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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 06/12/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 03/19/2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 06/12/2026, claims 52-82, 84 and 86-90 are pending.
The 102 and 103 rejections are withdrawn in response to claim amendments which have necessitated new grounds of rejections.
New Claim Rejections – necessitated by claim amendments
Claim Objections
Claims 70-73 and 79-82 have the incorrect status and should state (Previously Presented) since they were examined in the previous Office Action. Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 52-64, 67-72, 74-82, 84 and 86-90 is/are rejected under 35 U.S.C. 103 as being unpatentable over EP 3 034 539 A1 (ETHRIS GMBH [DE]) 22 June 2016 (2016-06-22 of record 04/11/2022 IDS), Debus et al. ("Delivery of messenger RNA using poly (ethylene imine)–poly (ethylene glycol)-copolymer blends for polyplex formation: Biophysical characterization and in vitro transfection properties." Journal of Controlled Release 148.3 (2010): 334-343 of record 892 03/19/2026), Rafael, Diana, et al. ("Lipoplexes and polyplexes: gene therapy." Encycl. Biomed. Polym. Polym. Biomater (2015): 4335-4347 of record cited on 892 mailed 03/19/2025), Günther et al. ("Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung." European Journal of Pharmaceutics and Biopharmaceutics 77.3 (2011): 438-449 of record 892 03/19/2026), Goula, D., et al. ("Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system." Gene therapy 5.5 (1998): 712-717 of record 892 03/19/2026), Liu, Yu, et al. ("Biophysical characterization of hyper-branched polyethylenimine-graft-polycaprolactone-block-mono-methoxyl-poly (ethylene glycol) copolymers (hy-PEI-PCL-mPEG) for siRNA delivery." Journal of controlled release 153.3 (2011): 262-268 of record cited on 892 mailed 03/19/2025) and Kasper et al. ("Formulation development of lyophilized, long-term stable siRNA/oligoaminoamide polyplexes." European Journal of Pharmaceutics and Biopharmaceutics 85.2 (2013): 294-305 of record cited on 892 mailed 09/03/2024).
Regarding claims 52, 54-56, 63, 68, 69 and 86-87, EP 3 034 539 teach compositions comprising:(a) single stranded RNA; and (b) polyethyleneimine [see page 2] wherein the RNA encodes a protein, wherein the polyethyleneimine has a N:P ratio of 2 to 15 or 6 to 12 [see para. 0058, 0064] claim 86, wherein the molecular weight is from 1000 to 500,000 Da [see paragraph 0029], the polyethyleneimine is formulated in polyplex particles [see para. 0104, page 21] with a neural or slightly acidic [0073] claim 63, pH below 7.5 [0033] claim 55, 87 and has the general formula as in claims 54 and 56 [see page 18, claim 12]. EP 3 034 539 A1 teach the composition in an aqueous solution [0058] claims 68, 69. EP 3 034 539 does not teach a combination of long and short polyethyleneimine wherein the short has a mass of 0.6 to 11kDA and the long has a mass of 20 to 40 kDa.
Regarding claim 57, EP 3 034 539 A1 teach the polyethyleneimine are protonatable [0062] and it would have been obvious and within the skill of the artisan to determine the percentage of N atoms to develop the best carrier for the RNA, steps that are routine to one of skill in the art. MPEP 2144.05 sates “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Regarding claims 58-60, 64 and 67, EP 3 034 539 A1 further teach the composition comprises one or more additives [see para. 0067-0068, page 13], claims 58, is in a phosphate buffer solution [see page 0081], lipids [0056], ethylene glycol [0065], claim 59, 60 and wherein the single stranded RNA can be a long coding RNA of greater than 200 nt. [see para. 0043] claim 64. EP 3 034 539 teach compositions comprising peptides [0068] claim 67. EP 3 034 539 A1 on page 14 describes adjusting the ionic strength but does not specifically teach adjusting the strength to 25 mM or less that thereby increases the transfection rate.
Regarding claims 70-72, EP 3 034 539 A1 teach the composition is formulated for intramuscular administration to a subject and thus teach administration to a muscle cell [see para. 0082]. EP 3 034 539 teach also teach methods of treatment of disease such as cancer [0085]. EP 3 034 539 do not teach the RNA encodes a cancer antigen.
Regarding Claim 52 limitation of teach a combination of long and short polyethyleneimine and Claim 90, Debus et al. teach polyplexes with blends of short low molecular weight PEI(5kDa) and long PEI(25 kDa)–PEG(20kDa)1-block copolymer showed higher protein expression as compared with a single PEI(25 kDa) (abstract and page 341 second col.) and also combined the advantage of increased stabilization of an RNA molecule (see page 335 2nd para). It would have been obvious to one of ordinary skill in the art to try a combination of long and short polyethyleneimine wherein the short has a mass of 5kDA and the long has a mass of 25kDa in the claimed RNA composition given it has increased expression and stabilization as compared to a PEI at 25kDa which is used in EP 3 034 539 [see para. 0104, page 21].
Regarding claims 88 and 89, Debus et al. teach particle sizes in compositions comprising RNA polyplexes of PEI are generally below 200 nm (see page 337 3.2 and Fig. 2). Therefore it would have been obvious to use polyplexes less than 200 mm in a composition of EP 3 034 539 comprising a N:P ratio between 6 and 15 and a pH between 6 and 7.5.
Regarding the limitation of “ionic strength of the composition is 25 mM or less, thereby increases the transfection rate and claim 84, Rafael et al. teach polyplexes of oligonucleotides and polymers, such as PEI, buffer conditions wherein the complexes formed in low ionic strength conditions are usually smaller, more stable and have a lower tendency to aggregate (see page 769 section Cationic Polymers).
Gunther et al., who teach polyethyleneimines for delivery of siRNA, also states that buffer conditions during complexation are important with complexes formed in low ionic strength conditions (water, 5% glucose) being smaller and physically rather stable when compared to PEI complexes prepared in 150 nM saline (see page 440 second para.). Because both water and glucose are non-ionic compounds, the ionic strength of these compositions is zero. One of skill in the art would have been motivated to use buffer conditions with low ionic strength of 25 mM or less given both Rafael et al. and Gunther et al. teach the complexes were small and more stable with a lower tendency to aggregate.
Moreover, one of ordinary skill in the art would have expected that PEI compositions with low ionic strength would have increased transfection efficiency based on Goula et al. Goula et al. teach a PEI/DNA complex with N/P ratios of 2, 4 and 6 in 5% glucose (see Figure 1 and page 1291). Goula et al. found that PEI/DNA formed in NaCl were one order of magnitude less effective in transfection in the newborn brain that those formed in glucose (page 716 col. 2, para. 1). Not only did the prior art teach PEI compositions for nucleic acid delivery with 5% glucose (low ionic strength of 25 mM or less), but one would have been motivated to formulate the composition in 5% glucose for the advantage of increasing the transfection efficiency in view of Goula et al. Further one of skill in the art would have expected to get the same results using the claimed composition comprising PEI and RNA. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that it would have been obvious to use a known technique to improve a similar product in the same way.
Regarding claim 52, the specification describes the term “ionic strength” preferably relates to the presence of monovalent ions and the concentration of divalent ions can be 0 (20 nM or less)(see page 16 lines 8-15). Thus the limitation is met by Gunther et al. and Goula et al.
Regarding claims 61 and 62, Liu et al. teach using polyplexes comprising PEI and RNA oligonucleotides in buffer comprising HBG containing 5% glucose and 10 nM HEPES. (see page 263 2.7 and Fig. 4) and showed efficient delivery of the RNA to cells. Given Liu et al. teach using a composition with an ionic strength 25 mM or less, one would have used a buffer comprising HGB since it was shown it efficiently delivered RNA to cells.
EP 3 034 539 A1 does not teach lyophilization of the composition.
Regarding claims 74-82, Kasper et al. teach it was well known in the art that RNA PEI polyplexes can be lyophilized using % w/v of sucrose, trehalose, lactosucrose prepared in HEPES buffer and lyophilized and teach methods of preparing lyophilized compositions (see pages 295-296). It would have been obvious to use this method for preparing lyophilized compositions for optimal storage of the claimed composition and it would have been obvious to use routine optimization for find the right concentration of reagents for storage of the composition. MPEP 2144.05 sates “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claim(s) 52-82, 84 and 86-90 is/are rejected under 35 U.S.C. 103 as being unpatentable EP 3 034 539 A1 (ETHRIS GMBH [DE]) 22 June 2016 (2016-06-22 of record 04/11/2022 IDS), Debus et al. ("Delivery of messenger RNA using poly (ethylene imine)–poly (ethylene glycol)-copolymer blends for polyplex formation: Biophysical characterization and in vitro transfection properties." Journal of Controlled Release 148.3 (2010): 334-343 of record 892 03/19/2026), Rafael, Diana, et al. ("Lipoplexes and polyplexes: gene therapy." Encycl. Biomed. Polym. Polym. Biomater (2015): 4335-4347 of record 892 mailed 03/19/2025), Günther et al. ("Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung." European Journal of Pharmaceutics and Biopharmaceutics 77.3 (2011): 438-449), Goula, D., et al. ("Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system." Gene therapy 5.5 (1998): 712-717 of record 892 03/19/2026), Liu, Yu, et al. ("Biophysical characterization of hyper-branched polyethylenimine-graft-polycaprolactone-block-mono-methoxyl-poly (ethylene glycol) copolymers (hy-PEI-PCL-mPEG) for siRNA delivery." Journal of controlled release 153.3 (2011): 262-268 of record 892 mailed 03/19/2025), Kallen et al. (US 20160166678 of record IDS 04/11/2022) and Iavarone et al. ("Mechanism of action of mRNA-based vaccines." Expert review of vaccines 16.9 (2017): 871-881. teach the use of alphaviruses, such as VEEV to efficiently deliver RNA of record 892 mailed 03/19/2025).
Regarding claims 52-55, 63, 68, 69 and 87, EP3034 539 teach compositions comprising:(a) single stranded RNA; and (b) polyethyleneimine [see page 2] wherein the RNA encodes a protein, wherein the polyethyleneimine has a N:P ratio of 2 to 15 or 6 to 12 [see para. 0058, 0064] wherein the molecular weight is from 1000 to 500,000 Da [see paragraph 0029], is formulated for intramuscular administration [see para. 0082], the polyethyleneimine is formulated in polyplex particles [see para. 0104, page 21] with a neural or slightly acidic [0073] claim 63, pH below 7.5 [0033] claim 55, 87 and has the general formula as in claims 54, 56 with a weight average in the ranges claimed [see page 18]. EP 3 034 539 teach the composition in an aqueous solution [0058] claims 68, 69.
Regarding claim 57, EP3034539 A1 teach the polyethyleneimine are protonatable [0062] and it would have been obvious and within the skill of the artisan to determine the percentage of N atoms to develop the best carrier for the RNA, steps that are routine to one of skill in the art. MPEP 2144.05 sates “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claims 58-60, 64 and 67, EP3034 539 A1 further teach the composition comprises one or more additives [see para. 0067-0068, page 13], claims 58, is in a phosphate buffer solution [see page 0081], lipids [0056], ethylene glycol [0065], claim 59, 60 and wherein the single stranded RNA can be a long coding RNA of greater than 200 nt. [see para. 0043] claim 64. EP 3 034 539 teach compositions comprising peptides [0068] claim 67. EP 3 034 539 A1 on page 14 describes adjusting the ionic strength but does not specifically teach adjusting the strength to 25 mM or less that thereby increases the transfection rate. EP 3 034 539 does not teach a combination of long and short polyethyleneimine wherein the short has a mass of 0.6 to 11kDA and the long has a mass of 20 to 40 kDa.
Regarding Claim 52 limitation of teach a combination of long and short polyethyleneimine and Claim 90, Debus et al. teach polyplexes with blends of short low molecular weight PEI(5kDa) and long PEI(25 kDa)–PEG(20kDa)1-block copolymer showed higher protein expression as compared with a single PEI(25 kDa) (abstract and page 341 second col.) and also combined the advantage of increased stabilization of an RNA molecule (see page 335 2nd para). It would have been obvious to one of ordinary skill in the art to try a combination of long and short polyethyleneimine wherein the short has a mass of 5kDA and the long has a mass of 25kDa in the claimed RNA composition given it has increased expression and stabilization as compared to a PEI at 25kDa which is used in EP 3 034 539 [see para. 0104, page 21].
Regarding claims 61 and 62, Liu et al. teach using polyplexes comprising PEI and RNA oligonucleotides in buffer comprising HBG containing 5% glucose and 10 nM HEPES. (see page 263 2.7 and Fig. 4) and showed efficient delivery of the RNA to cells. Given Liu et al. teach using a composition with an ionic strength 25 mM or less, one would have used a buffer comprising HGB since it was shown it efficiently delivered RNA to cells.
Regarding claims 70-72, EP 3 034 539 A1 teach the composition is formulated for intramuscular administration to a subject and thus teach administration to a muscle cell [see para. 0082]. EP 3 034 539 teach also teach methods of treatment of disease such as cancer [0085].
Regarding the limitation of “ionic strength of the composition is 25 mM or less, thereby increases the transfection rate and claim 84, Rafael et al. teach polyplexes of oligonucleotides and polymers, such as PEI, buffer conditions wherein the complexes formed in low ionic strength conditions are usually smaller, more stable and have a lower tendency to aggregate (see page 769 section Cationic Polymers).
Gunther et al., who teach polyethyleneimines for delivery of siRNA, also states that buffer conditions during complexation are important with complexes formed in low ionic strength conditions (water, 5% glucose) being smaller and physically rather stable when compared to PEI complexes prepared in 150 nM saline (see page 440 second para.). Because both water and glucose are non-ionic compounds, the ionic strength of these compositions is zero. One of skill in the art would have been motivated to use buffer conditions with low ionic strength of 25 mM or less given both Rafael et al. and Gunther et al. teach the complexes were small and more stable with a lower tendency to aggregate.
Moreover, one of ordinary skill in the art would have expected that PEI compositions with low ionic strength would have increased transfection efficiency based on Goula et al. Goula et al. teach a PEI/DNA complex with N/P ratios of 2, 4 and 6 in 5% glucose (see Figure 1 and page 1291). Goula et al. found that PEI/DNA formed in NaCl were one order of magnitude less effective in transfection in the newborn brain that those formed in glucose (page 716 col. 2, para. 1). Not only did the prior art teach PEI compositions for nucleic acid delivery with 5% glucose (low ionic strength of 25 mM or less), but one would have been motivated to formulate the composition in 5% glucose for the advantage of increasing the transfection efficiency in view of Goula et al. Further one of skill in the art would have expected to get the same results using the claimed composition comprising PEI and RNA. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that it would have been obvious to use a known technique to improve a similar product in the same way.
Regarding claims 88 and 89, Debus et al. teach particle sizes in compositions comprising RNA polyplexes of PEI are generally below 200 nm (see page 337 3.2 and Fig. 2). Therefore it would have been obvious to use polyplexes less than 200 mm in a composition of EP 3 034 539 comprising a N:P ratio between 6 and 15 and a pH between 6 and 7.5.
Regarding claim 65, Kallen et al. teach a composition comprising :(a) single stranded RNA; and (b) polyethyleneimine [see para. 0128], wherein the N:P ratio is 0.1-10 [0123], wherein the single stranded RNA is an alphavirus replicon [see para. 0072], wherein the RNA comprises an open reading frame encoding a peptide or protein of interest, wherein the composition is formulated for use in therapy and is a vaccine composition [see para 0002]. Kallen et al. teach additives such as buffering substance, phosphate buffers and polysaccharides [0261, 0268]. Kallen et al. do not teach the alphavirus Venezuelan equine encephalitis (VEEV).
Regarding claim 66 and 73, Iavarone et al. teach the use of alphaviruses, such as VEEV to efficiently deliver RNA (see 3.2 page 875 and 4.1.3 page 875) wherein the RNA can encode a cancer antigen (see Table 1). Thus one of ordinary skill in the art would have wanted to use VEEV as the alphavirus in the methods of Kallen et al. with a reasonable expectation of success and would have been capable of using an RNA encoding a cancer antigen to treat cancer, as taught by EP 3 034 539 A1.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Response to Applicant’s Arguments
Applicant argues the claimed invention exhibits unexpected results over the cited references and is nonobvious because the claimed composition with "polyethyleneimine in a combination of a short polyethyleneimine and a long polyethyleneimine" exhibits an enhanced transfection efficacy and higher expression levels.
In response, this result is not unexpected in view of Debus et al. who teach polyplexes with blends of short low molecular weight PEI(5kDa) and long PEI(25 kDa)–PEG(20kDa)1-block copolymer showed higher protein expression as compared with a single PEI(25 kDa) (abstract and page 341 second col.) and also combined the advantage of increased stabilization of an RNA molecule (see page 335 2nd para). One of skill in the art would have expected that using the combination of long and short polyethyleneimine wherein the short has a mass of 5kDA and the long has a mass of 25kDa with the claimed RNA would have an increased transfection efficiency leading to higher expression. "Expected beneficial results are evidence of obviousness of a claimed invention” MPEP 716.02(c).
Conclusion
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).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636
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