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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on September 10, 2025, that includes a reply to the Final Office Action mailed November 9, 2022, has been entered. Claims 1 and 6 have been amended; claims 3, 5, and 13-24 have been canceled; and claims 25-31 have been newly added. Claim 12 has previously been withdrawn. Claims 26-29 are directed to non-elected species of blunt-hairpin RNA sequence (i.e. the elected species is SEQ ID NO. 1) and are thus hereby also withdrawn. Claims 1, 2, 4, 6-11, 25, 30, and 31 are under examination.
Withdrawal of Prior Objection - Specification
The disclosure has been satisfactorily amended. Moreover, Applicant’s argument with respect to claim-formatted material in the middle of the specification is being accepted. Therefore, the objection to the specification presented in the Final Office Action mailed November 9, 2022 is hereby withdrawn.
Abstract
The abstract of the disclosure remains objected to for the following:
1. The abstract should be a concise summary of the key technical aspects of the invention which are new to the art to which the invention pertains. If the invention is a composition, the abstract should recite the key requisite ingredients. The abstract appears to inform the reader that the invention is porous silica particles carrying RNA in the pores. This is generally not new to the art at all. While the abstract mentions that the composition “may include” blunt-ended hairpin RNA, this element appears to be optional, and not a key requisite ingredient of the invention.
3. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art. However, this is precisely what the abstract appears to do, with the phrase “to sufficiently support the RNA and stably deliver the supported RNA into the body”. The invention appears to pertain to a composition, and the abstract should merely inform the reader of the requisite key ingredients of the composition. The abstract is not intended to be a promotional ad for the composition.
Correction is required. See MPEP § 608.01(b).
Claim Objections
Claim 1 is objected to because of the following:
1. Claim 1 contains an extraneous colon between “comprising” and “a blunt-ended”. The colon would be proper if e.g. there was a complete sentence before the colon, or e.g. if the claim was in bulleted format, but neither is the case here.
2. There should be a semicolon between “formula 1” and “wherein”.
3. The entire section starting from the line stating “wherein P is a phosphoric acid group” to the line stating “of the porous silica particles being positively charged” is in improper English grammatical format, with improper punctuation, extraneous “and” in places, and missing “and” in other places.
4. There should be a semicolon rather than a comma between “positively-charged” and “wherein”, between “14 to 100 nt” and “wherein”, and between “5 to 65 mV” and “wherein”.
5. There should be an “and” between “5 to 65 mv,” and “wherein a weight ratio”.
Appropriate correction is required.
Applicant demands that a legal statute or MPEP rule be provided for this issue. The basis of this issue is not a U.S. Patent statute, U.S. Supreme Court decision or other case law, or even the MPEP. The basis is simply English grammar. Moreover, in stark contrast to Applicant’s assertion, there is no bulleted list. The colon appears in the middle of a single, complete sentence reciting one element which the composition contains. There is no bulleted list.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 6-11, 25, 30, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Brinker et al. (U.S. Patent Application Pub. No. 2016/0287717), in view of Yong et al. (Frontiers in Immunology. 2018; 9: 1-9).
Applicant Claims
Applicant’s elected subject matter is directed to a composition comprising i) a blunt-ended hairpin RNA with formula 5’-Pa-SEQ ID NO 1-3’, wherein P is a phosphoric acid group and a is 2-4; and ii) porous silica particles with diameter of 50-500 nm, an average pore diameter 7-25 nm, a zeta potential of 10-70 mV, and a BET surface area of 280-680 m2/g; wherein the porous silica particles carry the blunt-ended hairpin RNA in the pores, and the weight ratio of the particles and the blunt-ended hairpin RNA is 1:5-20.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Brinker et al. disclose a composition comprising e.g. i) hairpin RNA, and ii) mesoporous silica nanoparticles with diameter of 5-500 nm, an average pore diameter 0.5-25 nm, preferably a cationic zeta potential of e.g. 10-40 mV, and a BET surface area of 100-1,000 m2/g; wherein the porous silica particles carry the hairpin RNA in the pores, the weight ratio of the hairpin RNA to the particles can be e.g. 1:19, and wherein the composition is employed in e.g. treating viral infections (abstract; paragraphs 0003, 0006, 0007, 0009, 0011, 0015, 0016, 0070, 0071, 0073, 0080, 0099, 0100).
Yong et al. disclose that 5’pppRNA is an effective antiviral agent shown to stimulate host antiviral response via RIG-1 specific activation, that hairpin RNA species triggered a potent interferon response and were more potent that oseltamivir against influenza A H1N1, and that an effective RNA sequence shown to target RIG 1 to stimulate a robust IFN 1 response, and which is regarded as a promising antiviral and viral vaccine adjuvant, is 5’-GGAUCGAUCGAUCGUUCGCGAUCGAUCGAAUCC-3’.
Ascertainment of the Difference Between the Scope of the Prior Art and the Claims (MPEP §2141.02)
Brinker et al. do not explicitly disclose that the hairpin RNA has a sequence covered by Formula 1. This deficiency is cured by the teachings of Yong et al.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious for one of ordinary skill in the art at the time the present application was filed to combine the respective teachings of Brinker et al. and Yong et al., outlined supra, to devise Applicant’s presently claimed composition.
Brinker et al. disclose a composition comprising e.g. i) hairpin RNA, and ii) mesoporous silica nanoparticles with diameter of 5-500 nm, an average pore diameter 0.5-25 nm, preferably a cationic zeta potential of e.g. 10-40 mV, and a BET surface area of 100-1,000 m2/g; wherein the porous silica particles carry the hairpin RNA in the pores, the weight ratio of the hairpin RNA to the particles can be e.g. 1:19, and wherein the composition is employed in e.g. treating viral infections. Since Yong et al. disclose that 5’pppRNA is generally an effective antiviral agent shown to stimulate host antiviral response via RIG-1 specific activation, that hairpin RNA species in particular triggered a potent interferon response and were more potent that oseltamivir against influenza A H1N1, and that an effective RNA sequence shown to target RIG 1 to stimulate a robust IFN 1 response, and which is regarded as a promising antiviral and viral vaccine adjuvant, is 5’-GGAUCGAUCGAUCGUUCGCGAUCGAUCGAAUCC-3’; one of ordinary skill in the art would thus be motivated to employ a hairpin 5’pppRNA containing the sequence 5-GGAUCGAUCGAUCGUUCGCGAUCGAUCGAAUCC-3’ or a very similar sequence suitable for the formation of the optimal hairpin RNA structure, with the reasonable expectation that the resulting composition will effectively stimulate a host antiviral response via RIG-1 specific activation for the successful treatment of a viral infection.
Brinker et al. disclose that the optimal loading of cargo is about 0.01-10% (see paragraph 0099). With a cargo load of e.g. 5%, the mesoporous silica nanoparticles thus represent 95%, and the weight ratio is 1:19, which falls within the claimed range of 1:10-20.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive.
i) Applicant contends that “neither Brinker nor Yong discloses or suggests that a blunt-ended hairpin RNA of 14-100 nucleotides is carried in silica pores that are both 7-25 nm in diameter and internally positively charged”; that “Brinker mentions general cargo loadings” but “does not disclose” a “weight ratio of RNA to particles of 1:5-20”; that “efficient and stable loading of blunt-ended hairpin RNA requires a specific balance between pore charge, RNA length, and RNA:particle ratio” and “the claimed 1:5-20 ratio was not arbitrarily chosen, it is ties to achieving stable electrostatic interaction between the negatively charged phosphate backbone of the RNA and the positively charged inside pore surfaces”; that “Brinker is silent on RNA:particle ratio as a parameter for RNA stability…it does not identify RNA length, pore internal charge, or loaded zeta potential as relevant to ratio selection”; that “claim 25 requires covalently bound alkoxysilane-derived amine groups on the inside pore surfaces, functionalized after surfactant removal” and “Brinker describes functionalization before surfactant removal, leaving pores blocked, and provides no teaching of enhanced loading efficiency”; that “claim 30 specifies reagents…applied after surfactant removal” and “Brinker teaches the addition of these reagents before surfactant removal, preventing internal modification”; and that “claim 31 requires 10-40 mV specifically at pH 7.4” and “Brinker does not disclose measurements at physiological pH”.
The Examiner, however, would like to point out the following:
1. First, it is noted that newly added claims 26-29 are directed to non-elected subject matter and are thus now withdrawn. Newly added claims 25 and 30 are product-by-process claims. Brinker also discloses that their surface contains alkoxysilane-derived amine groups that impart a positive charge, and Brinker also removes the surfactant. While Applicant’s product-by-process includes adding the surface amine groups after surfactant removal, while Brinker’s product is made by adding the surface amine groups with surfactant present and then subsequently removing the surfactant, Applicant has not established with any hard evidence that their product is significantly different from the Brinker product in any way whatsoever. Newly added claim 31 stipulates in a wherein clause that “the zeta potential of the porous silica particles carrying the blunt-ended hairpin RNA in the pores is 10 to 40 mV at pH 7.4. This is simply a property of the product. One of ordinary skill in the art, in following the teachings and reasonable suggestions of the cited prior art would thus arrive at the presently claimed product. The Patent Trial and Appeal Board has affirmed this position. Since the product is the same, it can only be concluded that the properties must be the same as well, absent hard evidence to the contrary. Applicant has not established with any hard evidence that the product one of ordinary skill in the art would thus arrive at following the teachings and reasonable suggestions of the cited prior art would not have a zeta potential 10-40 mV at pH 7.4.
2. All limitations presented in claims 1, 2, 4, 6-9, 10, and 11 have already been addressed in prior actions. The 35 USC 103 rejection has been affirmed by the Patent Trial and Appeal Board. Applicant’s claimed product is prima facie obvious in view of the cited prior art. Brinker’s product can comprise e.g. i) hairpin RNA, and ii) mesoporous silica nanoparticles with diameter of 5-500 nm, an average pore diameter 0.5-25 nm, preferably a cationic zeta potential of e.g. 10-40 mV, and a BET surface area of 100-1,000 m2/g; wherein the porous silica particles carry the hairpin RNA in the pores, the weight ratio of the hairpin RNA to the particles can be e.g. 1:19, and wherein the composition is employed in e.g. treating viral infections. Yong discloses that an effective RNA sequence shown to target RIG 1 to stimulate a robust IFN 1 response, and which is regarded as a promising antiviral and viral vaccine adjuvant, is 5’-GGAUCGAUCGAUCGUUCGCGAUCGAUCGAAUCC-3’. It would no doubt be obvious to employ Yong’s specific blunt-ended hairpin RNA as the hairpin RNA in Brinker to arrive at a product that is not patentably distinct from the claimed product.
3. Hence, one of ordinary skill in the art in following the teachings and reasonable suggestions of the cited prior art, would thus arrive at the claimed product, and this is sufficient to preclude the patentability of the claimed product. The cited prior art need not disclose Applicant’s specific reasons for combining the various elements to arrive at the claimed product. Indeed, one of ordinary skill in the art may have their own motivations for combining the various requisite elements. The cited prior art also need not disclose that “the RNA:particle ratio is important for RNA stability”, and that “RNA length, pore internal charge, or loaded zeta potential are relevant to the RNA:particle ratio selection”. Indeed, it is noted that the product one of ordinary skill in the art would thus arrive at from following the cited prior art would have the claimed RNA length, the required charge, and, as has been readily calculated, the required RNA:particle ratio. Indeed, if, as Applicant contends, “efficient and stable loading of blunt-ended hairpin RNA requires a specific balance between pore charge, RNA length, and RNA:particle ratio”, then the product one of ordinary skill in the art would thus arrive at would also have the required “efficient and stable loading”, even if the cited prior art does not expressly disclose this phrase verbatim.
Furthermore, comments presented in the Examiner’s Answer are repeated here for further clarity of the Office’s position:
1. In stark contrast to Appellant’s assertion, paragraph [0132] of Brinker never actually discloses anywhere at all that the pore surface is not positively charged, should not be positively charged, and/or cannot be positively charged. This is Appellant’s own limitation, not Brinker’s, which has been imposed without concrete scientific evidence. Indeed, Appellant appears to be relying on Fig. 1AX for their position that paragraph [0132] provides for an embodiment wherein the pore surface is not positively charged. However, Fig. 1AX is really nothing more than a simple cartoon drawing that has no real scientific rigor or merit in definitively establishing the truth as to whether the pore surface is actually positively charged or not in Brinker’s example 2. Rather, Fig. 1AX is obviously intended to merely help illustrate the basic idea. But, of course, anyone who understands the difference between the real world and simplified cartoon drawings would, without question, understand that Fig. 1AX cannot support Appellant’s argument that the pore surface is absolutely not positively charged any more than it could support an assertion that the actual chemical structure of PEI is a little squiggly line. Moreover, paragraph [0132] pertains to but merely one specific example in Brinker, i.e. example 2. Brinker, however, is not limited to example 2, or to any of the other examples or preferred embodiments, and these do not constitute a “teaching away” from the broader disclosure and even the non-preferred embodiments.
2. Brinker discloses mesoporous silica nanoparticles. Anyone who understands mesoporous silica will immediately know that the pores are like little pockets or indentations in the surface of the silica particle. Mesoporous silica is thus different from a capsule, in which there is an external shell and an internal core. In mesoporous silica particles, the pore surface is continuous with the “external” surface, and typically no distinction is made between these surfaces. Consistent with this basic understanding of mesoporous silica particles, Brinker never makes any distinction between an “external” or “outer” surface and a “pore” surface of the particles. Brinker merely discusses the “surface” generally. More to the point, Brinker never makes any distinction between an “external” or “outer” surface charge and a “pore” surface charge. Brinker merely discusses a surface charge. Hence, in stark contrast to Appellant’s mischaracterization of Brinker, Brinker discloses that “the surface” can be positively charged (i.e. cationic), but Brinker does not, as Appellant would want us to believe, stipulate that the “outer surface” in particular, as opposed to the “pore surface”, can be positively charged. Brinker simply never teaches that the “outer surface” can be positively charged, while the “pore surface” must not be positively charged.
3. What does Brinker actually teach about surface charge distribution? Brinker expressly teaches a “uniform spatial distribution of charge” or simply “a uniform surface charge distribution” (see e.g. paragraphs 0006, 0009). Further, paragraph [0074] states that “the term “uniform surface” is used to describe a surface which contains a uniform surface charge. Uniform surfaces occur for MSNPs (preferably PEgylated) which contain quaternary amines such as the charge is consistently projected on the whole surface of the MSNP without appreciable patches or gaps in the surface charge”. In other words, a uniform surface charge would be understood to mean a consistent and uniform distribution of charges “on the whole surface of the MSNP”, that is “without appreciable patches or gaps”. Again, Brinker does not make any distinctions at all between the “outer surface” and the “pore surface”, but simply talks about the surface as a whole. Again, as already noted, supra, as anyone who understands anything about mesoporous silica particles would immediately understand, the “outer surface” and the “pore surface” are simply one continuous surface. Hence, if Brinker discloses a uniform charge distribution “on the whole surface of the MSNP without appreciable patches or gaps” this means the entire surface including the “pore surface”. It is noted that Brinker also provides embodiments in which there is a “non-uniform” surface charge distribution. However, as also noted, supra, an example of a “non-uniform” surface charge distribution does not teach away from the broader disclosure. Brinker clearly and without question expressly teaches a uniform surface charge distribution, as just discussed, and a uniform surface charge distribution is obvious.
4. Furthermore, Brinker discloses that the mesoporous silica particles as a whole are preferably about 10-100 nm in size, while the pores are from about 1-20 nm in diameter (see e.g. paragraph [0070]). Clearly and without question, the pores are absolutely large enough to contain PEG-silane and PEI-silane. The pores are even large enough to contain PEG-silane or PEI-silane, and surfactant (i.e. CTAB), simultaneously. Appellant’s argument that since the pores contain surfactant they somehow would not be able to also contain the PEG-silane or PEI-silane just doesn’t seem to really make any sense. Finally, Appellant makes the assertion that “in the claimed invention, since the blunt-ended hairpin RNA having phosphoric acid groups at their ends thus having a negative charge is carried in the pores, an inside pore surface of the porous silica particles is modified to have a positively charge”. It’s not entirely clear what Appellant means by this point. However, if Appellant is asserting a cause-effect relationship, such that the mere presence in the pores of the “blunt-ended hairpin RNA having phosphoric acid groups at their ends” itself produces the positive charges on the pore surface that Appellant refers to, then it should be pointed out that Brinker has not been cited for individually anticipating the claimed subject matter under 35 USC 102. Rather, the prior art rejection is under 35 USC 103, based on the combination of Brinker and Yong. One of ordinary skill in the art, in following the express teachings and reasonable suggestions of the cited prior art, would thus arrive at the claimed composition with a reasonable expectation of success, as discussed in the 35 USC 103 rejection. Since one of ordinary skill in the art would arrive at a composition that is the same as the claimed composition, the properties must be the same as well, including the claimed positive charge on the pore surface induced by the presence in the pores of the “blunt-ended hairpin RNA having phosphoric acid groups at their ends”.
5. In summary, then, Brinker expressly discloses a uniform surface charge distribution such as the charge is consistently projected on the whole surface of the MSNP without appreciable patches or gaps in the surface charge. Consistent with the general understanding in the art, Brinker never makes any distinction whatsoever between the “outer surface” and the “pore surface”, since these are understood to be one continuous surface, and, in stark contrast to Appellant’s assertion, never states that the “outer surface” is positively charged, while the “pore surface” is not positively charged, or should not be positively charged. More to the point, paragraph [0132] never actually discloses that the “pore surface” is not positively charged or cannot be positively charged. The cartoon of Fig. 1AX cannot support Appellant’s argument that the pore surface is absolutely not positively charged any more than it could support an assertion that the actual chemical structure of PEI is a little squiggly line. Finally, Brinker discloses pores that are 1-20 nm in diameter, a size certainly larger enough to contain PEG-silane or PEI-silane, with or without surfactant. Hence, Appellant’s argument that since the pores contain surfactant, they somehow would not be able to also contain the PEG-silane or PEI-silane just doesn’t seem to really add up and make any sense.
For the foregoing reasons, the 35 USC 103 rejection is hereby maintained.
Conclusion
No claims are allowed.
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/DAVID BROWE/Primary Examiner, Art Unit 1617