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 17-48, 50-97, 99-106, and 109-133 have been cancelled. Claims 1-4, 7-11, 16, 49, 98, 107, and 108 have been amended.
Claims 1-16, 49, 98, 107, and 108 are pending and under examination.
2. The objections to claims 1, 2-4, 7-11, 16, 49, 98, 107, and 108 are withdrawn in response to the amendments filed on 07/15/2026.
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1-16, 49, 107, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Nano Research, February 2019, 12: 855-861), in view of all Dong et al. (WO 19/027999; published on 02/07/2019), Met et al. (Breast Cancer Res Treat, 2011, 125: 395-406), and Bazin et al. (Tetrahedron Letters, 2016, 57: 2063-2066).
Zhang et al. teach conjugates between paclitaxel or camtothecin and an ionizable cationic lipid (PAL and CAL, respectively). PAL and CAL are obtained by reacting the -OH group of paclitaxel/camtothecin with the -COOH group of Lipid 1. The synthetic route is shown below:
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(see p. 856, Fig. 1; Supplementary Material, Fig. S1). Zhang et al. teach nanoparticles comprising PAL/CAL, DOPE, cholesterol, and DMG-PEG; the nanoparticles encapsulate a p53-encoding mRNA and are used to simultaneously deliver the encapsulated mRNAs and the drug to the same cell (claims 16, 49, 107, and 108) (see paragraph bridging p. 855 and 856; p. 856-857). Zhang et al. teach that the nanoparticle platform could be used with a broad category of chemotherapy drugs (see p. 858, column 1)
While Zhang et al. teach conjugating to chemotherapy drugs, Dong et al. teach that ionizable cationic lipids could be conjugated to diverse compounds of interest (such as carbohydrates, phosphate, and vitamins) and formulated into nanoparticles for mRNA delivery (see p. 1, line 30 through p. 2, line 20; p. 5, lines 7-25; p. 6, lines 7-13; p. 34; p. 36, lines 10-14; p. 42, lines 3-5; p. 45, lines 15-23; p. 48, lines 18-30; p. 51-52; p. 84; claims 21 and 28).
Based on the combined teachings of Zhang et al. and Dong et al., one of skill in the art would have reasonably concluded that, in addition to chemotherapeutic drugs, Lipid 1 taught by Zhang et al. could be used to obtain conjugates with a variety of other compounds of interest.
While neither Zhang et al. nor Dong et al. teach a TLR agonist as the compound of interest, using a TLR agonist is suggested by the prior art. For example, Dong et al. teach that administering dendritic cells (DCs) transfected with antigen-encoding mRNAs induces antigen-specific immune responses (see p. 1, lines 19-24). Met et al. teach that DCs transfected with an mRNA encoding p53 could be used to induce immune response against tumors expressing high levels of mutated p53 (see Abstract; paragraph bridging p. 395 and 396; p. 396, column 1, last paragraph). Bazin et al. teach that, since TLR7 and TLR8 are expressed by DCs, agonists which potently activate both TLR7 and TLR8 (such as resiquimod) are useful as vaccine adjuvants capable of eliciting innate and adaptive immune responses against cancer. Bazin et al. teach that, since TLR7/8 are located in the endosomal compartment, cellular uptake of the TLR7/8 agonists is a prerequisite for DC activation; cellular uptake is achieved via conjugating the TLR7/8 agonists to lipids. The TLR7/8 agonists taught by Bazin et al. are:
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(resiquimod or R848)
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(see p. 2063).
Based on these teachings, one of skill in the art would have found obvious to modify Zhang et al. by replacing paclitaxel/camtothecin with the TLR7/8 agonists taught by Bazin et al. to achieve the predictable result of obtaining nanoparticles suitable for obtaining DCs capable of eliciting enhanced immune responses against tumors expressing high levels of mutated p53, when eliciting immune responses against these tumors was desired. By doing so one of skill in the art would have reacted the -OH group of the TLR7/8 agonists with the -COOH group of Lipid 1 and would have obtained compounds set forth by Formulae A and I (claims 1, 7, and 8). By conjugating R848 to Lipid 1, one of skill in the art would have obtained a conjugate as recited in claim 2-6 and 9-14.
With respect to claim15, Dong et al. teach that that the branched lipid tail aldehyde
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could be used to obtain cationic ionizable lipids for conjugation with compounds of interest (see p. 56; p. 63). Modifying Zhang et al. and Bazin et al. by replacing lauraldehyde (highlighted in the synthetic route above) with
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would have been obvious to one of skill in the art to achieve the predictable result of obtaining nanoparticles suitable for eliciting enhanced immune responses against tumors expressing high levels of mutated p53. By doing so, one of skill in the art would have obtained the compound recited in claims 13 and 15.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
5. Claims 1-16, 49, 98, 107, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. taken with all Dong et al., Met et al., and Bazin et al., in further view of Murugaiyan et al. (Clin. Exp. Immunol., 2007, 149: 194-202).
The teachings of Zhang et al., Dong et al., Met et al., and Bazin et al. are applied as above for claims 1-16, 49, 107, and 108. Zhang et al., Dong et al., Met et al., and Bazin et al. do not teach a composition comprising a ligand for a costimulatory molecule and nanoparticles encapsulating an mRNA encoding the costimulatory molecule (claim 98). Murugaiyan et al. teach that the interaction between CD40 and its ligand CD40-L plays an important role in the anti-tumor immune responses. Murugaiyan et al. teach that the anti-tumor immune responses are dependent on the levels of CD40 expression on DCs and CD40-L on T-cells; higher levels promote tumor regression, while the low levels induced during tumor progression promote tumor growth. Murugaiyan et al. teach that strong CD40 stimulation by agonistic antibodies or peptidomimetic small molecules is needed for generating enhanced anti-tumor immune responses (see Abstract; paragraph bridging p. 194 and 195; p. 202, column 1). Based on these teachings, one of skill in the art would have reasonably concluded that transfecting DCs with a nucleic acid encoding CD40 and contacting the transfected DCs with a CD40 ligand would provide the strong stimulation necessary for anti-tumoral activity. One of skill in the art would have found obvious to modify the nanoparticles of Zhang et al., Dong et al., Met et al., and Bazin et al. by further encapsulating a CD40-encoding mRNA and incorporate the resultant nanoparticles in a kit containing a CD40 agonistic antibody to achieve the predictable result of obtaining a composition suitable for eliciting enhanced immune responses against tumors expressing high levels of mutated p53, when treating these tumors was desired.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation.
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 the cited references do not provide the motivation and the reasonable expectation that paclitaxel/camtothecin could be substituted with a TLR agonist.
This is not found persuasive. 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). In this case, the combined teachings of the prior art suggest making the modification. The argument of lack of reasonable expectation of success in making the modification is not supported by any evidence.
The argument of lack of expectation that TLR7/8 agonists could be formulated into amino lipids is not found persuasive. Zhang teaches coupling via reacting the -OH group of paclitaxel/camtothecin with the -COOH group of Lipid 1. Since the TLR7/8 agonists contain an -OH group, one of skill in the art would have reasonably expected to be successful in attaching the TLR7/8 agonists to Lipid 1.
The applicant argues that none of the references discloses that paclitaxel and camtothecin are recognized equivalents of TLR agonists.
However, the rejection does not state that paclitaxel/camtothecin and TLR agonists are equivalent. Based on the teachings in the cited prior art, it would have been obvious to replace paclitaxel/camtothecin with TLR7/8 agonists such as to obtain vaccines for treating tumors expressing high levels of mutated p53. While TLR7/8 agonists are potent vaccine adjuvants, paclitaxel/camtothecin cannot act as vaccine adjuvants. Making the substitution to obtain the vaccine would have been obvious.
The argument that the modification would render Zhang’s PAL/CAL unsatisfactory for their purpose is not found persuasive. The principle of operation is to kill the cancer cells expressing mutant p53. Replacing paclitaxel/camtothecin with TLR7/8 agonists would not change the principle of operation because killing the cancer cells is achieved regardless of whether the nanoparticles carry paclitaxel/camtothecin or TLR7/8 agonists.
The teaching of personalized medicine in Zhang referred to by the applicant relates to tumors expressing mutant p53, hence personalized medicine with nanoparticles encapsulating p53-encoding mRNA. The only modification is replacing paclitaxel/camtothecin with TLR7/8 agonists. The resultant nanoparticles would still encapsulate the p53-encoding mRNA required for the personalized medicine.
Conclusion
8. THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
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/ILEANA POPA/ Primary Examiner, Art Unit 1633
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