Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-61 have been cancelled. Claims 62-91 are new.
Claims 62-91 are pending and under examination.
Claim Objections
2. Claims 62-65, 67, 68, 79, and 80 should include “(w/w)” after each recited threshold value (as in claim 86).
3. Claim 69 is objected to because of the recitation “a cationic lipid composition of claim 1. Correction to “the composition of claim 1” is required.
4. Claim 70 should recite “and DOPG” in the last line.
5. It is suggested that claim 74 be amended to recite:
The method of claim 69, wherein the length of the mRNA is equal to or greater than about 0.5kb, 1 kb, 1.5 kb, 2 kb, 2.5 kb, 3 kb, 3.5 kb, 4 kb, 4.5 kb, or 5 kb.
6. It is suggested that claim 78 be amended to recite:
The method of claim 69, wherein the method is for treating a disease or disorder and wherein the mRNA encodes a therapeutic protein.
7. Consistent with the specification, claim 84 should be amended to recite:
The method of claim 79, wherein the lipid nanoparticle is a liposome, and wherein the size of the liposome is less than 250 nm.
8. Claim 91 is objected to because of the recitation “wherein the composition is the pharmaceutical composition of claim 79”. However, claim 79 is a method, not a composition claim. It is suggested that claim 91 be amended to recite:
A method of manufacturing a composition comprising an mRNA encoding a therapeutic protein, the method comprising the step of encapsulating the mRNA encoding the therapeutic protein within a lipid nanoparticle, wherein the lipid nanoparticle comprises:
one or more non-cationic lipids, one or more cholesterol-based lipids, one or more PEG-modified lipids,
and one or more chemical entities of formula I:
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127
384
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a pharmaceutically acceptable salt thereof,
characterized in that greater than 50% of the total amount of chemical entities of formula I in the composition are chemical entities of formula I.a.i:
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144
384
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Double Patenting
9. 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.
10. Claims 62-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,104,652. 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 nanoparticle encapsulating an mRNA, which could encode a therapeutic protein, and to the same methods of using the nanoparticle to deliver mRNA in vivo.
The patent specification discloses that: the length of the mRNA is as recited in the instant claims 74 and 85; the mRNA could be unmodified or modified with pseudouridine and 5-methylcytidine as recited in the instant claims 76 and 77; the mRNA encodes the proteins recited in the instant claim 86; the liposome has a size of less than 250 nm, as recited on the instant claims 73 and 84 (see paragraph bridging columns 11 and 12; column 38, lines 23-49; column 39, lines 18-20; column 42, lines 60-64; column 44, lines 30-36).
Thus, the instant claims and the patent claims are obvious variants.
11. Claims 62-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No.10,138,213, in view of Dong et al. (WO 13/063468; cited on the IDS filed on 03/13/2025). 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 lipid nanoparticle encapsulating an mRNA.
The patent claims do not recite delivery in vivo. Dong et al. teach that cKK-E12 compounds set forth by the claimed formula I could be used to formulate liposomes suitable for the delivery of nucleic acids including nucleic acids encoding a therapeutic protein or polypeptide (see [0005]; [0015]-[0016]; [0019]-[0020]; [0405]; [0416]; [0424]; [0433]; [0479]). Based on these teachings, one of skill in the art would have reasonably concluded that the lipid nanoparticles recited in the patent claims could be used to deliver therapeutic mRNAs to subjects in need of therapy. Further claiming the method would have been obvious to one of skill in the art.
The patent specification defines that: the lipid nanoparticle comprises the noncationic lipids recited in the instant claim 70; the length of the mRNA is as recited in the instant claims 74 and 85; the mRNA could be unmodified or modified with pseudouridine and 5-methylcytidine as recited in the instant claims 76 and 77; the PEG-lipid is as recited in the instant claim 72; the liposome has a size of less than 250 nm, as recited in the instant claims 73 and 84; the mRNA encodes a therapeutic protein as recited in the instant claim 78; the mRNA encodes the proteins recited in the instant claim 86 (see column 11, lines 24-27; column 31, lines 42-45; column 33, lines 39-55; column 34, lines 27-30; column 37, lines 22-49; column 38, lines 19-21; column 41, lines 60-84; column 43, lines 30-36).
Thus, the instant claims and the patent claims are obvious variants.
Claim Rejections - 35 USC § 101
12. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
13. Claim 91 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. Claim 91 does not fall within at least one of the four categories of patent eligible subject matter because the claim does not recite any method step, and thus, it is not drawn to a proper process claim under 35 U.S.C. 101. While the preamble of the claim recites “A method of manufacture of a medicament”, the claim does not recite any positive step for producing the medicament. The recitation “for treating a disease or disorder by delivery of a composition comprising an mRNA encoding a therapeutic protein” in the preamble is just an intended use. The recitation in the body of the claim “wherein the mRNA encoding the therapeutic protein is encapsulated within a liposome such that the administration of the composition results in the expression of the protein encoded by the mRNA in the subject” in the body of the claim describes the composition and the intended use for the composition. None is a positive method step, let alone a positive step for producing the medicament.
Claim Rejections - 35 USC § 112(b)
14. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
15. Claim 91 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 91 is indefinite because it merely recites “A method of producing a medicament” without setting forth any active, positive step delimiting how this method is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
Claim Rejections - 35 USC § 112(d)
16. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
17. Claims 63 and 65-68 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 63 recites that the first threshold is 70, 80, or 95%. However, the parent claim 62 is limited to a first threshold of 50%. Thus, claim 63 fails to include all the limitations of the parent claim 62.
Claim 65 recites that the second threshold is 70, 80, 90, or 95%. However, the parent claim 64 is limited to a second threshold of 50%. Thus, claim 65 fails to include all the limitations of the parent claim 64.
Claim 66 recites a third threshold of 85% for the compound of formula I.a. The parent claim 62 recites a first threshold However, Hof 50% for the compound of formula I.a. Both the first and the third thresholds are for the same compound of formula I.a. By reciting the threshold for the compound of formula I.a is 85%, claim 66 fails to include all the limitations of the parent claim 64, which is limited to a threshold of 50% for the compound of formula I.a.
Claim 67 recites that the third threshold is 90, 95, or 98%. Thus, the claim fails to include all the limitations of the parent claims 62 and 66, which are limited to a threshold of 50% and 85%, respectively.
Claim 68 recites that the third threshold is 98%. Thus, the claim fails to include all the limitations of the parent claim 62, which is limited to a threshold of 50%.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
18. 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
19. Claims 62-86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Dong et al. (WO 13/063468; published on 5/2/2013), in view of each Lopez-Cobenas et al. (Synthesis, 2005, 9: 3412-3422), Mahon et al. (U.S. Patent No. 8,450,298), and Terp et al. (International Journal of Pharmaceutics, 2012, 430: 328-334). All references are of record in the parent application 14/749,027.
Dong et al. teach lipopeptides (named APPLs) set forth by formula III; the APPLs are used together with PEGylated lipids to formulate liposomes having a size of 1-100 nm; the liposomes encapsulate nucleic acids encoding a therapeutic protein or polypeptides (such as an enzymes or secreted protein) and are used to treat a disease or disorder (claims 69, 73, 75, 76, 78, 79, 84, 86, and 91) (see Abstract; [0005]-[0006]; [0019]-[0020]; [0022]; [0214]-[0215]; [0267]; [0269]; [0416]; [0420]-[0422]; [0424]; [0429]; [0433]; [0434]; [0438]; Tables 2 and 3; [0472]; [0479]).
Although Dong et al. do not specifically teach that the nucleic acid encoding the protein or polypeptide is an mRNA (claim 69 and 79), there are only two species of nucleic acids that can encode proteins or polypeptides, specifically DNA and mRNA. Furthermore, Dong et al. that the nucleic acids could be modified with C5-bromuridine, C5-fluoruridine, C5-ioduridine, or C5-propynyl-uridine (claims 76, 88, and 89). Based on these teachings, one of skill in the art would have readily envisaged mRNA as the species of nucleic acids disclosed by Dong et al., where the mRNA could be modified or unmodified. One of skill in the art would have found obvious to use a modified (claim 76, 88, and 89) or unmodified mRNA (claims 77 and 90) as the nucleic acid encoding the polypeptide to achieve the predictable result of obtaining a composition suitable for the delivery of the therapeutic protein.
Dong et al. teach that the lipopeptides are obtained from linear or cyclic peptides and epoxides via alkylating the terminal amino group of the linear or cyclic peptides with epoxides bearing long alkyl chains. Dong et al. teach that the lipopeptides comprise asymmetric centers and that they could be present as individual enantiomers ([0025]). One of the lipopeptides is cKK-E12 set forth by the claimed formula I (claim 62); cKK-E12 exhibits enhanced potency and it is obtained by alkylating cyclic lysine-lysine (cKK) with epoxide E12; E12 alkylates the N-terminal groups of the 4-aminobutyl substituents on cKK (see [0015]; [0016]; Table 2 on p. 166; Table 3 on p. 172; Table 4 on p. 194; Example 2 on p. 220-221; [00484]; [00485]). Dong et al. teach that nanoliposomes comprising cKK-E12, cholesterol, DSPC, and PEG2000-DMG, which are very efficient in vivo delivery agents (claims 70-73 and 81-83) (see [00434]; [00479]; [00484]-[00486]).
Although they generally teach enantiomers, Dong et al. do not specifically teach the specific cKK-E12 enantiomers recited in the instant claims. However, obtaining these enantiomers is suggested by the prior art. For example, Dong et al. teach that cKK-E12 could also be obtained by alkylating lysine before cyclization (see [00214]). Lopez-Cobenas et al. teach that chiral disubstituted diketopiperazines can normally be obtained in pure form when using commercially available chiral amino acid; the method of Lopez-Cobenas et al. involves the preparation of a linear dipeptide from chiral amino acids, followed by cyclization (see p. 3412, column 2, first full paragraph; p. 3414-3415). Furthermore, Mahon et al. teach N-terminal alkylation with chiral epoxides, such as chiral E12, to obtain chiral lipoids for transfection (see Abstract; column 3, lines 58-63; column 6, lines 34-59; column 8, line 55 through column 9, line 2; columns 119 and122, line 35; column 122, lines 1-15; column 146, line 55 through column 147, line 14). Mahon et al. teach that libraries of different lipoids can be prepared from different amines and epoxides (see column 146, lines 55-62). Based on these teachings, one of skill in the art would have known that a library of cKK-E12 enantiomers could be obtained by using all possible combinations of chiral N-terminally alkylated lysines and chiral E12s. One of skill in the art would have found obvious to obtain all possible cKK-E12 enantiomers from chiral lysines by alkylating their side chain with chiral E12s, forming linear chiral alkylated lysine-lysine dipeptides and cyclization, with a reasonable expectation of success. One of skill in the art would have been motivated to do so because the prior indicates that enantiomeric lipids could have different properties, including different transfection efficiencies (see Mahon et al., column 146, line 55 through column 147, line 14; see Terp et al., Abstract). One of skill in the art would have reasonably expected to be successful in doing so because the prior art teaches that enantiomeric disubstituted diketopiperazines can be successfully obtained via asymmetric synthesis. By doing so, one of skill in the art would have obtained the individual cKK-E12 enantiomers and the amounts recited in claims 62-68, 79, and 80.
With respect to claim 74, it is noted that there is no unexpected or superior results associated with any of the recited molecular weights. One of skill in the art would have known that the molecular weight of the mRNA is related to the molecular weight of the encoded gene. One of skill in the art would have found obvious to use the liposome for the delivery of any mRNA encoding a protein of interest, and thus, would have varied the molecular weight of the encoding mRNA.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
20. Claims 62-91 are rejected under 35 U.S.C. 103 as being unpatentable over Dong et al. taken with all Lopez-Cobenas et al., Mahon et al., and Terp et al., in further view of Watson et al. (Gene Therapy, 2006, 13: 917-925).
The teachings of Dong et al., Lopez-Cobenas et al., Mahon et al., and Terp et al. are applied as above for claims 62-86 and 88-91. Dong et al., Lopez-Cobenas et al., Mahon et al., and Terp et al. do not specifically teach that the enzyme encoded by the mRNA is associated with a lysosomal storage disorder (claim 87). Watson et al. teach gene therapy to treat MPSI via the delivery of a nucleic acid encoding IDUA (see Abstract). One of skill in the art would have found obvious to modify Dong et al. by using an IDUA-encoding mRNA as the enzyme-encoding nucleic acid and further administering the resultant composition to a MPS1 subject affected, to achieve the predictable result of treating the disorder in this patient.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
21. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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