DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/05/2026 has been entered.
Claims 2-6, 10, 12, 13, 15, 17, and 20 have been cancelled.
Claims 1, 7-9, 11, 14, 16, 18, 19, and 21-23 are pending and under examination.
Claim Rejections - 35 USC § 103
2. 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
3. Claims 1, 8, 9, 11, 14, 16, 18, 19, 21, and 22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tzeng et al. (Int. J. Nanomed., 2011, 6: 3309-3322), in view of all Furuhata et al. (Bioconjugate Chem,. 2006, 17: 935-942), Mather et al. (Progr. Polym. Sci., 2006, 31: 487-531), and Akinc et al. (Bioconjugate Chem., 2003, 14: 979-988).
Tzeng et al. teach the acrylate-terminated PBAE B4S5 obtained via the Michael addition of the amine 5-amino-1-pentanol (S5) to the acrylate groups of 1,4-butanediol diacrylate (B4). B4S5 has the formula:
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116
288
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i.e., L3 is -CH2-(CH2)2-CH2-, R4 is
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91
96
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and R3 is –(CH2)5OH (claims 1 and 11). Tzeng et al. teach end-capping B4S5 via the Michael addition of 2-methylpentane-1,5-diamine (S4) to the terminal acrylate groups of B4S4 to obtain PBAE B4S5E4 (454), useful for polynucleotide delivery; 454 encapsulates the polynucleotide (such as DNA and siRNA) to form nanoparticles; encapsulation takes place by mixing 454 and the polynucleotide (claims 16, 18, 19, 21, and 22) (see p. 3310, Fig. 1; paragraph bridging p. 3310 and 3311; p. 3311, column 1, second full paragraph; p. 3314, Fig. 6; p. 3316, column 1; p. 3319, column 1, first paragraph).
454 has the structure:
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94
480
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i.e., Ry is -NH-CH2-CH(CH3)-(CH2)2-NH2) (claims 1, 8, and 14)
Tzeng et al. do not teach capping with an oligopeptide (claims 1 and 8). However, capping with an oligopeptide is suggested by the prior art. For example, Furuhata et al. teach that the conjugation of R4 (a cell penetrating peptide) to delivery vehicles enhances cellular uptake (see Abstract; p. 938, Fig. 4). Mather et al. teach that using the thiol group on cysteine (Cys) over amine offers advantages: selectivity, as Michael addition is selective to thiol over amine; increased addition by when Cys is adjacent to arginine groups (see p. 519; p. 523, paragraph bridging columns 1 and 2). Based on these teachings, one of skill in the art would have found obvious to modify R4 with Cys to obtain Cys-R4 and further use one or two Cys-R4 for capping with the reasonable expectation that doing so would result in a PBAE capable of enhanced transfection. By doing so, one of skill in the art would have obtained a first PBAE set forth by formula I where R1 and R2 are R4 linked to L1 and L2 via a thioether bond. The cited prior art teaches Cys-R4, not Cys-R3 as required by claim 1. 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). In this case, there is no evidence of record showing that R3 offers any advantage over R4.
With respect to “n” being 5-10,000 (claim 1) or 5-20 (claim 9), Akinc et al. teach that molecular weight is a factor impacting transfection efficiency (see Abstract; p. 979, column 2). One of skill in the art would have found obvious to use routine experimentation and vary the molecular weight (i.e., “n”) with the reasonable expectation that doing so would identify the range mediating optimal transfection. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed ranges 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 it was made.
4. Claims 1, 7-9, 11, 14, 16, 18, 19, 21, and 22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tzeng et al. taken with all Furuhata et al., Mather et al., and Akinc et al., in further view of Lo et al. (Biomaterials, 2008, 29: 2408-2414).
Claim 7 recites the limitation of a second polymer where R1 and R2 comprise “histidine in addition to said cysteine”. This recitation is reasonable interpreted as meaning modifying the Cys-oligopeptide by further incorporating histidine.
The teachings of Tzeng et al., Furuhata et al., Mather et al., and Akinc et al. are applied as above for claims 1, 8, 9, 11, 14, 16, 18, 19, 21, and 22. Tzeng et al., Furuhata et al., Mather et al., and Akinc et al. do not teach modifying Cys-H4 by incorporating histidine (claim 7). Lo et al. teach that incorporating histidine into cell penetrating peptides enhances transfection efficiency by disrupting endosomal membranes and promoting endosomal escape (see Abstract). One of skill in the art would have found obvious to also obtain a second PBAE where Cys-R4 further comprises a histidine with the reasonable expectation that doing so would improve transfection efficiency. Furthermore, one of skill in the art would have found obvious to combine the first and the second PBAEs to achieve the predictable result of obtaining a composition suitable for transfection. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus, the claimed invention was prima facie obvious at the time it was made.
5. Claims 1, 8, 9, 11, 14, 16, 18, 19, and 21-23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tzeng et al. taken with all Furuhata et al., Mather et al., and Akinc et al., in further view of Green et al. (PGPUB 2010/0196492).
The teachings of Tzeng et al., Furuhata et al., Mather et al., and Akinc et al. are applied as above for claims 1, 8, 9, 11, 14, 16, 18, 19, 21, and 22. Tzeng et al., Furuhata et al., Mather et al., and Akinc et al. do not teach spray drying, double emulsion, or phase inversion (claim 23). Green et al. teach spray drying, double emulsion, and phase inversion for obtaining PBAEs particles (see Abstract; [0011]; [0013]; [0047]; [0050]; [0102]). Using spray drying, double emulsion, or phase inversion would have been obvious to one of skill in the art to achieve the predictable result of obtaining PBAE nanoparticles.
Thus, the claimed invention was prima facie obvious at the time it was made.
Response to Arguments
6. The arguments and the references provided to support the arguments have been considered but not found persuasive. The provided references do not evidence that R4 could not have been reasonably expected to enhance cellular uptake of PBAEs nanoparticles.
The argument that Furuyama points to unpredictability of using R4-conjugated liposomes is not new and was previously addressed. The fact that the exact mechanism for endocytosis was not known is not evidence of unpredictability. Furuhata provides evidence that R4 enhances transfection; thus, there is no unpredictability with respect to R4-mediated transfection.
With respect to R3, the rejection does not state replacing R4 with R3. The rejection states there is no evidence of record showing that R3 offers any advantage over R4. Using R3 instead of R4 is not significant if it does not produce a novel feature.
The applicant argues that, as evidenced by Exhibit A, the cellular uptake of liposomes and polymer nanoparticles takes place via different mechanisms.
While this may be true, the rejection is based on extrapolating R4 activity to PBAE nanoparticles. None of the references provided by the applicant provides evidence of unpredictability in doing so.
The applicant argues that, due to the divergence of mechanisms, there was no reasonable expectation that the mechanism of endosomal escape for liposomes would promote endosomal escape for polymeric nanoparticles.
This argument is not material to the rejection because the rejection is not based on extrapolating the mechanism of liposomal endosomal escape to polymeric nanoparticles.
Furuhata teaches that R4 (a cell penetrating peptide; CPP) enhances internalization into cells via its ability to penetrate the cell membranes. The rejection is based on conjugating R4 to PBAE to enhance intracellular delivery, not endosomal escape. There is no evidence of record showing or even suggesting that doing so would not enhance the cellular uptake of the PBAE nanoparticles. It was common knowledge in the prior art that CPPs are capable of effectively deliver diverse molecules and particles (Forged, Expert Opin. Drug Deliv., 2008, 5: 105-117; see p. 111, paragraph bridging columns 1 and 2). Thus, the prior art provides the reasonable expectation of success.
The applicant argues that Exhibit A points to the unpredictability of promoting endosomal escape by cationic polymers.
This argument is not material to the rejection because the rejection is not based on replacing one cationic polymer with another.
The argument of surprising effectiveness for the oligopeptide-capped PBEAs is not found persuasive because this was reasonably expected from the teachings in the cited prior art. Dosta (the reference provided by the applicant) does not provide any evidence to the contrary
7. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Forged (Expert Opin. Drug Deliv., 2008, 5: 105-117) was cited in response to the argument of lack of reasonable expectation of success. The reference provides evidence that one of skill in the art would have reasonably expected to enhance the transfection of the PBAE nanoparticles by capping the PBAE with oligopeptides such as R4.
8. 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
