the isolated lipids would have been important to know when choosing the proper combination and percentages of tertiary amine cationic lipid with other lipids in order to ensure that the prepared liposome would have a neutral charge in circulation but become positively charged upon uptake by endosomes as taught by Hope (WO 2010).
However, in regard to step (1) of the pKa determination method, MacLachlan is silent with respect to mixing TNS reagent in a 9:1 ethanol:methanol mixture.
In regard to the use of ethanol and methanol for the TNS suspension of step (1), Kazuya teaches methods for preparing suspensions of TNS, as well as the naphthalenesulfonic acid ANS in either ethanol or methanol (Examples 1 & 7, see Figs. 1, 2, and 15).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and substitute ethanol or methanol for the suspension of TNS with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Kazuya because of the low solubility of TNS (p. 2 of the translation in reference to Fig. 16).
However, in regard to a 9:1 ethanol:methanol mixture as per step (1).
In regard to the use of only 10% methanol for the TNS suspension of step (1), Sasaki teaches methods for preparing suspensions of lipids, wherein no more than 10% methanol is used (col 7, 2nd para.).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al. with an initial TNS suspension in ethanol or methanol, and substitute a 90% ethanol 10% methanol for the suspension of TNS based on the teachings of Sasaki with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to because although methanol is a superior solvent because of its increased polarity over ethanol, greater than 10% methanol can cause lipid aggregation as taught by Sasaki (col 7, 2nd para.); thus, a 90% ethanol 10% methanol mixture would have been predictably obvious for preparing the initial TNS stock solution to be mixed with the lipids.
However, in regard to step (1) and steps (2-9) of the pKa determination method, MacLachlan is silent with respect to mixing the 400 ml (V1) of the 2 mM (M1) lipid with 800 mL (V2) of 0.3 mM (M2) TNS reagent, which is then diluted to 1:33 (i.e., 7.5 L per 250 L) in the pH buffer for use in the TNS assay.
Nevertheless, MacLachlan teaches admixing the final concentration of 20 M SNALP lipid with 6 M fluorescent TNS probe for the TNS assay.
Although, MacLachlan is silent with respect to the molar volumes claimed and the diluting steps to reach the final molar concentration of lipid and TNS reagent for measurements in the pH buffer, it has been held that to be entitled to patentable weight in method claims, the recited structure limitations of a step therein must affect the method in a manipulative sense. Ex parte Pfeiffer, 1962 C.D. 408 (1961). In instant case, the claimed steps result in a final concentration of lipid of 20 M (i.e., 2 mM diluted to 0.66 mM with TNS reagent and then diluted again 1:33 in the pH buffer to reach a final molarity of 0.02 mM). Similarly, the claimed steps result in a final concentration of TNS reagent of 6 M (i.e., 0.3 mM diluted to 0.22 mM with lipid buffer and then diluted again 1:33 in the pH buffer to reach a final molarity of 0.006 mM). Therefore, since the admixing step of MacLachlan reach the same final molarity of lipid and TNS reagent for the measurement steps in the pH buffer as the admixing steps claimed, these steps are functionally equivalent. MPEP 2144.05(I) states “a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
However, in regard to steps (2-9) of the pKa determination method, MacLachlan is silent with respect to varying the range of the pH to from 4.4 to 11.12.
In regard to steps (2-9) Hope (WO2011) teaches a method for determining the pKa of a SNALP lipid by varying the range from 2 up to 11 (pgs. 134-135, Example 5 of provisional 61/287,995).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and to combine step of measuring the TNS fluorescence emission from pH 4.4 to 11.12 with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, as stated supra, MacLachlan teaches the lower pH is 4.5, which is about 4.4, and Hope (WO2011) teaches the upper pH is 11, which is about 11.12. Thus, it would have been obvious to measure over the range from 4.4 to 11.12 because MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
However, in regard to steps (2-9) of the pKa determination method, MacLachlan is silent to the mixtures comprising at least 8 sub-ranges of 4.44-4.52, 5.27, 6.15-6.21, 6.57, 7.10-7.2, 7.72-7.8, 8.27-8.33, 10.47-11.12 for the pKa determination.
Nevertheless, MacLachlan cites the prior art of Bailey and Cullis (1994) for methods of determining the pKa of cationic lipids with TNS reagent (see [0212] of MacLachlan).
Bailey and Cullis teach a method of determining the pKa of cationic lipids with TNS reagent comprising a titration curve comprising measurements of pH buffers at pH values of about 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10 (p. 12575, Fig. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and to combine step of measuring the TNS fluorescence emission to include at least 8 pH buffer sub-ranges from 4-11 with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because in the case where the claimed ranges overlap ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Furthermore, as stated supra, the since Baily and Cullis teach the concept of measuring at every pH unit, including ½ units in the range of 5-8, and as stated supra, MacLachlan and Hope (WO2011) suggests a range from about 4.4 to about 11.12; thus these pH sub-values suggested by Daily and Cullis are close enough that one skilled in the art would have expected them to have the same properties as the claimed ranges for measuring the pKa of a lipid.
However, in regard to steps (2-9) of the pKa determination method, MacLachlan uses cuvette measurements of the pKa for the lipid/TNS mixture, and they are silent to a 96 well plate assay in a volume of 250 l for each of the pH measurements.
In regard to steps (2-9), McGown teaches a method for using a 96 well plate reader for quantitative fluorescent measurements of nucleic acids in a volume of about 250 l.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and to substitute the cuvette based method with a 96 well plate in a volume of 250 l for each of the pH measurements as taught by McGown with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by McGown because a 96 well plate allows higher throughput compared to traditional cuvettes (p. 1, 1st para.), the volume of 250 l represents the near maximum volume for a well in a 96 well plate (p. 2, 3rd para.).
However, in regard to steps (10) and (11), MacLachlan et al. are silent with respect to measuring the TNS fluorescence emission with a 420 nm cut-off filter.
In regard to steps (10) and (11), Schedin-Weiss et al., (2008) teach the step of measuring TNS fluorescent emissions with a 420 nm cut-off filter (p. 5, 1st para.).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and to combine step of measuring the TNS fluorescence emission with a 420 nm cut-off filter as taught by Schedin-Weiss with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Schedin-Weiss because using a narrow band for emission ensured that no background TNS fluorescence changed (p. 5, 1st para.).
However, in regard to steps (10) and (11), MacLachlan et al. are silent with respect to measuring the TNS fluorescence emission of an empty well thereby obtaining a blank fluorescence, and then subtracting the blank fluorescence from the absolute fluorescence.
In regard to steps (10) and (11), Qa’Dan et al. (2000) teach the step of measuring TNS fluorescent emissions of an semi-empty vessel comprising TNS and buffer alone, thereby obtaining a blank fluorescence, and then subtracting the blank (i.e., background) fluorescence from the absolute fluorescence (p. 2472, Results, Figs. 3-5).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the pKa of a tertiary amine cationic lipid as suggested by MacLachlan et al., and to combine steps of measuring TNS fluorescent emissions of a semi-empty well comprising TNS and buffer alone, thereby obtaining a blank fluorescence, and then subtracting the blank fluorescence from the absolute fluorescence as taught by Qa’Dan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Qa’Dan because subtracting the background fluorescence allowed the determination of a relative TNS fluorescence that was comparable among separate experiments (p. 2474, Figs. 3-5). In regard to the difference between an empty well as claimed, compared to the semi-empty well devoid of lipid but having TNS in buffer as taught by Qa’Dan, since Schedin-Weiss teaches that as long as a 420 cut-off filter is used, there is no background TNS fluorescence (p. 5, 1st para.), thus it would have been obvious to one having ordinary skill in the art at the time the invention was made to use an empty well since the background fluorescence would have been the same as a TNS only well, yet would have also saved TNS reagent.
In regard to claim 35, as stated supra, MacLachlan the liposome comprises not only a cationic lipid, but also a phospholipid such as DSPC (see Example 1 [0196], Example 7, [0216]).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 27-33 and 36 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023), Hofmann et al., (J Lip Res, 1984, 25:1477-1489, see IDS filed 11/14/2023), Hope (WO 2011/075656, filed 12/17/2010, with priority to provisional 61/287,995 filed 12/18/2009, see IDS filed 11/14/2023), Kazuya (JP2010025644, published 2/04/2010, see IDS filed 11/14/2023), and Sasaki et a. (US 6,048,546, patented 4/11/2000, see IDS filed 11/14/2023), Bailey and Cullis (Biochem, 1994, 33:12573-12580, see IDS filed 11/14/2023), McGown (BioTechniques, 2000, 28:60-64, see IDS filed 11/14/2023), Schedin-Weiss et al. (Biochemistry, 2008, 47:13610-13619, see IDS filed 11/14/2023), and Qa’Dan et al. (Infect & Immun, 2000, 68:2470-2474, see IDS filed 11/14/2023), as applied to claim 26, in further view Thalhamer et al., (WO 2009/040443, filed 9/29/2008, published 4/02/2009, see IDS filed 11/14/2023)
As stated supra, MacLachlan et al. suggest a formulation comprising a self-replicating RNA that encodes a polypeptide immunogen encapsulated in a liposome comprising a tertiary amine cationic lipid DLinDMA.
However, in regard to claims 27-28, MacLachlan et al. are silent with respect to the mRNA comprising a 5’ guanosine cap linked 5’ to 5’ to the first 5’ nucleotide (i.e. cap0) structure, as well as where the guanosine ribonucleotide comprises a 2’-methylated ribose (i.e., cap1) structure.
Nevertheless, Perri appears to disclose that the self-replicating RNA comprises a “m7G” cap (see adjacent excerpt of Figure 1):
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98
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Furthermore, Thalhamer teaches a formulation comprising a RNA vaccine (Abstract, p. 3, 2nd and 3rd para.), wherein the RNA is formulated in a cationic liposome (p. 13, last para., p.14, 1st para.). Specifically, Thalhamer teaches the RNA comprises either a 5’ 7meGpppG (i.e. cap0) structure or a 5’ 7meGpppGme (i.e., cap1) structure, wherein the guanosine ribonucleotide comprises a 2’-methylated ribose (p. 9, 5th para., p. 10, 1st para., p. 12, 5th & 6th para., p. 16, 3rd & 6th para., see Claim 8 of Thalhamer).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate mRNA encapsulated in cationic lipid liposome as suggested by MacLachlan et al., and to combine a 5’ cap0 or 5’cap1 structure with the mRNA as taught by Thalhamer with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Thalhamer because 5’ cap0 mRNA is important for binding translation initiation factors and contributed to mRNA stability, while the 5’ cap1 structure further increases translation efficiency (p. 18, last para., p. 10, first para.).
In regard to claim 29, as stated supra, MacLachlan suggests said RNA liposomes to generate an immune response against the polypeptide expressed by the gene. Specifically, MacLachlan teaches the vaccine comprises viral antigens capable of treating a pathogenic infection [0084, 0174]. Furthermore, Martinon reduces to practice a mRNA based influenza A vaccine, which is taught be safer than alternative vaccines using non-recombinant viral material (p. 1719, Introduction). Thus, choosing a influenza A immunogen would have been predictably obvious for the vaccine of MacLachlan.
In regard to claims 30-32, and 36, as stated supra, MacLachlan the liposome comprises not only a cationic lipid, but also a phospholipid such as DSPC, a sterol such as cholesterol at 48%, and a pegylated lipid at 2% (see Example 1 [0196], Example 7, [0216]). Specifically, MacLachlan suggests that the liposome comprises up to about 60% of the cationic lipid, and specifically recites about 40% (p. 12, [0051]), which is about the molar percent range used in working Examples 1 and 8-12). Furthermore, MacLachlan demonstrates that about 40% of DLinDMA exhibit the best activity for siRNA (p. 63, last para, see Fig. 6). Moreover, Guild et al. disclose examples of mRNA liposomes comprising the tertiary amine cationic lipid DODAP, together with DSPC, cholesterol, and a pegylated lipid wherein the cholesterol is at about 40% and the PEG-lipid is at about 4 mol% (Examples 2, 4 & 5, pgs. 28-33 of 61/265,653 priority document).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to generate a RNA liposome comprising about 40-60% of the tertiary amine cationic lipid DLinDMA, together with DSPC, cholesterol between 40-50 mol%, and a pegylated lipids between 2-4% as suggested by MacLachlan et al., with reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
In regard to claim 33, as stated supra, Hope discloses that DLinDMA has a pKa of about 6.4.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 34 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Maclachlan et al., (WO2005/120152, see IDS filed 11/14/2023), in view of Perri et al., (US 2009/0104226, see IDS filed 12/22/2021, see IDS filed 11/14/2023), Schlesinger et al., (Curr Op Biotech, 1999, 10:434-439, , see IDS filed 11/14/2023), and Dubensky et al., (US 6,015,686, see IDS filed 11/14/2023, Hope (WO 2010/042877, filed 10/09/2009, see IDS filed 11/14/2023), Martinon et al., (Eur J Immuno, 1993, 23:1719-1722, see IDS filed 11/14/2023), and Guild et al., (US 2011/0244026, see provisional 61/265,653 filed 12/01/2009, see IDS filed 11/14/2023), Hofmann et al., (J Lip Res, 1984, 25:1477-1489, see IDS filed 11/14/2023), Hope (WO 2011/075656, filed 12/17/2010, with priority to provisional 61/287,995 filed 12/18/2009, see IDS filed 11/14/2023), Kazuya (JP2010025644, published 2/04/2010, see IDS filed 11/14/2023), and Sasaki et a. (US 6,048,546, patented 4/11/2000, see IDS filed 11/14/2023), Bailey and Cullis (Biochem, 1994, 33:12573-12580, see IDS filed 11/14/2023), McGown (BioTechniques, 2000, 28:60-64, see IDS filed 11/14/2023), Schedin-Weiss et al. (Biochemistry, 2008, 47:13610-13619, see IDS filed 11/14/2023), and Qa’Dan et al. (Infect & Immun, 2000, 68:2470-2474, see IDS filed 11/14/2023) and Thalhamer et al., (WO 2009/040443, filed 9/29/2008, published 4/02/2009, see IDS filed 11/14/2023), as applied to claims 26-32, in further view of Manoharan et al., (WO2009/132131, filed 4/22/2009, published 10/29/2009, see IDS filed 11/14/2023).
As stated supra, MacLachlan et al. suggest a formulation comprising a self-replicating RNA that encodes a polypeptide immunogen encapsulated in a liposome comprising a tertiary amine cationic lipid DLinDMA.
In regard to claim 34, as stated supra, MacLachlan teaches that the formulation comprises not only the tertiary amine cationic lipid, but also other lipids such as PEG conjugated lipids (see Example 1 [0196]). However, although MacLachlan teaches methoxyPEG conjugated lipids [0058-0059, 0069, 0195], and generally suggests the PEG conjugated lipid is dimyristoyl C14 chain [0066-0068, 0072], they are silent to a methoxyPEG conjugated DMG.
Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as taught by MacLachlan and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-11 of U.S. Patent No. 9,254,265 (Geall et al., Patented 2/09/2016)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, that are more specific, as well as the use of a RNA Cap0/1. Nevertheless, RNA Caps were well known to contribute to RNA stability, and it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-11 of U.S. Patent No. 9,254,265 (Geall et al., Patented 2/09/2016)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-20, and 33-66 of U.S. Patent No. 11,324,770 (Geall et al., Patented 5/10/2022)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-20, and 33-66 of U.S. Patent No. 11,324,770 (Geall et al., Patented 5/10/2022)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 40-71 of U.S. Patent No. 11,596,645 (Geall et al., Patented 3/07/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 40-71 of U.S. Patent No. 11,596,645 (Geall et al., Patented 3/07/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-36 are rejected on the grounds of nonstatutory double patenting over claims 1-30 of U.S. Patent No. 11,638,693 (Geall et al., Patented 5/02/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses diameters that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-30 of U.S. Patent No. 11,638,694 (Geall et al., Patented 5/02/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, and diameters that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-30 of U.S. Patent No. 11,638,694 (Geall et al., Patented 5/02/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,690,861 (Geall et al., Patented 7/04/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,690,861 (Geall et al., Patented 7/04/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,690,864 (Geall et al., Patented 7/04/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,690,864 (Geall et al., Patented 7/04/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,707,482 (Geall et al., Patented 7/25/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,707,482 (Geall et al., Patented 7/25/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,730,754 (Geall et al., Patented 8/22/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,730,754 (Geall et al., Patented 8/22/2023)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-36 are rejected on the grounds of nonstatutory double patenting over claims 1-32 of U.S. Patent No. 11,786,467 (Geall et al., Patented 10/17/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses diameters that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are made obvious by cited patent claims, said claims are not patentably distinct.
Claims 15-36 are rejected on the grounds of nonstatutory double patenting over claims 1-33 of U.S. Patent No. 11,839,686 (Geall et al., Patented 12/12/2023)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses diameters and percentages of cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are made obvious by cited patent claims, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,857,562 (Geall et al., Patented 1/02/2024)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,857,562 (Geall et al., Patented 1/02/2024)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-36 are rejected on the grounds of nonstatutory double patenting over claims 1-30 of U.S. Patent No. 11,857,681 (Geall et al., Patented 1/02/2024)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent anticipates the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,865,080 (Geall et al., Patented 1/09/2024)
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition comprising a self-replicating RNA with a tertiary amine cationic lipid cited patent makes obvious the composition of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious by cited patent claims, said claims are not patentably distinct.
Claims 22 and 34 are rejected on the grounds of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,865,080 (Geall et al., Patented 1/09/2024)
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced patent as follows: the immunogenic composition of cited patent makes obvious the composition of instant application. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by cited patent and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited patent claims in view of Manoharan, said claims are not patentably distinct.
Provisonal Double Patenting
Claims 15-21, 23-33, and 35-36 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 18/463,099. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the immunogenic composition of cited application makes obvious the composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious over cited application claims, said claims are not patentably distinct.
Claims 22 and 34 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 18/463,099, in view of Manoharan et al., (WO2009/132131, filed 4/22/2009, published 10/29/2009, see IDS filed 11/14/2023).
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced application as follows: the immunogenic composition of cited application makes obvious the composition of instant application. The difference between the cited application claims and the instant claims lies in the fact that the cited application claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by Application and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited application claims in view of Manoharan, said claims are not patentably distinct.
Claims 15-21, 23-33, and 35-36 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 13-25 of copending Application No. 18/954,638. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the immunogenic composition of cited application makes obvious the composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that the instant application uses tertiary lipid pKa’s, diameters and percentages of tertiary lipids, cholesterols, and PEG lipids, that are more specific. Nevertheless, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Since the instant application claims are obvious over cited application claims, said claims are not patentably distinct.
Claims 22 and 34 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 13-25 of copending Application No. 18/954,638, in view of Manoharan et al., (WO2009/132131, filed 4/22/2009, published 10/29/2009, see IDS filed 11/14/2023).
As stated supra, the subject matter claimed in the instant application is disclosed in the referenced application as follows: the immunogenic composition of cited application makes obvious the composition of instant application. The difference between the cited application claims and the instant claims lies in the fact that the cited application claims do not require mPEG-DMG as the PEG-lipid.
In regard to instant claims, Manoharan teaches formulation comprising a cationic lipid, and a 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (alias 1,2-dimyristoyl-sn-glycerol-(methoxy(polyethylene glycol or CAS# 160743-62-4) (pgs. 124-125, Example 21, Preparation of compound 4a).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to prepare the formulation comprising the tertiary amine cationic lipid, as well as the PEG conjugated lipid as claimed by Application and choose the mPEG-DMG as taught by Manoharan with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Manoharan because formulations using the mPEG-DMG were excellent candidates for testing against human disease conditions (p. 130, last para.).
Since the instant application claims are obvious over cited application claims in view of Manoharan, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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