DETAILED ACTION
This Action is in response to the amendment filed on 03/13/2026.
It is noted that the amendment amends at least claim 1, cancels claims 1-2 and 8, and adds new claims 99-100.
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 .
Status of the Claims
Claims 1, 6-7, 13-19, 21, 27-28, 30-31, 37, 43, 63, 80, 84, 91, 93-94, 99-100 are pending.
As previously indicated, Applicant’s election of Group I and species: EWSR1-FLI1 in the reply filed on 07/11/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 21, 31, 37, 43, 63, 80, 84, 91, 93-94 and 100 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/11/2025, as acknowledged by Applicant in the 07/11/2025 response. It is noted that new claim has been withdrawn from consideration because it does not include the elected species (EWS-FLI1).
Claims 1, 6-7, 13-19, 27-28, 30, 99 are examined herein as they read on the elected subject matter.
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, 6-7, 13-19, 27-28, 30, 99 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 fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
To satisfy the written description requirement, MPEP §2163 states, in part “…a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “…disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The claims have been amended so that they are now drawn to a nanoparticle comprising a liposome comprising RNA molecules and a cationic lipid, wherein the nanoparticle comprises a positively charged surface and an interior comprising (i) a core and (ii) at least two RNA layers wherein each RNA layer is positioned between a cationic lipid bilayer, and wherein the RNA molecules encode a region of a fusion protein expressed by a tumor, the region comprising (i) a junction of the fusion protein or (ii) an amino acid sequence which binds to a MHC class II, wherein the fusion protein is selected from the list provided in claim 1 (see claim 1), wherein the tumor is a sarcoma (claim 6), wherein the tumor is a resistant supratentorial ependymoma or a metastatic alveolar rhabdomyosarcoma (claim 7). The application discloses that the nanoparticle comprising the RNA is useful for the treatment of cancer as the epitope increases the immune response against a tumor that expresses the epitope (e.g., see abstract).
To be clear, the claims have been amended so that they now encompass a region of a fusion protein expressed in a tumor (i.e., a fragment of the fusion protein) that binds a MHC II molecule and stimulates an immune response against the tumor.
Searching to determine the state of the art, it was discovered that the prior art (Evans et al. Clinical Cancer Research, 2012; 18(19):5341-5351) teaches that fragments of the tumor fusion protein EWS-FLI1 (the elected species) were tested to determine whether the peptides could induce human CTLs in vitro, which would indicate an ability to stimulate an immune response and teaches none of the fragments of the EWS-FLI1 fusion protein stimulated an immune response, and that only one specific modified fragment was able to stimulate an immune response against tumor cells. Specifically, Evans et al. teaches:
“EWS-FLI-1 type 1 peptides were unable to stabilize cell surface HLA-A2.1 and induced weak CTL activity against Ewing sarcoma cells. In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing sarcoma cells presenting endogenous (native) peptides. The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing sarcoma xenografts. YLNPSVDSV-specific CTL displayed potent killing of multiple ESFT types in vitro: Ewing sarcoma, pPNET, Askin's Tumor, and Biphenotypic sarcoma. Stimulation of human peripheral blood mononuclear cells with YLNPSVDSV peptide resulted in potent CTL-killing.” (see abstract).
The specification disclose a larger number of different tumor antigens that may be potentially useful in the claimed invention (e.g., see Figures 25-28), the specification only appears to provide evidence that one specific epitope is capable of stimulating an immune response against a tumor cells that express the epitope, as indicated in Example 4, the K7M2 lung tumors vaccinated with ML-RNA-NPs with tumor-specific RNA. The specification does not provide any guidance which would indicate which of the disclosed fusion proteins let alone which fragments (i.e., “regions”) of the disclosed fusion proteins would have the required function (ability to bind MHC II and stimulate an immune response against the tumor).
It is noted that the specification does not appear to identify the tumor-specific RNA used in the experiment.
Accordingly, without sufficient guidance, further experimentation would be required to identify which of the disclosed fusion proteins and fragments thereof would have the required functions and which would not, which is an indication that Applicant was not in possession of the claimed genus of fusion proteins and regions thereof required by the claims.
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself.
The specification does not provide adequate written description or guidance that would allow one of skill to distinguish the functional epitopes from the non-functional epitopes without empirical determination. In other words, further experimentation would be required to determine which of the tumor epitopes encompassed by the claims, which includes fragments of the disclosed fusion proteins, would bind a MHC II and result in stimulation of an immune response against the tumor, and which ones would not. Thus one of skill at the time of the invention could not have concluded that Applicant was in possession of the genus of epitopes that could be successfully used in the claimed nanoparticles.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 6-7, 13-18, 27-28, 30, 99 are rejected under 35 U.S.C. 103 as being unpatentable over US20190351040 (hereafter “Valiante”, of record) and JP-2017-500312-A (hereinafter “JP-2017”; of record – IDS citation, Google English translation provided) in view of Evans et al. Clinical Cancer Research, 2012; 18(19):5341-5351; hereinafter “Evans”).
As indicated above, claim 1 has been amended to a nanoparticle comprising a liposome comprising RNA molecules and a cationic lipid, wherein the nanoparticle comprises a positively charged surface and an interior comprising (i) a core and (ii) at least two RNA layers wherein each RNA layer is positioned between a cationic lipid bilayer, and wherein the RNA molecules encode a region of a fusion protein expressed by a tumor, the region comprising (i) a junction of the fusion protein or (ii) an amino acid sequence which binds to a MHC class II, wherein the fusion protein is selected from the list provided in claim 1.
Valiante teaches an RNA cancer vaccine comprising a RNA polynucleotide having an open reading frame encoding at least one cancer antigenic peptide or immunogenic fragment thereof capable of inducing an immune response to cancer (e.g., see paragraph [0007]). Valiante teaches that the RNA can encode a fusion linking two or more components of the construct which may be referred to as “multimers” (e.g., see [0289], [1373], etc.).
Valiante teaches that the cancer vaccine can comprise a lipid nanoparticle (LNP) having one or more mRNA each encoding 1-500 peptide epitopes that include a cancer antigen and a universal type II T-cell epitope (e.g., [0010]).
Valiante teaches that the LNP can comprise a cationic (i.e., positively charged) lipid (see [0048]), which can interact with negatively charged phospholipids of a membrane such that fusion to a membrane can allow one or more elements of the LNP to pass through the membrane (see [1146]), indicating that the LNP can have a positively-charged (cationic) surface (outermost layer).
Valiante teaches that the LNPs can be vesicles including one or more lipid bilayers and can include two or more concentric bilayers separated by aqueous compartments that can include one or more ligands, proteins, or channels (Emphasis added, see [1304]) wherein having two or more concentric bilayers indicates that the nanoparticle has an internal core that comprises a lipid bilayer. It is noted that Valiante states, “In some preferred embodiments the cancer therapeutic agents… are delivered in the form of mRNA encoding the cancer therapeutic agents, e.g., anti-PD1, cytokines, chemokines or stimulatory receptors/ligands (e.g., OX40.” (see [0613]).
Valiante teaches that the LNPs can have mean diameter in the range of 50-150nm, including 80-100nm (see [1313]), and have a zeta potential in the range of about 40mV to about 60mV, including about 50mV (e.g., see [1332]).
Valiante teaches that the nucleic acid molecule and cationic lipid ratio can be in the range of about 1 to 5 to about 1 to 20, including explicitly teaching that the ration can be 1 to 15 (see [1299]-[1300], where 15:1 is a ratio of 15 nucleotide component to 1 lipid component).
Valiante teaches that the RNA vaccine is administered to a subject having cancer (see [0101], claim 104, etc.) such that the RNA vaccine expresses the cancer antigenic peptide in the subject, indicating that the vaccine is delivered into a cell (i.e., a cell comprising the RNA vaccine nanoparticle). Valiante also teaches the RNA vaccine can include an RNA an APC-reprogramming molecule that can reprogram a non-APC into an antigen presenting cell (APC) (see [0226]) indicating that the cell that RNA vaccine is delivered to can be a cell that is reprogrammed to be an antigen presenting cell (APC).
Valiante teaches pharmaceutical compositions including cancer RNA vaccines and RNA vaccine compositions and/or complexes in combination with one or more pharmaceutically acceptable excipients (e.g., see [0599]).
Valiante teaches that the LNP can include two or more concentric bilayers separated by aqueous compartments that can include one or more ligands, which indicates that when there are more than two concentric bilayers separated by an aqueous compartment, the aqueous compartments can include one or more of fusion proteins. Nevertheless, the prior art also teaches that LNPs comprising multiple layers with RNA molecules present between the layers was known. For instance, JP-2017 teaches multi-layered nanoparticles for delivery of RNA to cells wherein the nanoparticles comprise core nanoparticles that are alternately coated with positively charged polymer layers and negatively charged polymer layers, wherein at least one of the negatively charged polymer layers is RNA (see abstract), and further teaches that the multilayer nanoparticle can comprise 3-10 layers (see bottom of page 3 through top of page 4 of the translated document).JP-2017 also teaches that multilayer nanoparticles have the ability to provide high uptake efficiency as well as local RNA release as a highly customizable delivery system and that degradation of the nanoparticle occurs gradually within the cell allowing the release of the multilayered cargo loads (see bottom of page 3). JP-2017 teaches that multilayered nanoparticle have the advantage of providing a sustained release of RNA in the cell and the activity of the RNA can be measured at least 2 weeks after the multilayered nanoparticles have contacted the cell (see middle of page 4 of the translated document).
Valiante does not teach that RNA molecule encodes a region of a fusion protein expressed by a tumor, wherein the fusion protein is EWS-FLI1 (the elected species).
However, Evans teaches a modified fragment of EWS-FLI1 (a fusion protein that is a tumor antigen) that induces potent CTL killing of Ewing sarcoma cells presenting endogenous peptides and resulted in enhanced survival of mice with established Ewing sarcoma xenografts. (e.g., see abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to combine the cited references and arrive at the invention of the instant claims, with a reasonable expectation of success. That is, it would have been prima facie obvious to make and use a LNP comprising multiple layers wherein an RNA that encodes a the EWS-FLI1 tumor antigen is present within multiple layers of the LNP. Since Valiante and JP-2017 teach LNPs comprising RNA in multiple layers within the LNP, and considering that Evans teaches a EWS1-FLI1 epitope that induces potent CTL killing of Ewing sarcoma cells, it would have been prima facie obvious to make a multilayer LNP comprising mRNA encoding the EWS-FLI1 epitope in multiple layers. One reason a person of ordinary skill in the art would have made the LNP with mRNA that encodes and expresses the EWS-FLI1 epitope would be to delivery and express the EWS-FL1 epitope in CTLs to use in in vitro experiments or in adoptive transfer of CTLs for use in vivo wherein the multilayered nanoparticle provides sustained release of the RNA. Furthermore, the positive results reported by the cited references provides a reasonable expectation of success.
Claims 1, 6-7, 13-18, 19, 27-28, 30, 99 are rejected under 35 U.S.C. 103 as being unpatentable over US20190351040 (hereafter “Valiante”, of record) and JP-2017-500312-A (hereinafter “JP-2017”; of record – IDS citation, Google English translation provided) in view of Evans et al. Clinical Cancer Research, 2012; 18(19):5341-5351; hereinafter “Evans”), as applied to the rejection of claims 1, 6-7, 13-18, 27-28, 30, 99 in the rejection above, and further in view of US20200297634 (hereafter “Karmali”; of record).
Valiante, JP-2017, Evans render the nanoparticle of claims 1, 6-7, 13-18, 27-28, 30 and 99 prima facie obvious for the reasons indicated in the rejection above.
The cited references dos not teach that the nanoparticle comprises the cationic lipid DOTMA.
However, it was well known that DOTMA was a cationic lipid that could be used in a LNP. For instance, Karmali teaches a lipid-encapsulated RNA nanoparticle comprising DOTMA (e.g., see abstract, [0152], etc.).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to use DOTMA as the cationic lipid in the nanoparticle suggested by Valiante, JP-2017 and Evans indicated above, with a reasonable expectation of success.
The combination of prior art cited satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 USPQ2d 1385 (2007):
“Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.”
In this case it would have been a matter of simple substitution of one known element for another to obtain predictable results and/or obvious to try from a finite number of identified, predictable solutions, with a reasonable expectation of success. Furthermore, there would have been a reasonable expectation of success based on the fact that DOTMA was a cationic lipid well-known for use in nanoparticles, as evidenced by Karmali.
Response to Arguments
The amendment obviates the Sequence Compliance issue.
With respect to the rejection of claims under 35 USC 112(a), 35 USC 102 and 35 USC 103 it is noted that the amendment adds new limitations which were not previously present in the claims and thus not specifically addressed in the previous rejection. Accordingly, the upon further consideration of the amended claims new grounds of rejection is made in this action for the reasons indicated above. The amendment necessitates the new grounds of rejection and the new grounds of rejection supersede the previous rejections. It is noted that Applicant’s arguments are directed to the previous version of claims while the instant rejections address the amended claims comprising new limitations. Accordingly, the arguments have been fully considered but do not overcome the instant rejection as the arguments do not address the new rejections as applied herein.
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). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to J. E. Angell whose telephone number is (571)272-0756. The examiner can normally be reached Monday-Friday (8:30-5:00).
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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