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 .
1. 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. Claim 1 has been amended.
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. All rejections pertaining to claims 36 and 71-73 are moot because the claims were cancelled with the reply filed on 12/18/2025.
The obviousness-type rejections set forth in the non-final Office action mailed on 09/18/2025 are withdrawn in response to the amendment to exclude DSPC from the claims. New grounds of rejection are set forth below.
Maintained Rejections
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 60-77 of copending Application No. 17/320,946 (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, where the LNPs comprise DOPE, DOPC, DOPG, POPC, POPE, , DOPE-mal, or SOPE. While the application claim 77 recites less than 5 mM citrate, the application specification discloses that less than 5 mM citrate could be less than 3 mM or less than 1 mM citrate (see [0102]). The instant specification discloses that the mRNA-LNPs are purified by tangential flow filtration, that the mRNA solution is mixed at a flow rate of 150-250 ml/min, the lipid solution is prepared in an amphiphilic polymer such as poloxamers (i.e., pluronic), the cationic lipid is CKK-E12, and the LNPs also comprise DOPE and cholesterol (see [0027]; [0037]; [0105]; [0186]). The application specification discloses that the mRNA solution comprises about 150 mM NaCl (see [0104]). 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.
5. 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. 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.
New Rejections
Claim Rejections - 35 USC § 103
6. 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.
7. 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, and SOPE (claim 1). However, Chivukula et al. teach that the method yields an encapsulation efficiency of more than 95% and also 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 mRNA encapsulating efficiencies of at least 88% could be achieved when using noncationic lipids other than DSPC, such as DOPE, POPE, and DMPC (see Supplemental Information, Table S1). Based on these teachings, one of skill in the art would have reasonably expected that using noncationic lipids other than DSPC would result in very high encapsulation efficiency. Replacing DSPC with any one of 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 mRNA into LNPs.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. 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.
9. 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
10. Double patenting
The applicant argues that one of skill in the art would not combine the process recited in the application claims with Jeff’s process which requires very high citrate concentrations.
This argument is not new and was previously addressed.
With respect to the ‘628 application, the applicant additionally argues that the application claims do not recite that the noncationic lipid is one of DOPE, DOPE-mal, DOPC, DOPG, POPC, POPE, and SOPE.
However, as set forth in the rejection, the application specification discloses that the non-cationic lipid could be DOPE, POPC, POPE, DOPE-mal, or SOPE (see [0009]; [0049]; [0152]). 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 argument that Chivukula only discloses high encapsulation efficiency when using DSPC and 5 mM citrate is not found persuasive. Chivukula teaches that the method yields an encapsulation efficiency of more than 95%; this teaching is not limited to DSPC (see [0063]; [0142]-[0143]). Oberli teaches that encapsulating efficiencies of more than 90% can be achieved when using noncationic lipids such as DOPE, POPE, or DOPS. Thus, one of skill in the art would have reasonably expected high encapsulation levels when using noncationic lipids other than DSPC.
For these reasons, the following arguments are not found persuasive:
(1) high encapsulating efficiency in Chivukula is the result of using DSPC;
(2) Chivukula does not provide a teaching or motivation to replace DSPC. It is also noted that the rejection is not based on the TSM rationale; the rejection is based on substituting one known element for another to obtain a predictable result, i.e., achieving high encapsulation efficiency;
(3) lack of reasonable expectation of success.
The applicant argues that Chivukula does not teach that using 5 mM citrate would increase encapsulation efficiency.
However, Chivukula does not have to disclose that it is the use of 5 mM citrate which leads to high encapsulation efficiency. Chivukula teaches a method using 5 mM citrate which achieves more than 95% encapsulation efficiency; this is enough to meet the claim limitation regarding the encapsulating efficiency.
The applicant argues that one of skill in the art would not have been motivated to
decrease the citrate concentration in Chivukula from 5 mM to 0.5-1 mM.
However, the rejection is not based on reducing 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.
The applicant cites Kaufmann to support the argument that it would have been unexpected to achieve improved encapsulation efficiencies when using low citrate concentrations and an unsaturated noncationic lipid.
This is not found persuasive for the reasons set forth above.
While Kaufmann teaches that LNPs comprising DSPC have an encapsulation efficiency of 51%, Chivukula’s method results in 97.7% encapsulation efficiency for formulations comprising DSPC (i.e., about 2-fold more). While Kaufmann teaches that LNPs comprising DOPE have an encapsulation efficiency of 36%, Oberli teaches that using unsaturated noncationic lipid such as DOPE, POPE, and DMPC leads to high encapsulation efficiency (Supporting Information, Table S1, see formulations A-5, A-6, A-8, A-9, B-11). Furthermore, Oberli teaches that formulations A-6 (DSPC) and B-11 (DOPE) provide similar mRNA expression levels (see p. 1328, column 2, first paragraph; Fig. 2C). Based on these teachings, one of skill in the art would have reasonably expected to achieve at least 70% encapsulation efficiency and efficient mRNA expression when using Chivukula’s method with unsaturated noncationic lipids such as DOPE.
The arguments addressing DeRosa and Tendeloo individually are not found
persuasive because these references do not have to teach every claim limitation
Conclusion
11. 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