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 1-3, 5-19, 21, 23, 25-30, 32-37, 39-46, 50, 52-54, and 90-100 have been cancelled. Claim 101 has been withdrawn. Claims 4, 20, 22, 38, 51, 86, 87, 89, 102, and 103 have been amended. Claims 104 and 105 are new.
Claims 4, 20, 22, 24, 31, 38, 47-49, 51, 85-89, and 102-105 are under examination.
2. All objections/rejections pertaining to claims 1-4, 8, and 16 are moot because the claims were cancelled with the reply filed on 03/17/2026.
The objections to claims 4, 22, 24, 38, and 51 are withdrawn in response to the amendments filed on 03/17/2026 and applicant’s arguments.
The provisional nonstatutory double patenting rejection of claim 4 over claim 19 of copending Application No. 17/642,314 is withdrawn in view of the amendment to limit the claim to lipids not recited in the application claim.
The rejection of claim 22 under 35 U.S.C. 112(b) is withdrawn in response to the amendment to delete the trademark doggyboneTM from the claim.
The anticipation rejection of claims 4, 8, 20, 22, 24, 31, 38, 85, and 86 and the obviousness-type rejections of claims 4, 20, 22, 24, 31, 38, 47-49, 51, 85-89, 102, and 103 are withdrawn in response to the amendment to limit the claims to lipids not disclosed by Tanaka. New grounds of rejection are set forth below.
Specification
3. 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.
The arguments have been considered but not found persuasive because the term doggyboneTM is not capitalized and it is not accompanied by its generic terminology. It is noted that doggyboneTM is the trademark of a specific DNA vector; The term “DNA vector” is too general and does not identify the specific DNA vector associated with the trademark doggyboneTM. The specification should be amended to capitalize the term “doggyboneTM” at each occurrence and include the generic terminology identifying the specific DNA vector associated with the trademark doggyboneTM.
4. The claim listing is objected to because claim 101 is improperly identified as “previously presented”. The correct status identifier is “withdrawn”. Appropriate correction is required.
Claim Objections
5. Claim 24 should recite “a non-cationic lipid other than sterol” in line 2.
6. Claims 31 should “the non-cationic lipid other than sterol” in the second to last line.
New Rejections
Claim Rejections - 35 USC § 103
7. 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.
8. Claims 4, 20, 22, 24, 31, 38, 47, 51, 85-88, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Navarro et al. (WO 21/123332; cited on the IDS filed on 09/04/2024).
Navarro et al. teach LNPs encapsulating an mRNA, where LNPs have a diameter of 77-200 nm and comprise an ionizable cationic lipid (59 mol%), a PEG-lipid, cholesterol (29.4 mol%), and a neutral lipid other than cholesterol (10 mol%); the ionizable cationic lipid has one of the structures:
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(claims 4, 20, 22, 24, 31, 38, 51, and 102) (see Abstract; p. 3, lines 3-6 and 12-14; p. 26, lines 4-6 and 33-39; p. Table 1 on p. 42-44; p. 55, lines 29-33; p. 65, lines 44-45; p. 73, lines 10-12; p. 168-169; Fig. 1).
These compounds are similar to the claimed compounds set forth by the general formula
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(claim 4) and to the last compound recited in claim 102, except that R5 and R5’ are not exactly the same. However, the claimed compounds are homologs of the compounds taught by Navarro et al. due to their close structural similarity of the prior art compounds. There is nothing in the specification indicating that the claimed compounds are associated with unexpected properties as compared to the prior art compounds. Thus, the claimed compounds are considered to be obvious analogs due to their close structural similarity to the prior art compounds and the common use. MPEP § 2144.09 states:
2144.09 Close Structural Similarity Between Chemical Compounds (Homologs, Analogues, Isomers)
REJECTION BASED ON CLOSE STRUCTURAL SIMILARITY IS FOUNDED ON THE EXPECTATION THAT COMPOUNDS SIMILAR IN STRUCTURE WILL HAVE SIMILAR PROPERTIES
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1991) (discussed below and in MPEP § 2144 <http://www.uspto.gov/web/offices/pac/mpep/documents/2100_2144.htm>) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08 <http://www.uspto.gov/web/offices/pac/mpep/documents/2100_2144_08.htm>, paragraph II.A.4.(c).
HOMOLOGY AND ISOMERISM ARE FACTS WHICH MUST BE CONSIDERED WITH ALL OTHER RELEVANT FACTS IN DETERMINING OBVIOUSNESS
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
With respect to claim 47, Navarro et al. teach that the LNP comprises a ligand as a targeting moiety (see p. 72, lines 39-41).
With respect to claims 85-88, Navarro et al. teach treating a disease in a human subject by administering the LNPs to the subject (i.e., Navarro et al. teach a pharmaceutical composition) (see p. 86, lines 7-9).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
9. Claims 4, 20, 22, 24, 31, 38, 47-49, 51, 85-88, 102, and 103 are rejected under 35 U.S.C. 103 as being unpatentable over Navarro et al., in view of Kumar et al. (Mol. Ther.--- - Nucleic Acids, 2014, 3: 1-7; of record).
The teachings of Navarro et al. are applied as above for claims 4, 20, 22, 24, 31, 38, 47, 51, 85-88, and 102. Navarro et al. do not teach that the ligand is GalNac conjugated to PEG, nor do they 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 LNPs of Navarro 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, when delivery to the liver was desired.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
10. Claims 4, 20, 22, 24, 31, 38, 47, 51, 85-89, 102, and 105 are rejected under 35 U.S.C. 103 as being unpatentable over Navarro et al., in view of Mannucci et al. (Blood Transfus., 2017, 15: 365-368; of record).
The teachings of Navarro et al. are applied as above for claims 4, 20, 22, 24, 31, 38, 47, 51, 85-88, and 102. Navarro et al. do not teach treating hemophilia A in human patients (claims 89 and 105). 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 Navarro 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.
11. Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (Heliyon, 2018, p. 1-16), in view of both Sullivan et al. (WO 18/237369) and Maier et al. (Mol. Ther., 2013, 21: 1570-1578).
Tanaka et al. teach the ionizable cationic lipid ssPalmO-Paz4-C2 having the structure:
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, i.e., a lipid similar to the claimed lipid, except that the tertiary amine is
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(piperazine) and not
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(piperidine), and the lipid tails have double bonds instead of ester bonds. Tanaka et al. teach that ssPalmO-Paz4-C2 is an efficient transfection agent (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).
Sullivan et al. teach that, in lipids similar to ssPalmO-Paz4-C2, either piperidine or piperazine can be used in the headgroup. Sullivan et al. teach that replacing piperazine with piperidine results in 2 log higher expression (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 enhanced transfection. 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”.
Furthermore, Maier et al. teach that modifying the ionizable cationic lipids by introducing degradable ester linkages within the alkyl tails improves tolerability via generating short fragments upon digestion by the intracellular esterase or lipase, 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. Maier et al. teach that it is advantageous for lipids to be readily metabolized into water-soluble products with substantially reduced partitioning into biological membranes; placing the ester bond centrally within the tail yields relatively short hydrophilic products which can be easily eliminated (see Abstract; p. 1571). Based on these teachings, one of skill in the art would have reasonably expected that modifying Tanaka et al. and Sullivan et al. by replacing the central double bonds of the lipid tails 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 the central double bonds with central 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 the ionizable cationic lipid:
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(i.e., having -(CH2)7-(CO)O-(CH2)7CH3 tails).
While the tails are -(CH2)7-(CO)O-(CH2)7CH3 and not -(CH2)7-(CO)O-(CH2)8CH3 as required by claim 104, there is no evidence of record indicting that a difference of one carbon in the alkyl chain following the second ester group (i.e., C8 vs C9) leads to unexpected properties. Furthermore, one of skill in the art would have readily recognized that ionizable cationic lipids where alkyl chain comprise 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.
Response to Arguments
12. The arguments are answered below to the extent that they pertain to the new rejections.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The applicant argues that Tanaka provides no reason to modify ssPalmO-Paz4-C2.
This is not found persuasive. Just because Tanaka teaches that ssPalmO-Paz4-C2 is a promising mRNA vector does not mean there is no room for further improvement. Furthermore, Tanaka does not have to provide a reason. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
The applicant argues that one of skill in the art would not have been motivated to replace piperazine with piperidine because the compounds disclosed by Sullivan are structurally different from ssPalmO-Paz4-C2. The applicant argues that Sullivan provides no information that would lead one of skill in the art to believe that piperidine would achieve any beneficial result in the context of ssPalmO-Paz4-C2 structure.
This is not found persuasive. One of skill in the art would have known that Sullivan’s ssPalmE-Paz4-C2 and Tanaka’s ssPalmO-Paz4-C2 have similar structures having the same piperazine-based headgroup:
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Since Sullivan teaches that replacing piperazine with piperidine in the headgroup of ssPalmE-Paz4-C2 results in 2 log higher expression (see [0135]), one of skill in the art would have reasonably expected that this teaching in Sullivan could be extrapolated to Tanaka’s ssPalmO-Paz4-C2. Apart from arguments, the applicant did not provide any evidence to the contrary.
The applicant argues that one of skill in the art would not have been motivated to introduce an ester linkage as taught by Mayer because Tanaka’s lipid is already cleavable as it contains a disulfide linkage.
This is not found persuasive. Tanaka’s lipid contains a disulfide linkage in the headgroup and one ester linkage in each tail, indicating that Tanaka recognized the benefit of having cleavable linkages in the headgroup as well as the tails. Maier teaches that it is advantageous for lipids to be readily metabolized into water-soluble products with substantially reduced partitioning into biological membranes. Maier teaches placing the ester bond centrally within the tail to yield relatively short hydrophilic products which can be easily eliminated (see Abstract; p. 1571). Since Maier teaches that the double bond can be replaced by an ester linkage, one of skill in the art would have readily recognized that replacing the central double bond in Tanaka’s lipid with an ester bond would generate shorter hydrophilic products and would further improve biocompatibility.
Conclusion
10. 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
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