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 .
Election/Restrictions
1. Applicant’s election without traverse of Lipid 1 (claim 102) and hemophilia A in the reply filed on 09/24/2025 is acknowledged.
Upon further considerations, the election requirement between the distinct ionizable lipids is withdrawn.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 5-7, 9-15, 17-19, 21, 23, 25-30, 32-37, 39-46, 50, 58-54, and 90-100 have been cancelled. Claims 27, 31, 38, 48, 49, 51, and 89 have been amended. Claims 101-103 are new.
Claim 101 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4, 8, 16, 20, 22, 24, 31, 38, 47-49, 51, 85-89, 102, and 103 are under examination.
Specification
2. The use of the term doggyboneTM, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
3. Claims 2, 3, 8, 16, 20, and 86 are objected to because of the recitation “a pharmaceutically acceptable salt thereof”. Correction to “the pharmaceutically acceptable salt thereof” is required.
4. Claim 4 is objected to because of the recitation “a pharmaceutically acceptable salt thereof”. Correction to include this recitation in the preamble (i.e., “The ionizable lipid of claim 1 or the pharmaceutically acceptable salt thereof, wherein the ionizable lipid is”) and delete this recitation whenever it appears in the body of the claim is required.
5. Claim 22 is objected to because of the recitation “a viral RNA vector” in line 6. Correction to “an RNA viral vector” is required.
6. Claims 24 and 38 are objected to because of the recitation “further” in line 1. Correction to delete the term “further” is required.
7. Claim 51 is objected to because of the recitations: “a mean diameter ranging from about 30 nm to about 110 nm”; and “a mean diameter of less than about 100 nm, less than about 75 nm, less than about 70 nm, or less than about 65 nm”. A mean value is not a range; it is rather a single value representing the average of the multiple values within a range.
Correction to “wherein the lipid nanoparticle has a diameter ranging from about 30 nm to about 110 nm”; or wherein the lipid nanoparticle has a diameter of less than about 100 nm, less than about 75 nm, less than about 70 nm, or less than about 65 nm” is required.
8. Claim 38 should recite “a non-cationic lipid other than cholesterol” in line 2.
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 1-4 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 19 of copending Application No. 17/642,314 (reference application), in view of Maier et al. (Mol. Ther., 2013, 21: 1570-1578). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to similar ionizable cationic lipids. The application claim 19 recites the following lipids:
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, which has a structure similar to the lipids set forth by Formula I recited in the instant claims 1; and
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, which comprise piperidine as a heterocycle and which also has a structure similar to the lipids set forth by Formula I recited in the instant claims 1. The instant claim 1 defines that, in Formula I, R2/R3 and R2’/R3’ could form a heterocycle together with their intervening N atom. The heterocycle piperidine (present in the lipid recited in the application claim) anticipates the genus recited in the instant claim 1. Conversely, the instant specification defines that the heterocycle in Formula I could be piperidine (see p. 71, Scheme 2).
The only difference is that the lipids recited in the application claim contain double bonds and not –(CO)-O- (ester) linkages. Maier et al. teach that modifying the ionizable cationic lipids by introducing degradable ester linkages within the alkyl tails improves tolerability, while maintaining their potency. Maier et al. teach that, similar to double bonds, ester linkages introduce kinks in the alkyl chains maintaining the spacing between the alkyl chains shown to be important for efficacy; thus, the double bond can be replaced by an ester linkage (see Abstract; p. 1571). Based on these teachings, one of skill in the art would have reasonably expected that replacing the double bonds in the lipid recited in the application claim with ester linkages would improve its tolerability, without affecting its potency. One of skill in the art would have found obvious to modify the lipid recited in the application claims by replacing the double bonds with ester bonds, with the reasonable expectation that doing so would improve its tolerability. By doing so, one of skill in the art would have obtained an ionizable cationic lipid encompassed by the instant formula I where R4 and R4’ are interrupted by –(CO)-O-, having a structure as recited in the instant claims 1-4 and 8. 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 § 112(b)
11. 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.
12. Claim 22 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 22 contains the trademark/trade name “doggyboneTM”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a specific nucleic acid and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
13. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
14. Claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tanaka et al. (Heliyon, 2018, p. 1-16).
Tanaka et al. disclose the ionizable cationic lipids ssPalmM and ssPalmO, each comprising a head group having two tertiary amines bound via a disulfide bond, each tertiary amine being coupled to a fatty acid tail; ssPalmM and ssPalmO have the structures:
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, i.e., set forth by the claimed formulas I, III, V, VIII, and IX where R1 and R1’ are C1 alkylene; R2 and R2’ are C1 alkylene; R3 and R3’ are C1 alkyl; R4 and R4’ are C4 alkylene interrupted with -C(O)O-; and R5 and R5’ are C12 alkyl;
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, i.e., set forth by the claimed formulas I, III, V, VIII, and IX where R1 and R1’ are C1 alkylene; R2 and R2’ are C1 alkylene; R3 and R3’ are C1 alkyl; R4 and R4’ are C4 alkylene interrupted with -C(O)O-; and R5 and R5’ are C16 alkenyl (claims 1-4). Tanaka et al. disclose nanoparticles comprising ssPalmO, DOPC, cholesterol, (molar ratio 60/10/30), PEG-DSG, and an encapsulated mRNA, where the nanoparticles are suspended in PBS (claims 8, 20, 22, 24, 31, 38, 85, and 86). See Tanaka et al., Abstract; p. 3, Fig. 1a; paragraph bridging p. 7 and 8; p. 8, Table 1; p. 11, first paragraph.
Thus, Tanaka et al. teach all claim limitations and anticipate the claimed invention.
Claim Rejections - 35 USC § 103
13. 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.
16. Claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al., in view of Sullivan et al. (WO 18/237369).
The teachings of Tanaka et al. are applied as above for claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86. In addition, Tanaka et al. teach nanoparticles comprising ssPalmO-Paz4-C2 instead of ssPalmO, where ssPalmO-Paz4-C2 is an efficient transfection agent; ssPalmO-Paz4-C2 has the structure:
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, i.e., a lipid similar to the claimed Formulas IV and X (claim 4), except that the tertiary amine is piperazine and not piperidine (see p. 5, Scheme 1; paragraph bridging p. 7 and 8; p. 10, Fig. 3; p. 11, legend for Fig. 3; paragraph bridging p. 11 and 12).
However, Sullivan et al. teach that piperidine can be used instead of piperazine (see [0006]; [0021]; [0107]; [0124]; [0135]). One of skill in the art would have found obvious to modify ssPalmO-Paz4-C2 by replacing piperazine with piperidine, with the reasonable expectation that doing so would result in a lipid suitable for transfection. Using prior art means that accomplishes the same goal would have been reasonably obvious to one of skill in the art. As held In re Peterson, 315 F.3d 1325, 1329-30, there is “a normal desire of scientists or artisans to improve upon what is already generally known”.
By doing so, one of skill in the art would have obtained the lipid:
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, i.e., set forth by formulas IV, VI and X (claim 4).
With respect to Formulas II and VII recited in claim 4, one of skill in the art would have readily recognized that Formulas II and VI are homologs of Formulas III, V, VIII, and IX differing by one CH2 group. In searching for new lipids, one of skill in the art would have found obvious to modify Formulas I, III-VI, and IX by one CH2 group, with the reasonable expectation that doing so would result in a compound suitable to be used as a transfection agent (see MPEP 2144.09). As held In re Peterson, 315 F.3d 1325, 1329-30, there is “a normal desire of scientists or artisans to improve upon what is already generally known”.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
17. Claims 1-4, 8, 16, 20, 22, 24, 31, 38, 85, 86, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. taken with Sullivan et al., in further view of Maier et al. (Mol. Ther., 2013, 21: 1570-1578).
The teachings of Tanaka et al. and Sullivan et al. are applied as above for claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86. Tanaka et al. and Sullivan et al. teach:
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, which does not have any of R5 and R5’ interrupted with -(CO)-O- (ester linkage) (claim 16 and 102).
Maier et al. teach that modifying the ionizable cationic lipids by introducing degradable ester linkages within the alkyl tails improves tolerability, while maintaining potency. Maier et al. teach that, similar to double bonds, ester linkages introduce kinks in the alkyl chains maintaining the spacing between the alkyl chains shown to be important for efficacy; thus, the double bond can be replaced by an ester linkage (see Abstract; p. 1571). Based on these teachings, one of skill in the art would have reasonably expected that replacing at least one of the double bonds in the lipid of Tanaka et al. and Sullivan et al. with an ester linkage would improve its tolerability without affecting its potency. One of skill in the art would have found obvious to modify the lipid of Tanaka et al. and Sullivan et al. by replacing one or both double bonds with ester bonds, with the reasonable expectation that doing so would improve its tolerability.
By replacing one double bond, one of skill in the art would have obtained an ionizable cationic lipid where R5’ is interrupted with -(CO)-O- (claim 16).
By replacing both double bonds, one of skill in the art would have obtained an ionizable cationic lipid where both R5’ and R5’ are interrupted with -(CO)-O- having a structure similar to the claimed Lipid 3 recited in claim 102, except that R5 and R5’ are C8 and not C9. However, one of skill in the art would have readily recognized that ionizable cationic lipids where R5 and R5’ are either C8 or C9 are homologs differing by one CH2 group. In searching for new ionizable cationic lipids, one of skill in the art would have found obvious to modify the lipid taught by the prior art with the reasonable expectation that doing so would result in a compound suitable to be used for nucleic acid delivery (see MPEP 2144.09). As held In re Peterson, 315 F.3d 1325, 1329-30, there is “a normal desire of scientists or artisans to improve upon what is already generally known”.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
16. Claims 1-4, 8, 20, 22, 24, 31, 38, 47-49, 85, 86, and 103 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. taken with Sullivan et al., in further view of Kumar et al. (Mol. Ther.--- - Nucleic Acids, 2014, 3: 1-7).
The teachings of Tanaka et al. and Sullivan et al. are applied as above for claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86. Tanaka et al. and Sullivan et al. do not teach using 0.5 mol% GalNac-PEG-DSG (claims 47-49 and 103). Kumar et al. teach incorporating 0.5 mol% GalNac-PEG-DMG into lipid nanoparticles to increase the efficacity of hepatic delivery by PEGylated lipid nanoparticles (see p. 4; paragraph bridging p. 5 and 6). One of skill in the art would have found obvious to modify the lipid nanoparticle of Tanaka et al. and Sullivan et al. by incorporating 0.5 mol% GalNac-PEG-DMG to achieve the predictable result of obtaining a composition suitable to deliver mRNAs to the liver.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
17. Claims 1-4, 8, 20, 22, 24, 31, 38, and 85-89 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al., in view of Mannucci et al. (Blood Transfus., 2017, 15: 365-368).
The teachings of Tanaka et al. are applied as above for claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86. Tanaka et al. do not teach treating hemophilia A in human patients (claims 87-89). Mannucci et al. teach treating human patients affected by hemophilia A by administering porcine FVIII to these patients (see Abstract; p. 365, column 1, paragraph bridging p. 366 and 367, second paragraph). One of skill in the art would have found obvious to modify Tanaka et al. by using an mRNA encoding porcine FVIII as the mRNA in their lipid nanoparticles and further administering the resultant composition to a human patient with the reasonable expectation that doing so would treat the disease in the patient.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
18. Claims 1-4, 8, 20, 22, 24, 31, 38, 51, 85, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al., in view of Togashi et al. (J. Control. Rel., 2918, 279: 262-270).
The teachings of Tanaka et al. are applied as above for claims 1-4, 8, 20, 22, 24, 31, 38, 85, and 86. With respect to claim 51, Tanaka et al. teach that the optimal size for an mRNA carrier is about 110 nm (see p. 2, last paragraph). Togashi et al. teach that ionizable cationic lipids (having a head group with two tertiary amines bound via a disulfide bond), helper lipids, cholesterol, and PEG-lipids can be formulated into lipid nanoparticles having a size of 103 nm (see p. 264, Fig. 1 and Table 1). One of skill in the art would have found obvious to obtain the lipid nanoparticles of Togashi et al. with a size within the range of 103-110 nm with the reasonable expectation that doing so would result in a composition suitable for mRNA delivery.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
19. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633