DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
1. Claims 1-126 have been cancelled. Claims 137 and 139 have been amended.
Claims 127-145 are pending and under examination.
2. The following rejections are withdrawn in response to the amendment replacing the recitation “the antibody” with “the receptor:
The rejection under pre-AIA U.S.C. 35 U.S.C. 112nd paragraph;
The rejection under pre-AIA 35 U.S.C. 112, 4th paragraph.
Double Patenting
3. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web- based eTerminal Disclaimer may be filled out completely online using web- screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying- online/eterminal-disclaimer.
4. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 13-17, and 23-29 of U.S. Patent No. 10,143,758, in view of both Chen et al. (Mol. Ther., 2000, 2: 256-261), and Kozarsky et al. (Arterioscler. Thromb. Vasc. Biol., 2000, 20: 721-727). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method for the liver delivery of the same liposomes encapsulating an mRNA encoding a receptor or an antibody. The patent claims do not recite a composition as recited in the instant claim 128. However, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
Although the patent claim 17 recites two mRNAs encoding distinct proteins, the patent claims 17 does not recite that the distinct proteins are receptors, as required by the instant claim 141. Chen et al. teach that familial hypercholesterolemia (FH) caused by mutations leading to LDL receptor (LDLR) deficiency is characterized by premature elevated cholesterol levels and atherosclerosis; Chen et al. teach treating FH in subjects by delivering the gene for the very-low-density lipoprotein receptor (VLDLR); VLDLR expression in the liver decreases the serum cholesterol levels and reduces atherosclerosis in the subjects (see Abstract; p. 256, column 1, first paragraph). Based on these teachings, one of skill in the art would have found obvious to use an VLDLR-encoding mRNA as the receptor-encoding mRNA in the patent claims when treating FH was desired, with the reasonable expectation that doing so would result in VLDLR expression in the liver and FH therapy. Furthermore, Kozarsky et al. teach that the hepatic overexpression of class B scavenger receptor (SR-BI) significantly reduces atherosclerosis in LDLR-deficient subjects (see Abstract; paragraph bridging p. 723 and 724; p. 726, paragraph bridging columns 1 and 2). Based on the teachings in the prior art, one of skill in the art would have known that VLDLR and SR-BI are functional equivalents with respect to reducing atherosclerosis. One of skill in the art would have found obvious to further use an mRNA encoding SR-BI with the reasonable expectation that doing so would treat FH by suppressing atherosclerosis in the subject. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus, the patent claims and the instant claims are obvious variants.
5. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 9,061,021, in view of all Chen et al., Kozarsky et al., Zimmermann et al. (Nature, 2006, 441: 111-114), Madden et al. (WO 09/088891). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method for expressing a protein in hepatocyte, the method comprising administering at least one mRNA encapsulated into liposomes. The specific alterations to the 5’ and 3’ UTRs (i.e., using the CMV sequence set forth by SEQ ID NO: 1 as the 5’ UTR and the hGH sequence set forth by SEQ ID NO: 3 as the 3’ UTR) recited in the patent claims anticipate the genera recited in the instant claim 134. The patent specification discloses that the mRNA could have a molecular weight of at least 30 kDa (see column 10, lines 58-62). Although the patent claims do not recite intravenous administration, one of skill in the art would have found obvious to use intravenous administration because this administration route was routinely used in the prior art. Although the patent claims do not recite a composition as recited in the instant claim 128, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
With respect to the instant claims 127, the patent claims do not specifically recite that the protein encoded by the mRNA is a receptor. Chen et al. teach that familial hypercholesterolemia (FH) caused by mutations leading to LDL receptor (LDLR) deficiency is characterized by premature elevated cholesterol levels and atherosclerosis; Chen et al. teach treating FH in subjects by delivering the gene for the very-low-density lipoprotein receptor (VLDLR); VLDLR expression in the liver decreases the serum cholesterol levels and reduces atherosclerosis in the subjects (see Abstract; p. 256, column 1, first paragraph). Based on these teachings, one of skill in the art would have found obvious to use an VLDLR-encoding mRNA as the receptor-encoding mRNA in the patent claims when treating FH was desired, with the reasonable expectation that doing so would result in VLDLR expression in the liver and FH therapy. With respect to the instant claim 141, the patent claims do not recite an additional mRNA encoding a distinct receptor. Kozarsky et al. teach that the hepatic overexpression of class B scavenger receptor (SR-BI) significantly reduces atherosclerosis in LDLR-deficient subjects (see Abstract; paragraph bridging p. 723 and 724; p. 726, paragraph bridging columns 1 and 2). Based on the teachings of Chen et al. and Kozarsky et al., one of skill in the art would have known that VLDLR and SR-BI are functional equivalents with respect to reducing atherosclerosis. One of skill in the art would have found obvious to further use an mRNA encoding SR-BI with the reasonable expectation that doing so would treat FH by suppressing atherosclerosis in the subject. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
With respect to the instant claims 127, 128, and 130, Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph). Thus, modifying the patent claims by using SNALPs as the delivery vehicle would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in superior mRNA delivery.
With respect to the instant claims 129, 131, 142, and 144, Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; p. 79; Example 2 on p. 79-84; p. 85). Modifying the SNALPs by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for delivery to the liver.
Thus, the patent claims and the instant claims are obvious variants.
6. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,185,595, in view of all Chen et al., Kozarsky et al., Zimmermann et al., and Madden et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method for the delivery of mRNA to the liver. The specific species of polyA tails having a length of at least 90 and 500 nucleotides recited in the patent claims anticipates the genus of polyA recited in the instant claims. The patent specification discloses that the mRNA has a molecular weight of at least 30 kDa (see column 13, lines 61-65). Although the patent claims do not recite a composition as recited in the instant claim 128, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
The patent claims recites an enzyme-encoding, not at least one receptor-encoding mRNA as required by the instant claim 127. However, one of skill in the art would have reasonably concluded that the method recited in the patent claims can be used to deliver mRNA, including mRNAs encoding receptors. Furthermore, Chen et al. teach that familial hypercholesterolemia (FH) caused by mutations leading to LDL receptor (LDLR) deficiency is characterized by premature elevated cholesterol levels and atherosclerosis; Chen et al. teach treating FH in subjects by delivering the gene for the very-low-density lipoprotein receptor (VLDLR); VLDLR expression in the liver decreases the serum cholesterol levels and reduces atherosclerosis in the subjects (see Abstract; p. 256, column 1, first paragraph). Based on these teachings, one of skill in the art would have found obvious to use an VLDLR-encoding mRNA as the receptor-encoding mRNA in the patent claims when treating FH was desired, with the reasonable expectation that doing so would result in VLDLR expression in the liver and FH therapy. With respect to the instant claim 141, the patent claims do not recite an additional mRNA encoding a distinct receptor. Kozarsky et al. teach that the hepatic overexpression of class B scavenger receptor (SR-BI) significantly reduces atherosclerosis in LDLR-deficient subjects (see Abstract; paragraph bridging p. 723 and 724; p. 726, paragraph bridging columns 1 and 2). Based on the teachings of Chen et al. and Kozarsky et al., one of skill in the art would have known that VLDLR and SR-BI are functional equivalents with respect to reducing atherosclerosis. One of skill in the art would have found obvious to further use an mRNA encoding SR-BI with the reasonable expectation that doing so would treat FH by suppressing atherosclerosis in the subject. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
With respect to the instant claims 127, 128, and 130, Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph). Thus, modifying the patent claims by using SNALPs as the delivery vehicle would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in superior mRNA delivery.
With respect to the instant claims 129, 131, 142, and 144, Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; p. 79; Example 2 on p. 79-84; p. 85). Modifying the SNALPs by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for delivery to the liver.
Thus, the patent claims and the instant claims are obvious variants.
7. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,238,754, in view of both Zimmermann et al. and Madden et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method of in vivo production of a protein, where the method comprises administering an mRNA encoding the protein to a subject. The patent specification discloses that the lipid nanoparticle could deliver two mRNAs which could encode a receptor, and also that the target cells are hepatocytes (see column 9, lines 1-17; column 20, line 57 through column 21, line 3). The patent specification also discloses that the mRNA could have a molecular weight of at least 30 kDa (see column 3, lines 40-44). The instant specification discloses that the subject could be a human subject (see p. 29, lines 19-12). Although the patent claims do not recite a composition as recited in the instant claim 128, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
The patent claims do not recite the specific liposome recited in the instant claims. Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph). Thus, modifying the patent claims by using SNALPs as the delivery vehicle would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in superior mRNA delivery.
With respect to the instant claims 129, 131, 142, and 144, Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; p. 79; Example 2 on p. 79-84; p. 85). Modifying the SNALPs by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for delivery to the liver.
Thus, the patent claims and the instant claims are obvious variants.
8. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,413,618, in view of both Zimmermann et al. and Madden et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method for the in vivo production of a protein, the method comprising the in vivo administration of the mRNA encoding the protein. The specific species of polyA tails having a length of at least 90 and 500 nucleotides recited in the patent claims anticipates the genus of polyA recited in the instant claims. The patent specification discloses that the lipid nanoparticle could deliver two mRNAs which could encode a receptor, that the target cells are hepatocytes, and that the mRNA has a molecular weight of at least 30 kDa (see column 9, lines 10-26; column 13, lines 47-51; column 21, lines 1-14). Although the patent claims do not recite a composition as recited in the instant claim 128, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
The patent claims do not recite the specific liposome recited in the instant claims. Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph). Thus, modifying the patent claims by using SNALPs as the delivery vehicle would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in superior mRNA delivery.
With respect to the instant claims 129, 131, 142, and 144, Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; p. 79; Example 2 on p. 79-84; p. 85). Modifying the SNALPs by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for delivery to the liver.
Thus, the patent claims and the instant claims are obvious variants.
9. Claims 127-145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,350,303, in view of both Zimmermann et al. and Madden et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same method for the in vivo production of a protein, the method comprising the in vivo administering the mRNA encoding the protein. The specific species of polyA tails having a length of at least 90 and 500 nucleotides recited in the patent claims anticipates the genus of polyA recited in the instant claims. The patent specification discloses that the lipid nanoparticle could deliver two mRNAs which could encode a receptor, that the target cells are hepatocytes, and that the mRNA has a molecular weight of at least 30 kDa (see column 9, lines 15-30; column 13, lines 51-55; column 21, lines 3-16). The instant specification discloses that the subject could be a human subject (see p. 29, lines 19-12). Although the patent claims do not recite a composition as recited in the instant claim 128, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of the composition. One of skill in the art would have considered further claiming the composition an obvious variant.
The patent claims do not recite the specific liposome recited in the instant claims. Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph). Thus, modifying the patent claims by using SNALPs as the delivery vehicle would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in superior mRNA delivery.
With respect to the instant claims 129, 131, 142, and 144, Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; p. 79; Example 2 on p. 79-84; p. 85). Modifying the SNALPs by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for delivery to the liver.
Thus, the patent claims and the instant claims are obvious variants.
10. Claim 128 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,547,764. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 128 and the patent claims are drawn to the same composition comprising an mRNA encapsulated into a lipid nanoparticle comprising a cationic lipid, a non-cationic lipid, a PEG lipid, and cholesterol. The specific mRNA and lipids recited in the patent claims anticipate the genera of mRNA and lipids recited in the instant claims.
Thus, the patent claims and the instant claims are obvious variants.
11. For the reasons set forth above, the instant claims are rejected over claims 1-21 of U.S. Patent No. 11,291,734; over claims 1-18 of U.S. Patent No. 11,338,044; over claims 1-25 of U.S. Patent No. 11,730,825; and over claims 127-145 of copending Application No. 18/431,597.
Claim Rejections - 35 USC § 103
12. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
13. Claims 127, 128, 130, 132-136, 138, 140, 143, and 145 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kariko et al. (WO 07/024708), in view of all Chen et al. (Mol. Ther., 2000, 2: 256-261), Zimmermann et al. (Nature, 2006, 441: 111-114), and Stein et al. (J. Bioenerg. Biomembranes, July 2008, 40: 157-162), as evidenced by the Sino Biological Data Sheet.
Kariko et al. teach a method for the delivery of mRNA to a subject in need of therapy, the method comprising administering to the subject a lipoplex of lipofectin and an mRNA; the subject could be a subject affected by familial hypercholesteremia (FH), the mRNA could be modified to comprise pseudouridines, and administration could be intravenous (claims 127, 128, 133-135, and 138 (see [0010]; [0021]; [0027]; [0039]; [0052]; [0072]; [0094]-[0096]; [0099]-[0100]; [0161]; [0219]; [0237]). Kariko et al. teach that the mRNA comprises a 5’ cap structure and a poly A tail of about 200 nucleotides for enhanced stability and translation efficiency (claim 134) (see [0033]; [00231]-[00232]; [00238]; [00251]-[00253]; [00257]).
Also Kariko et al. teach treating FH, Kariko et al. do not teach that the mRNA encodes a receptor (claims 127 and 128). Chen et al. teach that familial hypercholesterolemia (FH) caused by mutations leading to LDL receptor (LDLR) deficiency is characterized by premature elevated cholesterol levels and atherosclerosis; Chen et al. teach treating FH in subjects by delivering the gene for the very-low-density lipoprotein receptor (VLDLR); VLDLR expression in the liver decreases the serum cholesterol levels and reduces atherosclerosis in the subjects (see Abstract; p. 256, column 1, first paragraph). One of skill in the art would have found obvious to use an VLDLR-encoding mRNA as the mRNA in Kariko et al. with the reasonable expectation that doing so would result in VLDLR expression in the liver and treat FH, when treating FH was desired. As evidenced by the Sino Biological Data Sheet, the VLDL cDNA has a length of 2622 bp. Thus, the VLDLR-encoding mRNA has a molecular weight of more than 30 kDa (claim 132).
Doing so would have resulted in a composition comprising an VLDLR-encoding mRNA encapsulated into lipofectin liposomes and not into the liposomes recited in claims 127, 128, and 130. However, Chen et al. teach liver-directed gene therapy and Kariko et al. teach that lipofectin mediates little expression in the liver (see [0238]; Fig. 12B). Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, the cationic lipid DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (claims 127, 128, 130, 143, and 145) (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph).
While Zimmermann et al. teach siRNA and not mRNA, the prior art teaches that lipofectin could be used to deliver both mRNA and siRNA (see Kariko et al. above; see Stein et al., paragraph bridging p. 157 and 158). Based on these teachings, one of skill in the art would have reasonably concluded that the SNALPs taught by Zimmermann et al. could be used to also deliver mRNAs. One of skill in the art would have found obvious to modify Kariko et al. and Ye et al. by replacing lipofectin with the SNALPs taught by Zimmermann et al. and further deliver the resulting composition to an LDLR-deficient subject with the reasonable expectation that doing so would result in superior mRNA delivery to the hepatocytes and efficient treatment of FH in the subject. By doing so, one of skill in the art would have achieved prolonged stable expression in the liver and the protein expression would have been detected at least 4 h post-administration because all that is required to achieve this is to administer SNALPs (claim 140). The specification does not teach more than this.
With respect to claim 136, Zimmermann et al. teach that SNALPS are suitable to deliver unmodified RNAs (see Supplementary Methods). Using an unmodified OTC-encoding mRNA would have been obvious to one of skill in the art with the reasonable expectation that doing so would deliver the OTC-encoding mRNA to hepatocytes and efficiently treat the OTC deficiency in the subject.
Thus, the claimed invention was prima facie obvious at the time it was made.
14. Claims 127-136, 138, 140, and 142-145 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kariko et al. taken with all Chen et al., Zimmermann et al., Stein et al. as evidenced by the Sino Biological Data Sheet, in further view of Madden et al. (WO 09/088891).
The teachings of Kariko et al., Chen et al., Zimmermann et al., and Stein et al. are applied as above for claims 127, 128, 130, 132-136, 138, 140, 143, and 145. Kariko et al., Chen et al., Zimmermann et al., and Stein et al. do not teach DOPE or PEG2000-DMG (claims 129, 131, and 144), nor do they teach a cationic lipid having a net positive charge at physiological pH (claim 142). Madden et al. teach that SNALPs for liver delivery could be also obtained by using DOPE and PEG2000-DMG instead of DSPC and PEG-DMA and also by using a cationic lipid having a net positive charge at physiological pH (see p. 5; p. 7, first paragraph; p. 25, first and last paragraphs; p. 29; Example 2 on p. 79-85). Modifying the teachings of Kariko et al., Chen et al., Zimmermann et al., Stein et al. by replacing DSPC and PEG-DMA with DOPE and PEG2000-DMG and/or by using a cationic lipid having a net positive charge at physiological pH would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable to treat FH.
Thus, the claimed invention was prima facie obvious at the time it was made.
15. Claims 127, 128, 130, 132-136, 138, 140, 141, 143, and 145 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kariko et al. taken with all Chen et al., Zimmermann et al., and Stein et al. as evidenced by the Sino Biological Data Sheet, in further view of and Kozarsky et al. (Arterioscler. Thromb. Vasc. Biol., 2000, 20: 721-727).
The teachings of Kariko et al., Chen et al., Zimmermann et al., and Stein et al. are applied as above for claims 127, 128, 132-136, 138, 140, 143, and 145. Kariko et al., Chen et al., Zimmermann et al., and Stein et al. do not teach two mRNAs encoding distinct receptors (claim 141). Kozarsky et al. teach that the hepatic overexpression of class B scavenger receptor (SR-BI) significantly reduces atherosclerosis in LDLR-deficient subjects (see Abstract; paragraph bridging p. 723 and 724; p. 726, paragraph bridging columns 1 and 2). Based on the teachings of Chen et al. and Kozarsky et al., one of skill in the art would have known that VLDLR and SR-BI are functional equivalents with respect to reducing atherosclerosis. One of skill in the art would have found obvious to further use an mRNA encoding SR-BI with the reasonable expectation that doing so would treat FH by suppressing atherosclerosis in the subject. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus, the claimed invention was prima facie obvious at the time it was made.
Response to Arguments
16. Double Patenting
The comments with respect to the ‘758 patent and ‘597 application are acknowledged. However, the rejection will be maintained until a terminal disclaimer is filed or claims are amended to obviate the rejection.
The arguments addressing the double patenting rejections over U.S. Patent Nos 9,061,021; 11,185,595; 10,238,754; 10,413,618; 10,350,303; 11,547,764; 11,291,734; 11,338,044; and 11,730,825 are not found persuasive.
The applicant refers to the PTAB decision in application 17/135,529. However, the facts in the application ‘529 are different from the facts in this application.
The claims of application ‘529 were rejected as being unpatentable over the claims of five patents. The Board noted that application ‘529 and the patents do not share a priority and do not stem from the same application family. Application ‘529 was the earlier filed, was published well before the earliest filing dates of the patents, and thus, it could have been used as prior art against the patents. The Board noted that, since the claims of the patents were allowed, the examiner determined that the patented claims were not obvious from the disclosure of the published ‘259 application. The Board also noted the examiner acknowledged that “the claims of the later-filed, now issued patents were non-obvious over the instant disclosure and could not have been presented in the instant application”. For these reasons only, the Board concluded that the pattern claims could not serve as reference claims against application ‘529 claims.
However, the instant application was published on 04/18/2024, i.e., after the earliest effective filing dates of the patents and it could not have been used as prior art against the patents. Thus, there was no determination that the patent claims were not obvious from the disclosure of the instant application. Furthermore, the examiner did not indicate non-obviousness of the patent claims over the instant claims, nor did the examiner indicate that the patent claims could not have been presented in the instant application.
In this case, the later-filed and later-expiring patent claims can serve as reference against the instant claims. See also p. 7-8 of the PTAB decision in application ‘529.
Because the instant claims and the pattern claims are obvious variants, there would be an unjust extension of the instant claims, and also possible harassment by multiple assignees.
35 U.S.C. 103(a)
The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation.
The applicant argues that Zimmermann provide no teaching or motivation for using SNALP for mRNA delivery and provides no reasonable expectation of success in doing so. The applicant argues that, since siRNAs and mRNAs have different structures and are processed by different cellular mechanism, it is not reasonable to conclude that using successful siRNA delivery with a liposome (as in Zimmermann) would extrapolate to successful mRNA delivery.
However, the rejection does not state that Zimmermann provides the teaching/motivation for using SNALP to deliver mRNA or that Zimmermann provides the reasonable expectation of success. The motivation to use SNALPs is provided by the combined teachings of Kariko, Chen, and Zimmermann. The reasonable expectation of success in using SNALPs to deliver mRNA to the liver is provided by the combined teachings Kariko and Stein. Kariko and Stein provide evidence that, albeit different structures and intracellular processing mechanisms, the same liposomal composition could deliver both siRNA and mRNA .
The applicant cites Barreau (2006) for teaching that liposome-mediated RNA transfection should be used with caution. As evidenced by the prior art published after 2006, this teaching did not impede persons of skill in the art to use liposomes for successful mRNA transfection. See Kariko. See Okumura (J. Gene Med., 2008, 10: 910-917; Abstract, p. 916, column 2, last paragraph).
The argument that Kariko does not provide a reasonable expectation of success in delivering mRNA to the liver is not material to the rejection. This is because the rejection is based on using SNALPs (not lipofectin as in Kariko) for mRNA delivery to the liver.
The argument that none of Madden and Kozarsky remedies the deficiencies in Kariko, Chen, Zimmermann, and Stein is not found persuasive because there is no deficiency to be remedied in the combined teachings of Kariko, Chen, Zimmermann, and Stein. Madden and Kozarsky were only cited for teaching a cationic lipid having a net positive charge at physiological pH and class B scavenger receptor, respectively, not for providing the reasonable expectation of success in delivering mRNA to the liver.
New Rejections
(necessitated by the amendment to claims 137 and 139)
Claim Rejections - 35 USC § 103
17. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
18. Claims 127, 128, 130, 133-140, 143, and 145 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kariko et al. (WO 07/024708), in view of all Fernandez-Botran (Exp. Opin. Invest. Drugs, 2000, 9: 497-514), Hodges et al. (Mol. Ther., 2002, 5, Abstract 988), Zimmermann et al. (Nature, 2006, 441: 111-114), and Stein et al. (J. Bioenerg. Biomembranes, July 2008, 40: 157-162).
Kariko et al. teach a method for the delivery of mRNA to a subject in need of therapy, the method comprising administering to the subject a lipoplex of lipofectin and an mRNA; the mRNA could encode a variety of proteins for a variety of therapeutic, including proteins to be systemically distributed by the transfected cell; the mRNA could be modified to comprise pseudouridines; administration could be intravenous (claims 127, 128, 133-135, and 138) (see [0010]; [0021]; [0027]; [0039]; [0052]; [0072]; [0094]-[0096]; [0099]; [0102]; [0104]-[0117]; [0161]; [0219]; [0237]; Example 19). Kariko et al. teach that the mRNA comprises a 5’ cap structure and a poly A tail of about 200 nucleotides for enhanced stability and translation efficiency (claim 134) (see [0033]; [00231]-[00232]; [00238]; [00251]-[00253]; [00257]).
Kariko et al. do not teach that the systemically distributed protein is a soluble receptor (claims 137 and 139). However, one of skill in the art would have reasonably concluded that the method of Kariko et al. could be used to deliver mRNAs encoding any systemically distributed protein of interest. Furthermore, Fernandez-Botran teaches soluble receptors as novel therapeutic agents; Fernandez-Botran teaches sTNFR-II:Fc for treatment of rheumatoid arthritis (RA) (see Abstract). Thus, one of skill in the art would have found obvious to use the method of Kariko et al. with an mRNA encoding sTNFR-II:Fc to achieve the predictable result of treating RA, when treating RA was desired.
Kariko et al. teach that lipofectin mediates little expression in the liver (see [0238]; Fig. 12B). Thus, the method of Kariko et al. and Fernandez-Botran does not result in sTNFR-II:Fc delivery to the liver (claim 127). Hodges et al. teach using the liver as a depot due to its ability to deliver high levels of transgene into circulation (see Abstract 988). Zimmermann et al. teach that 77-83 nm SNALPs consisting of PEG2000-DMA, the cationic lipid DLinDMA, DSPC, and cholesterol in a molar ratio of 2:40:10:48 are suitable to deliver nucleic acids to the liver upon intravenous administration (claims 127, 128, 130, 143, and 145) (see Abstract; p. 111, Fig. 1; paragraph bridging p. 111 and 112; p. 112; p. 113, column 2; Supplementary Information, p. 2, last paragraph).
While Zimmermann et al. teach siRNA and not mRNA, the prior art teaches that lipofectin could be used to deliver both mRNA and siRNA (see Kariko et al. above; see Stein et al., paragraph bridging p. 157 and 158). Based on these teachings, one of skill in the art would have reasonably concluded that the SNALPs taught by Zimmermann et al. could be used to also deliver mRNAs. One of skill in the art would have found obvious to modify Kariko et al. and Fernandez-Botran by replacing lipofectin with the SNALPs taught by Zimmermann et al. and further deliver the resulting composition to a subject affected by RA, with the reasonable expectation that doing so would result in superior mRNA delivery to the hepatocytes and efficient treatment of RA in the subject. By doing so, one of skill in the art would have achieved prolonged stable expression in the liver and the protein expression would have been detected at least 4 h post-administration because all that is required to achieve this is to administer SNALPs (claims 128 and 140). The specification does not teach more than this.
With respect to claim 136, Zimmermann et al. teach that SNALPS are suitable to deliver unmodified RNAs (see Supplementary Methods). Using an unmodified sTNFR-II:Fc -encoding mRNA would have been obvious to one of skill in the art with the reasonable expectation that doing so would deliver the sTNFR-II:Fc -encoding mRNA to hepatocytes and efficiently treat the RA in the subject.
Thus, the claimed invention was prima facie obvious at the time it was made.
Conclusion
19. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Okumura (J. Gene Med., 2008, 10: 910-917) was cited in response to the argument of lack of reasonable expectation of success. The reference provide evidence of reasonable expectation of success in using lipid nanoparticles to deliver mRNAs.
20. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ILEANA POPA/Primary Examiner, Art Unit 1633