DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/05/2026 has been entered.
Claims 2, 3, 5-12, 14-17, 19, 21, 23, 24, 26-29, 32, 34-36, 38-53, 55-60, 62, 63, 65, and 71-73 have been cancelled.
Claims 1, 4, 13, 18, 20, 22, 25, 30, 31, 33, 37, 54, 61, 64, 66-70, and 74 are pending and under examination.
2. The double patenting rejection over the claims of the copending Application No. 17/320,946 is withdrawn in response to applicant’s arguments.
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 1, 4, 13, 18, 20, 22, 25, 30, 31, 33, 37, 54, 61, 64, 66-70, and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 8, 11, 12, 15, 16, 22, 24, 26, 28, 29, 34, 35, 47, 52, and 55-57 of copending Application No. 17/450,628 (reference application), in view of Jeffs et al. (Pharmaceutical Research, 2005, 22: 362-372). 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 encapsulating mRNA into LNPs with an efficiency of greater than 70% and to the same composition comprising mRNA encapsulated into LNPs. The specific species of cationic lipid (ICE) recited in the application claims anticipates the genus recited in the instant claims. The application specification defines that less than 5 mM citrate could be about 1-2 mM or less than 1 mM citrate and that LNPs comprise DOPE, POPC, POPE, DOPE-mal, or SOPE (see [0009]; [0049]; [0152]).
The application claims do not recite a scaled-up process. Jeff et al. teach a scaled-up, single-batch method for the generation of large amounts (such as 5 g) of encapsulated nucleic acid-LNPs (see Abstract; p. 369, paragraph bridging columns 1 and 2; p. 371, column 1, last paragraph). Further practicing and claiming a scaled up, single batch process would have been obvious to one of skill in the art to achieve the predictable result of obtaining multigram amounts of mRNA-LNPs for clinical evaluation. Thus, the instant claims and the application claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
5. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claims 1, 4, 13, 18, 20, 31, 33, 37, 54, 61, 64, 66-70, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Chivukula et al. (WO 19/191780; published on 10/3/2019), in view of Oberli et al. (Nano Lett., 2017: 17: 1326-1335).
Chivukula et al. teach a method for encapsulating mRNA in LNPs (mRNA-LNPs) which yields an encapsulation efficiency of more than 95% and narrow particle distribution; the method is performed at room temperature and is scalable to 30 g mRNA/batch. The resultant LNPs have an N/P ratio within the range 5-10 and a diameter of less than 150 nm. Chivukula et al. exemplify encapsulating mRNA by mixing a solution of mRNA in 5 mM citric acid buffer (pH 3.5) with a lipid solution comprising a cationic ionizable lipid, the non-cationic lipid DSPC, cholesterol, and a PEG-modified lipid; the lipids are dissolved in ethanol; the method does not require heating the solutions prior to mixing (i.e., both solutions are at room temperature prior to mixing); the mRNA and the lipid solutions are mixed at a rate of 3:1; the encapsulation efficiency of 97.7% (claims 1, 4, 18, 20, 31, 33, 37, and 74) (see [0012]-[0013]; [0052]; [0060]; [0063]-0064]; [0066]; [0068]; Example 1, especially [0128], [0143]-[0144], [0146], and [0158]; Fig. 2-3).
The specification defines the term “about” as falling within the range 1-25% in each direction (see [0058]). Thus, the limitation “greater than about 3:1” in claim 64 encompasses the 3:1 ratio taught by Chivukula et al.
The method of Chivukula et al. must necessarily result in at least 10% higher encapsulation efficiency compared to encapsulation in 10 mM citrate because all that is required to achieve such is to use 5 mM citrate (claim 54). The specification does not teach more than this.
Chivukula et al. do not teach 0.5-1 mM citrate (claims 1, 61, and 66-70). However, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, MPEP 2144.05 III A states that "[a] modification of a process parameter may be patentable if it ‘produce[s] a new and unexpected result which is different in kind and not merely in degree from the results of the prior art." (citing Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” In this case, there is no evidence of a difference in kind or even degree when using 0.5-1 mM over 5 mM citrate.
With respect to claim 13, Chivukula et al. teach that the mRNA solution comprises 0.55 mg/ml (i.e., 6.6 g/12 L).
Chivukula et al. exemplify the LNPs comprising DSPC, and not DOPE, DOPE-mal, DOPC, DOPG, POPC, POPE, or SOPE (claim 1). However, Chivukula et al. teach that the method yields an encapsulation efficiency of more than 95; Chivukula et al. also teach that any of DOPE, DOPE-mal, DOPC, DOPG, POPC, POPE, and SOPE could be used in the method instead of DSPC (see [0078]; [0080]). Oberli et al. teach that, similar to LNP formulations comprising DSPC, very high mRNA encapsulating efficiencies could be achieved when the LNP formulations comprise DOPE or POPE (see Supplemental Information, Table S1). Based on these teachings, one of skill in the art would have reasonably expected that formulating the LNPs of Chivukula et al. with non-cationic lipids other than DSPC would also result in very high encapsulation efficiency. Formulating the LNPs of Chivukula et al. with any one of the disclosed DOPE, DOPE-mal, DOPC, DOPG, POPC, POPE, and SOPE would have been obvious to one of skill in the art, to achieve the predictable result of efficiently encapsulating the mRNA into LNPs.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
7. Claims 1, 4, 13, 18, 20, 22, 31, 33, 37, 54, 61, 64, 66-70, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Chivukula et al. taken with Oberli et al., in view of DeRosa et al. (PGPUB 2016/0038432).
The teachings of Chivukula et al. and Oberli et al. are applied as above for claims 1, 4, 13, 18, 20, 31, 33, 37, 54, 61, 64, 66-70, and 74. Chivukula et al. and Oberli et al. do not teach a citrate solution further comprising 150 mM NaCl (claim 22), DeRosa teach that citrate solutions comprising 150 mM NaCl and having a pH of 4.5 are suitable for mRNA-LNP preparation (see [0116]; [0118]). Using citric acid buffer having a pH of 4.5 and comprising 5 mM citric acid and 150 mM NaCl would have been obvious to one of skill in the art to achieve the predictable result of obtaining mRNA-LNPs.
With respect to claim 30, it is noted that there is no evidence showing that the claimed range of non-aqueous solvent is associated with an unexpected/superior result. Furthermore, DeRosa et al. teach that a suitable formulation for encapsulation contains 10-40% ethanol after mixing (see [0096]). One of skill in the art would have found obvious to use routine experimentation and vary the concentration of non-aqueous solvent in the lipid solution with the reasonable expectation that doing so would result on 10-40% ethanol after mixing and identify the concentrations resulting in optimal encapsulation. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed range was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. Claims 1, 4, 13, 18, 20, 25, 31, 33, 37, 54, 61, 64, 66-70, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Chivukula et al. taken with Oberli et al., in view of Tendeloo et al. (Blood, 2001, 98: 49-56).
The teachings of Chivukula et al. and Oberli et al. are applied as above for claims 1, 4, 13, 18, 20, 31, 33, 37, 54, 61, 64, 66-70, and 74. Chivukula et al. and Oberli et al. do not teach incubating the mRNA-LNPs (claim 25). Tendeloo et al. teach that post-mixing incubation at room temperature allows mRNA-lipid complexation (see p. 51, column 1, first full paragraph). Further adding an incubation step would have been obvious to one of skill in the art with the reasonable expectation that doing so would increase encapsulation efficiency.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
9. Double patenting
The argument that the examiner improperly relied on the specification is not found persuasive. The portions of the specification providing support for the patent claims may be considered. MPEP 804 B 2(a) states:
In analyzing the disclosure of the reference patent or application, a determination is made as to whether a portion of the disclosure is directed to subject matter that is encompassed by the scope of a reference claim. For example, assume that the claim in a reference patent is directed to a genus of compounds, and the application being examined is directed to a species within the reference patent genus. If the reference patent includes a disclosure of several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to determine whether the reference patent claim, as properly construed in light of that disclosure, anticipates or renders obvious the claim in the application being examined. Because that portion of the disclosure of the reference patent is an embodiment of the reference patent claim, it may be helpful in determining obvious variations of the reference patent claim.
35 U.S.C. 103
The arguments have been considered but were not found persuasive. As stated in the rejection, modification of a process parameter may be patentable if it produces a new and unexpected result which is different in kind from the results of the prior art. In this case, there is no evidence of a difference in kind when using 0.5-1 mM over 5 mM citrate with respect to cost and encapsulation efficiency.
Furthermore, apart from an argument, the applicant did not provide any evidence indicating that using 5 mM citrate does not offer the same flexibility as using 0.5-1 mM citrate.
The argument that one of skill in the art would not have lowered the concentration of citrate is not material to the rejection because the rejection is not based on lowering the concentration of citrate. The rejection states that using 0.5-1 mM is not given patentable weight because it does not produce an unexpected result over using 5 mM.
For these reasons, the following arguments are not found persuasive: (1) Oberli does not provide the motivation to reduce citrate composition; (2) DeRosa and Tendeloo do not teach using 0.5-1 mM; it is noted that DeRosa was only cited for teaching 150 mM NaCl; Tendeloo was only cited for providing the motivation to incubate the mRNA-LNPs).
Furthermore, just because Oberli teaches a formulation with DMPC, does not mean that using DOPE, and POPE would not have been obvious. It is true that Oberli does not teach that the encapsulation efficiency was the result of the non-cationic lipid alone. However, the rejection does not state this. Chivukula teaches encapsulation efficiency of more than 95% when using DSPC and also that DSPC could be replaced by any of DOPE, DOPE-mal, DOPC, DOPG, POPC, POPE, and SOPE. Oberli shows that high encapsulation efficiencies could be also obtained when using DSPC, DOPE, and POPE in different formulations. Thus, one of skill in the art would have reasonably expected that using noncationic lipids other than DSPC to obtain the LNPs taught by Chivukula would also result in very high mRNA encapsulation efficiency.
Conclusion
10. 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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