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 claims
The amendment filed on July 30, 2026 is acknowledged. Claims 1-21 and 26 have been canceled and claims 36-37, 39-40 and 42 have been withdrawn. Claims 22-25, 27-35, 38, and 41 are under examination in the instant office action.
Applicants' arguments, filed on July 30, 2026, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied in view of the amendments. They constitute the complete set presently being applied to the instant application. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Claim Rejections - 35 USC § 103
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 of this title, 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.
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.
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 22-23, 27-35, 38, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/143555 (hereafter, SAHIN; cited in the IDS filed on 5/31/2024) in view of Tanaka et al. (Expert Opinion on Drug delivery, 13 (7): 1015-1027, 2016).
SAHIN teaches a pharmaceutical composition comprising nanoparticles which comprises at least one cationic lipid such as 1,2-dioleoyl- 3-trimethylammonium-propane (DOTAP) and l, 2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and at least one help lipid (neutral lipid) such as l ,2-di-(9Z-octadecenoyl)-sn- glycero-3-phosphoethanolamine (DOPE), and 1 ,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), wherein the nanoparticles are loaded with a nucleic acid such as RNA (e.g., mRNA) (claims 1, 4, 6-9, and 11).
SAHIN further teaches that the molar ratio of the at least one cationic lipid to the at least one helper lipid is from 10:0 to 3:7, preferably 9: 1 to 3:7, 4: 1 to 1 :2, 4: 1 to 2:3, 7:3 to 1:1, or 2:1 to 1:1, preferably about 1:1 (claim 10). SAHIN specifically discloses nanoparticles of lipoplexes comprising DOTMA (quaternary ammonium) and DOPE (F4) liposomes (a molar ratio of DOTMA: DOPE= 1:1) and RNA, which are devoid of cholesterol or any steroid (p64, Example 2, F4).
In addition, SAHIN discloses that the positive charges are contributed by the at least one cationic lipid and the negative charges are contributed by the RNA (p6, para 1). SAHIN further discloses that the charge ratio of positive charges in DOTMA to negative charges in the RNA is 1.8:2 to 0.8:2, more preferably 1.6:2 to 1:2, even more preferably 1.4:2 to 1.1 :2 and even more preferably about 1.2:2 (p7, para 3-4). Since the positive charge is attributed to the number of amine functions of the lipids and the negative charge to the number of phosphate molecules as evidenced by the instant specification (see [0107]), the charge ratio of positive charge in DOTMA (lipid) to negative charge in the RNA disclosed in SAHIN (e.g., 1:2) meets the ratio of the number of amine functions of the lipids to the number of phosphate molecules of the nucleic acid (RNA) recited in instant claim 41 as amended.
SAHIN does not specifically teach LNP nanoparticles further comprising at least one pH-sensitive lipid which differs from the cationic lipid, including the elected species. (COATSOME® SS-M).
Tanaka et al. teach cellular environment-responsive nanomaterials for use in gene and siRNA delivery (title). Tanaka et al. further teach that since the endosome and cytoplasm are acidic (endosome) and reducing (cytoplasm) environments, respectively, a large variety of the materials have been developed that induce destabilization of endosome via its protonation, or are spontaneously collapsed in the cytoplasm (abstract). Tanaka et al. teach that the best combination of the current designs for nanoparticle carrier is theoretically a ‘neutral’ particle that mounts multi-functions of pH-triggered endosomal membrane destabilization and spontaneous collapse in response to a reducing environment (p1011, col 2, section 5.1). Tanaka et al. further teach that in an attempt to develop such a carrier, a SS-cleavable proton-activated lipid-like material (ssPalm) is developed (p1011, col 2, section 5.1). The ssPalm is functionalized so as to contain dual-sensing motifs that can respond to the intracellular environment; tertiary amines as a positively charged unit in response to an acidic compartment (endosome/lysosome) for membrane destabilization, and disulfide bonding as a reducing environment-triggered cleavage unit (abstract and section 5.1). As a first-generation ssPalm, myristic acid (C14) was employed as a hydrophobic scaffold (ssPalmM) (
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) (p1022, col 1, para 2 and Fig. 4), which is the elected compound for pH-sensitive lipid. The LNPs prepared with ssPalmM (LNPssPalmM) showed a higher gene transfection activity in the presence of serum, in comparison with the LNP prepared with DODAP and has low cytotoxicity (p1022, col 1, para 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further add the pH sensitive lipid such as ssPalmM (also known as COATSOME® SS-M) taught by Tanaka et al. for the LNPs of SAHIN because of the following reasons. SAHIN already teaches the use of one or more cationic lipids. Also, Tanaka et al. teach the cationic lipid such as ssPalmM having two tertiary amino groups and two lipid moieties, and a biodegradable group such as disulfide bond is advantageous for gene delivery because the disulfide bond contained in the compound is cleaved in the intracellular reductive environment and release of the encapsulated substance (nucleic acid) is promoted due to the destabilization of the lipid membrane structure. Thus, one of ordinary skill in the art would have been motivated to do so for preparing LNPs having advantageous properties taught by Tanaka et al. on the reasonable expectation that the addition of ssPalmM would provide LNPs having multi-functions of pH-triggered endosomal membrane destabilization and spontaneous collapse in response to a reducing environment, thereby improving efficiency of intracellular delivery of RNA while reducing cytotoxicity.
As to the mole ratio of the cationic lipid to the other lipids, SAHIN already teaches the molar ratio of the at least one cationic lipid to the at least one helper lipid is from 2:1 to 1:1, preferably about 1:1. Also, SAHIN teaches that most natural membranes are negatively charged, and therefore the attractive electrostatic interaction between the positively charged lipoplexes and the negatively charged biomembrane may play a role in cell binding and uptake of the lipoplexes (p1, para 3). In addition, SAHIN teaches that electro-neutral or negatively charged lipoplexes from RNA and liposomes lead to substantial RNA expression in spleen DCs after systemic administration (p3, para 3). Thus, one of ordinary skill in the art would have readily optimized the molar ratio of the cationic lipid to the other lipids for obtaining LNPs with optimal charge in order to provide sufficient uptake of RNA and to improve RNA expression in spleen DCs after systemic administration. In addition, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[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); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/143555 (hereafter, SAHIN) in view of Tanaka et al. (Expert Opinion on Drug delivery, 13 (7): 1015-1027, 2016) in further view of US 2022/0117902 (hereafter, LERNER).
SAHIN and Tanaka et al. as applied supra are herein applied for the same teachings in their entirety.
They do not teach the nanoparticles covered with anionic polysaccharide such as hyaluronic acid recited in claim 24-25.
LERNER teaches a lipid nanoparticle (LNP) comprising a cationic lipid such as DOTAP and a neutral lipid such as DOPE, wherein the LNP is loaded with a synthetic RNA viral genome encoding an oncolytic virus ([0011], [0007], and claims 1 and 28). US 2022/0117902 teaches that the nanoparticle is coated with a glycosaminoglycan (GAG) such as hyaluronic acid (HA) in order to modulate or facilitate uptake of the nanoparticle by target cells ([0176] and FIG. 2). In a particular embodiment, the surface of the nanoparticle is coated with HA and targets the particles for uptake by tumor cells ([0176]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to coat the nanoparticles with hyaluronic acid because coating LNPs with hyaluronic acid was taught to modulate or facilitate uptake of the LNPs by target cells as evidenced by LERNER. Thus, one of ordinary skill in the art would have been motivated to do so for targeted delivery of the LNPS on the reasonable expectation that the resulting nanoparticles would improve uptake of the LNPs by target cells such as tumor cells.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, it is concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
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 before the effective filing date of the claimed invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Response to Applicants’ argument:
Applicant argued that while the nanoparticles of SAHIN comprise a cationic lipid such as DOTAP or DOTMA and a helper lipid (neutral lipid) such as DOPE, they do not comprise a pH-sensitive lipid as required by claim 22. Applicant further argued that Tanaka et al. discuss ssPalm in the context of developing neutral particles specifically designed to avoid cationic materials and do not suggest adding ssPalm to cationic lipid formulation like SAHIN’s nanoparticles comprising one cationic lipid and one neutral lipid. Applicant further argued that the rationale for developing ssPalm was to overcome the well-documented drawbacks of cationic carriers, thus a person of ordinary skill in the art would understand that ssPalm was developed as an alternative to cationic lipid formulations not as an additive thereto. In addition, Applicant argued that the example supporting the experimental data supporting ssPalmM’s gene transfection activity comprises cholesterol as evidenced by Akita et al., which is cited by Tanaka et al.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is important to note that in an obvious rejection, it is not necessary that one reference addresses any limitation in a particular claim but that the references, when combined, do so.
In this case, SAHIN already teaches and suggests the use of at least one cationic lipid for the nanoparticles, thus, the nanoparticles of SAHIN encompass those comprising more than one cationic lipid. Tanaka et al. teach that ssPalm is functionalized so as to contain dual-sensing motifs that can respond to the intracellular environment; tertiary amines as a positively charged unit in response to an acidic compartment (endosome/lysosome) for membrane destabilization, and disulfide bonding as a reducing environment-triggered cleavage unit (see p1021, last para-p1022, para 1 and Fig. 4). Tanaka et al. further teach the LNPs prepared with ssPalmM (LNPssPalmM) showed a higher gene transfection activity in the presence of serum, in comparison with the LNP prepared with DODAP and has low cytotoxicity (see p1022, col 1, para 2). Thus, one of ordinary skill in the art would have recognized ssPalm as a cationic lipid having some advantageous properties. In addition, while Tanaka et al. disclose some drawbacks of cationic materials as Applicant argued, Tanaka et al. also disclose the merits of the use of a cationic material: first, they permit DNA and nucleic acids to be easily compacted into a nanosized particle, and second, the extensive compaction of DNA and nucleic acids with a high charge (+/–) ratio confers strong electrostatic associations with negatively charged constituents, such as heparan sulfate proteoglycans on the cellular surface, thus resulting in an enhanced cellular uptake (see p1021, para 1). Therefore, one of ordinary skill in the art would have been motivated to add the pH sensitive lipid such as ssPalmM (also known as COATSOME® SS-M) taught by Tanaka et al. for the LNPs of SAHIN on the reasonable expectation that the addition of ssPalmM would provide LNPs having multi-functions of pH-triggered endosomal membrane destabilization and spontaneous collapse in response to a reducing environment, thereby improving efficiency of intracellular delivery of RNA with reduced cytotoxicity while retaining the merits of the use of a cationic lipid (e.g., enhanced cellular uptake).
“[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. “[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal-and even common-sensical-we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references.” Id. at 1368, 80 USPQ2d at 1651.
Consistent with this reasoning, the skilled artisan, who is aware of the teachings of SAHIN and Tanaka et al., would have been motivated to use a cationic lipid such as DOTAP in combination with a pH-sensitive lipid such as ssPalmM (also known as COATSOME® SS-M) taught by Tanaka et al. for preparing nanoparticles on the reasonable expectation that the resulting nanoparticles would possess merits of both lipids taught by Tanaka et al. One having ordinary skill in the art would have been motivated to combine these references and make the modification because they are drawn to the same technical fields (nanoparticles for delivery of nucleic acid such as RNA), and pertinent to the problem which applicant concerns about. MPEP 2141.01(a).
In response to the argument as to Akita et al., while Applicant stated that Akita et al. reference is submitted concurrently herewith as Annex 1, it is noted that the Akita article was not provided and thus could not be considered. Also, the test for obviousness is not whether the feature of one reference may be bodily incorporated into the other to produce the claimed subject matter but simply what the combination of references makes obvious to one of ordinary skill in the pertinent art. See In re Bent, 52 CCPA 850, 144 USPQ 28 (1964); In re Nievelt , 179 USPQ 224 (CCPA 1973). In this case, SAHIN specifically discloses nanoparticles which are devoid of cholesterol or any steroid. Also, one of ordinary skill in the art would have recognized that cholesterol is a neutral lipid along with DOPE as evidenced by SAHIN (claim 9) and thus one of ordinary skill in the art would have recognized that it would not be required for the nanoparticles which already comprise the other neutral lipid such as DOPE. The examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). It is also noted that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
As to the alleged unexpected results, it is noted that it is applicant's burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be "clear and convincing" In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
In the instant case, the alleged unexpected and superior effect of the claimed nanoparticles is not commensurate in scope with the claims. The rejected claims encompass the use of any cationic lipid, any neutral lipid, and any pH-sensitive lipid at any N/P ratio. However, the tested nanoparticles in Fig, 6 are limited to a specific cationic lipid (DOTAP), a specific neutral lipid (DOPE), and a specific pH-sensitive lipid (Coatsome SS-M or Dlin-MC3-DMA) at the specific N/P ratios (1.5 or 3). The genus of cationic lipids, neutral lipids, and pH-sensitive lipids encompass those having distinct chemical strictures and different physical/biological properties. The results of limited examples (only two examples) do not provide sufficient evidence of the alleged unexpected effects for all the possible combinations encompassed by the claim. Thus, the evidence is insufficient to rebut the prima facie case of obviousness since a skilled artisan could not ascertain a trend in the exemplified data that would allow him to reasonably extend the probative value thereof to the entire scope of the subject matter claimed.
For the foregoing reasons, Applicant’s arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
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 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.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
