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 .
Election/Restrictions
Applicant’s election without traverse of arginines for D, SEQ ID NO:1 for C, and mRNA for oligonucleotide in the reply filed on July 3, 2026 is acknowledged.
Status of Claims
Claims 1-6, 8-10, and 12-22 are pending in the instant application. Claims 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Accordingly, claims 1-6, 8-10, and 14-22 are under examination on the merits in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 5, 2023, January 18, 2024, July 2, 2025, May 16, 2026, and August 9, 2026 have been considered by the examiner. Note that the non-English language NPL citation number 1 documents in each of IDS filed on July 2, 2025 and August 9, 2026 are not considered as the foreign language cannot be considered.
Claim Objections
Claim 9 is objected to because of the following informalities: “and oligonucleotide” should be “and an oligonucleotide”. Appropriate correction is required.
Claim 20 is objected to because “in which used to treat or prevent cancer or inflammatory diseases” is grammatically incorrect.
Claim 22 is objected to because “in which used to treat or prevent a disease” is grammatically incorrect.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10, 14, 17, and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
The term “oligonucleotide” in claims 10, 14, and 17 is used by the claims to mean “mRNA”, which is not deemed an “oligonucleotide” in the relevant art. The term “oligonucleotide” is conventionally understood to mean a relatively short chain of nucleotides such that “oligonucleotides may range from about 10 to 100 nucleotides in length.” See page 36 of Manoharan et al. (WO 2010/054401 A1, applicant’s citation). Hence, claims 10, 14, and 17 recite structurally conflicting limitations, thereby rendering the claims indefinite.
Claim 22 recites “a disease selected from the group”, wherein all of the disease species (e.g., “cleft palate” and “refractive error”) within the group are not deemed “inflammatory diseases” recited in claim 20, from which claim 22 depends. As such, claim 22 recites internally conflicting limitations pertaining to the “inflammatory diseases”.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8-10, and 14-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant specification is completely silent regarding the actual structural limitations for each of A, B, C, D, and E, forming the claimed “peptide-lipid conjugate”, which is used in Examples 3-5 to make the nanoparticles comprising an mRNA. That is, Examples 3-5 merely mention “peptide-lipid conjugate” by words only without any adequate description of what constitutes each of A, B, C, D, and E. The specification allegedly discloses “the peptide-lipid conjugate prepared in Example 1” (see paragraph 98); however, the actual peptides for the “peptide” portion and the actual lipid for the “lipid” portion are completely concealed thus are not adequately described in sufficient detail. As such, it remains unknown and undisclosed which structure for each of A, B, C, D, and E in “Formula 1”, allegedly forming the “peptide-lipid conjugate”, was used in order to form nanoparticles with an mRNA, which is claimed to be delivered “into cells” and also form a “pharmaceutical composition” for treating/preventing cancer and inflammatory diseases.
In view of the concealed information that should have been clearly disclosed in the specification “in such full, clear, concise, and exact terms” as required by 35 U.S.C. 112(a), it is impossible for any person of ordinary skill in the art to determine which species within the claimed genus of “Formula 1” forms a complex/nanoparticle with an mRNA, which is to be delivered to into cells and provide pharmaceutical function. Indeed, it is even impossible to conclude that “Formula 1” was indeed used in Examples 3-5 as there is no supporting description in sufficient detail. Accordingly, the instant specification fails to contain “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms”, thereby failing to comply with the written description requirement under 35 U.S.C. 112(a).
In addition to the undisclosed structure of “the peptide-lipid conjugate prepared in Example 1”, the instant specification does not appear to adequately describe that SEQ ID NO:16 for “E” is a peptide that recognizes any and all types of target cell surface as broadly and generically claimed. Even more interestingly, the specification does not even describe/identify which target cell surface is recognized by SEQ ID NO:16. Now, note that SEQ ID NO:16 is not disclosed in any of the prior art searched and examined by the examiner, nor is it disclosed in any of the references cited by applicant’s IDS filed in this application. That is, there is no prior art information pertaining SEQ ID NO:16 and as such, the instant specification must provide adequate written description support as to which target cell surface is recognized by SEQ ID NO:16 so as to adequately support that SEQ ID NO:16 is representative of the entire genus of all different types of target cell surface. See MPEP §2163 teaching that “there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement. Information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed.” (emphasis added). It is art-recognized knowledge that a specific target cell surface is recognized by a specific peptide sequence. See for instance Tiwari et al. (International Journal of Pharmaceutics, 2017, 531:281-291) teaching that “the peptide sequence LTVSPWY” can “specifically bind to breast cancer cells”, whereas the “peptide VRPMPLQ” is “capable of identifying malignant tissues in the human colon” thus can specifically bind to “adenocarcinoma of the colon.” See pages 281 and 289. In the instant case, the instant specification fails to adequately describe that SEQ ID NO:16 recognizes all different types of cell surface as claimed and encompassed by the instant claims, nor does it clearly identify which specific target cell surface is recognized by SEQ ID NO:16, which is the single peptide sequence that is disclosed for “E”.
Again, as noted above, the instant specification does not disclose any specific written description of the exact structure of Formula 1 used in encapsulating and delivering an mRNA into cells. That is, the specification is silent as to which “fatty acid or cationic lipid having 12 to 20 carbon atoms” (see “A”) is actually used to form a complex with an mRNA, and furthermore, the specification fails to adequately describe that any and all fatty acid/cationic lipid having 12-20 carbon atoms are capable of forming a peptide-lipid conjugate that binds an mRNA and delivers the mRNA into cells. As of the filing date sought in the instant application, it was known in the art that the type (e.g., carbon atom numbers or chain length) of fatty acid significantly impacts a nucleic acid encapsulation and intracellular delivery activity when the fatty acid is conjugated to a CPP, wherein the optimal fatty acid chain length highly depends on the actual CPP species. See Morais et al. (BBA-Biomembranes, 2018, 1860:2619-2634) at page 2620 disclosing the following: “The addition of a fatty acyl chain to the structure of a CPP causes alterations in the relative proportions of hydrophobic and hydrophilic regions, with impact on CPP/nucleic acid complex formation and stability, as well as on its interaction with the cell membrane and intracellular trafficking. Therefore, the contribution of acylation to an optimal range of CPP hydrophobicity varies for different CPPs, depending on their structure and composition, their bioactivity being, accordingly, differently impacted.” (emphasis added). Morais further reports that “acyl-peptides displayed remarkable differences regarding their interaction with membrane lipids” (emphasis added; see page 2627) and “the percentage of siRNA molecules accessible to PicoGreen intercalation (free siRNA) decreased as the length of the acyl chains incorporated into the peptide increased”, while “an increase of the acyl chain length did not induce a proportional increase in the extent of cellular internalization” (emphasis added; see page 2628). Based on the experimental findings with various fatty acid lengths (e.g., C10, C12, C14, C16, C18), Morais determined that C12 is the most optimal fatty acid length in a fatty acid-peptide conjugate for efficient intracellular delivery of an siRNA molecule. Indeed, the highly unpredictable nature of the fatty acyl chain length-dependent intracellular delivery function of a lipid-peptide conjugate was already recognized in the relevant art with regard to DNA as evidenced by Kusumoto et al. (US 2009/0170960 A1), who tested different lengths (C10, C12, C14, and C16) linked to an RE peptide for intracellular delivery of a plasmid DNA into CHO and HC cells and demonstrated a high level of unpredictability regarding the fatty acid length- and the cell type-dependent nature of a lipid-peptide conjugate DNA delivery carrier activity as shown in Figures 6A-6B reproduced below.
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As repeatedly noted above, the instant specification is so deficient in adequately describing the requisite structure-function correlation for the genus of “Formula 1” as there is no actually disclosed species for “A”, let alone other remaining elements: “B”, “C”, “D”, and “E”, for delivering an mRNA molecule into any given cell type, thereby providing the intended therapeutic and/or prophylactic function for any cancer and any inflammatory disease. Such deficiency in the instant specification’s disclosure is far from complying with the written description requirement especially in light of the art-recognized unpredictable nature of the claimed subject matter as amply evidenced by the aforementioned prior art knowledge. Again, note that the specificity and content of the specification’s disclosure is inversely correlated with the predictability in the relevant art. See MPEP §2163.
The lipid-peptide nucleic acid delivery structure comprising an endosomal escape peptide (e.g., HHHHHH), a nucleic acid-binding sequence, and a target cell surface binding petpide is not new but rather was known in the prior art as evidenced by Meng et al. (Nanoscale, 2018, 10:1215-1227), who disclose differently designed DNA delivery carriers comprising a stearyl fatty acid (C16) and peptides with different functions (DNA-binding TAT peptide, endosomal escape aiding His6 peptide (HHHHHH), and laminin receptor-binding targeting peptide YIGSR), wherein Meng teaches that “the gene transfection ability of peptide vectors is determined by many factors” such that the “sequence of a peptide can determine its secondary conformation and its effect on synergistic action” in gene delivery/transfection process and that “the conformation affected the gene delivery” (emphasis added). See pages 1219 and 1223. In fact, Morais et al. (BBA-Biomembranes, 2018, 1860:2619-2634) echo the same teachings of Meng such that the efficient siRNA intracellular delivery into human GBM U87 cells via the C12 lipid-peptide conjugate that “facilitated endosomal escape prior to endosome-lysosome fusion” is highly dependent on “the sequence of the 13 amino acid residues derived from the dermaseptin S4 peptide is crucial for the generation of the alpha-helical structure, which is most likely responsible for the wild-type peptide capacity to transpose cell membranes.” (emphasis added). See pages 2631-2632. In addition, Ryu et al. (Journal of Nanobiotechnology, 2021, 19:44, applicant’s citation) disclose the following: “The stability of the nanocomplex could be explained based on the properties of the peptides with different arginine lengths. S-R15 formed the most stable nanocomplex, which might show increased stability upon cellular uptake.” (emphasis added). See page 12. Even more interestingly, it was recognized and known in the relevant prior art that not all “RNA-binding” peptides of SEQ ID NOs:1-15 claimed in the instant case function equally or predictably as evidenced by Yu et al. (US 2011/0230367 A1), who expressly disclose that the peptide of SEQ ID NO:1, which is 100% identical to SEQ ID NO:1 claimed in the instant case, has the lowest, non-specific binding affinity to pre-let7a-1 and pre-miR16-1 compared to those having tryptophan substitutions as disclosed in Table 5, which is reproduced below.
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As shown above, peptide “2b” shows about a 253-fold increase in binding affinity to pre-let7a-1 compared to peptide “1” (SEQ ID NO:1). Even better, Yu’s Table 6 clearly demonstrates that the peptide’s binding affinity greatly differs depending on the type of actual RNA such that peptide “2b” showed about 15-fold decrease in binding “IRES” RNA compared to its specific and strong binding affinity to pre-let7a-1. Taken together, it was art-recognized knowledge that the RNA-binding affinity/activity of a peptide, especially applicant’s elected species of SEQ ID NO:1, cannot be predicted, especially regarding a long mRNA sequence, which is not shown or tested in Yu. Again, the instant specification is completely silent regarding which actual peptide is used for each of A, B, C, D, and E for binding an mRNA molecule, and furthermore, in light of the art-recognized high level of unpredictable nature of peptides as amply explained in detail hereinabove, one of ordinary skill in the relevant art would not deem the instant specification’s disclosure as being descriptive of the claimed subject matter or the claimed genus that is to be delivered into cells and provide the intended function “to treat or prevent cancer or inflammatory diseases.”
Regarding the “molecular weight ratio” of “1:1 to 1:100” between mRNA and the peptide-lipid conjugate forming the claimed nanoparticle size range of “10 to 200 nm”, it appears that the instant specification at best discloses that the molecular weight ratio of “1:10” between an mRNA molecule and the undisclosed structure of peptide-lipid conjugate, which together form the median diameter of about 100 nm, provides intracellular delivery of the mRNA molecule in human lung cancer H358 cells. The single ratio of “1:10” using the undisclosed structure of peptide-lipid conjugate forming about 100 nm diameter is not a representative number of species within the claimed broad range of “1:1 to 1:100” for the molecular weight ratio and the nanoparticle size range of “10 to 200 nm”. It was recognized in the relevant art that the amount/ratio of a nucleic acid and the peptide carrier is a factor that determines intracellular delivery efficiency of the nucleic acid as evidenced by Meng et al. (Nanoscale, 2018, 10:1215-1227) who report that “as the N/P ratio increased from 4 to 6, the transfection efficiency increased. In addition, the transfection efficiency decreased when the N/P ratio increased from 6 to 8. It could be suggested that the peptide vectors and DNA did not undergo optimal self-assembly at an N/P ratio of 4, although the two components combined completely from the point of view of electrophoresis. When the N/P ratio reached 6, the combination between the peptide vectors and DNA was optimal and stable self-assembled structures were formed, which also caused the transfection efficiency to reach an optimal level.” (emphasis added). See pages 1222-1223.
See MPEP §2162: “In exchange for the patent rights granted, 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, sets forth the minimum requirements for the quality and quantity of information that must be contained in the patent to justify the grant of a patent…The applicant must not conceal from the public the best way of practicing the invention that was known to the patentee at the time of filing the patent application. Failure to fully comply with the disclosure requirements could result in the denial of a patent, or in a holding of invalidity of an issued patent.” (emphasis added).
See also MPEP §2163: “The written description requirement has several policy objectives. “[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed.” In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to put the public in possession of what the applicant claims as the invention. See Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). The written description requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor ’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.” (emphasis added).
In view of the foregoing, it is concluded that the instant specification contains no substantial quality information thus fails to not only adequately describe the claimed subject matter/genus but also reasonably convey that the instant co-inventors completed and had possession of the entire genus as of the filing date sought in the instant case.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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