DETAILED ACTION
Receipt of Arguments/Remarks filed on January 26 2026 is acknowledged. Claims 2-4, 6, 16, 20-22, 24, 32-39, 41-42, 44, 47-48, 51, 54-55 and 59-77 were/stand cancelled. Claims 1 and 13 were amended. Claims 1, 5, 7-15, 17-19, 23, 25-31, 40, 43, 45-46, 49-50, 52-53 and 56-58 are pending. Claims 29-31, 45-46, 49-50, 52-53 and 56-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 July 10 2025. Claims 1, 5, 7-15, 17-19, 23, 25-28, 40 and 43 are directed to the elected invention.
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 .
Withdrawn Objections/Rejections
The amendments to the drawings filed January 26 2026 are sufficient to overcome the objection to the drawings. The drawings now include the required Fig. recitation.
The amendments to the specification filed January 26 2026 are partially sufficient to overcome the objection to the specification. Firstly, Applicants arguments with regards to Taxol are considered and persuasive. Paclitaxel (the generic name) is already associated with this term. The amendments to the other terms are sufficient. However, the objection included AlexaFluor as well which was not corrected. Thus, this objection is maintained below as none of the arguments indicate where the generic terminology is taught.
The amendments filed January 26 2026 are sufficient to overcome the objection of claim 13. The acronyms are now accompanied by the full name.
The amendments filed January 26 2026 are sufficient to overcome the rejection of claims 1, 5, 7, 9, 12-13, 25, 40 and 43 under 35 U.S.C. 102 (a)(1) as being anticipated by Caracciolo et al. The claims now exclude the presence of a neutral lipid which is present in the examples of Caracciolo et al.
The amendments filed January 26 2026 are sufficient to overcome the rejection of claims 1, 5, 7-15, 17-19, 23, 25, 40 and 43 under 35 U.S.C. 103 over Caracciolo et al. in view of Heirtlein et al. The claims as amended now exclude the presence of a neutral lipid and this combination of prior art does not render this limitation obvious.
Maintained and Modified Rejections Necessitated by the Amendments filed January 26 2026
Specification
The use of the term AlexaFlour®488 (page 51, paragraph 00190); which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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, 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, 5, 7-15, 17-19, 23, 25-28, 40 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Caracciolo et al. (Biochemica et Biophysica Acta, 2007, cited in the Office action mailed April 10 2025) in view of Heirtlein et al. (USPGPUB No. 20150157565, cited in the Office Action mailed on August 26 2025) and Betker et al. (WO2017062502, cited in the Office Action mailed on August 26 2026).
Applicant Claims
The instant application claims a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer and wherein the nanoparticle does not comprise a neutral lipid.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Caracciolo et al. is directed to transfection efficiency boost by designer multicomponent lipoplexes. Synthetic cationic liposomes form stable complexes with polyanionic DNA (page 2280, first sentence). Table 2 shows the hydrodynamic radius which indicates the lipoplexes are nanoparticle size. Taught are DOTAP-DOPC/DNA lipoplexes. As shown in Figure 13, multiple layers of DNA and cationic lipids wherein the outer layer is lipid. As shown in figure 13, electrostatic attractions let the lipoplex approach the anionic surface of the cell and attachment is followed by endocytosis (page 2291, left column). This suggest positive charged surface (to allow for electrostatic attractions with an anionic (aka negatively charged) surface.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Caracciolo et al. teaches multicomponent lipoplexes with a cationic surface, Caracciolo et al. is silent to the zeta potential. While Caracciolo et al. teaches delivery of nucleic acid, DNA, Caracciolo et al. does not teach an RNA. While Caracciolo et al. teaches a concentration of the DNA, Caracciolo et al. does not expressly teach the instantly claimed concentration. However, these deficiencies are cured by Heirtlein et al.
Heirtlein et al. is directed to pulmonary delivery of mRNA to non-lung target cells. Conventional gene therapy involves the use of DNA for insertion of genetic information into host cells (paragraph 0002). In contrast to DNA, the use of RNA as a gene therapy agent is substantially safer (paragraph 0003). One reason that mRNA has not been used more is because mRNA is far less stable than DNA (paragraph 004). Non-viral delivery of mRNA can be achieved by using lipoplexes or liposome entrapped mRNA (paragraph 0006). The mRNA is taught as encoding a protein (paragraph 0016). Some embodiments include a plurality of mRNA species encoding one or more proteins (paragraph 0018). Modified or unmodified mRNA may be used (paragraph 0071-0077). Cationic liposome/mRNA complexes can help protect mRNA from enzymatic degradation and facilitate intracellular delivery by interacting with the negatively charged cell membrane. The cationic surface of these lipoplexes also mediate strong interactions with negatively charged proteins that serve to reduce the half-life of the lipoplexes in vivo. This effect may be reduced by employing one or more of a mechanism to reduce the interaction between the cationic liposome/mRNA complex and negatively charged proteins. In most embodiments, the delivery vehicles used in the compositions and methods of the invention comprise nanoparticles constructed from a combination of one or more cationic lipids, non-cationic lipids, such as neutral or helper lipids, and PEG-modified lipids (paragraph 0102). Cationic lipids include DOTAP (paragraph 0108). Following administration the protein produce encoded by the mRNA is detectable at concentrations of at least 0.25-1.5 µg/ml (paragraph 0127). Particle sizes are less than about 500 µm. The compositions are formulated to provide at least 0.1 mg mRNA (paragraph 0129). Table 5 shows zeta potentials of 50 or 52.5 mV. Table 1 discloses proteins which include stimulating proteins and antigens. Taught is delivery of mRNA encoding various therapeutic proteins (paragraph 0163).
While RNA therapeutics are suggested, siRNA that is a PD-L1 inhibitor is not expressly taught or exclusion of a neutral lipid. However, these deficiencies are cured by Betker et al.
Betker et al. is directed to lipoplexes formulated for catalytic delivery. The delivery of therapeutic nucleic acids (e.g. siRNA, aptamers, encoded antigens) resulting in expression of these nucleic acids in the target tissue offers a distinct therapeutic advantage (page 4). Taught are lipoplexes that express siRNA known to locally inhibit the expression of PD-L1, a protein that plays a critical role in the ability of tumors to evade the immune system (page 4). Figure 16B shows the expression of siRNA against PD-L1 after transfection in the lipoplexes. It is taught that the lipoplexes may include any useful combination of lipid molecules (e.g. a cationic lipid, a neutral lipid, an anionic lipid) and other components that aid in the formation or stability of a lipoplex. A person of skill in the art would know how to optimize the combination that favor encapsulation of a particular agent, stability of the lipid formulation, scaled up reaction conditions or any other pertinent factor (page 18).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1, 14-15, 17 and 25-28:
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al., Heirtlein et al. and Betker et al. and utilize RNA with the lipoplexes of Caracciolo et al. One skilled in the art would have been motivated to utilize RNA in place of DNA as it is substantially safer as taught by Heirtlein et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al. and Heirtlein et al. and utilize mRNA that encodes proteins in the lipoplexes. One skilled in the art would have been motivated to utilize mRNA that encodes therapeutic proteins in order to treat a desired condition as taught by Heirtlein et al. Since Heirtlein et al. teaches delivery of mRNA in lipoplexes there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al., Heirtlein et al. and Betker et al. and utilize an siRNA which inhibits the expression of PD-L1. One skilled in the art would have been motivated to utilize this nucleic acid as PD-L1 is a protein which results in the ability of tumors to evade the immune system. Therefore, the use of an siRNA which inhibits expression of this protein would allow for a chemotherapeutic or immunotherapeutic effect as suggested by Betker et al. Since Betker et al. teaches the siRNA with lipoplexes there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al., Heirtlein et al. and Betker et al. and utilize a lipoplex without a neutral lipid. As taught by Betker et al. one skilled in the art would use any useful combination of lipid components that aid in formation of stability of a lipoplex. Therefore, based on these teachings one skilled in the art would manipulate the lipoplex and include or exclude a neutral lipid as deemed necessary by one skilled in the art in order to form a lipoplex with the desired level of stability.
Regarding claim 5, 7 and 13, as taught in Caracciolo et al., Table 2, outer layer is DOTAP which is cationic 1,2-dioleoyl-3-trimethylammonium-propane.
Regarding claim 8, Heirtlein et al. teaches following administration the protein produce encoded by the mRNA is detectable at concentrations of at least 0.25-1.5 µg/ml and compositions are formulated to provide at least 0.1 mg mRNA. Therefore, depending on the mRNA utilized and the desired therapeutic effect, one skilled in the art would manipulate the concentration in order to achieve the desired effect. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results. The amount of an active ingredient is a parameter that a person of ordinary skill in the art would routinely optimize based on the condition being treated, severity of the condition and desired dosing frequency, among other factors. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where 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, 105 USPQ 233 (CCPA 1955). NOTE: MPEP 2144.05.
Regarding claim 9, as shown in Caracciolo et al., table 2, all of the examples have a diameter falling within the scope claimed.
Regarding claims 10-11, Caracciolo et al. teaches that electrostatic attractions let the lipoplex approach the anionic surface of the cell and attachment is followed by endocytosis. Heirtlein et al. teaches that cationic liposome/mRNA complexes can help protect mRNA from enzymatic degradation and facilitate intracellular delivery by interacting with the negatively charged cell membrane. Therefore, the prior art suggests a cationic surface. Heirtlein et al. suggests that this cationic surface can provide a zeta potential of about 50 mV. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al. and Heirtlein et al. and utilize a cationic surface. Since cationic surfaces can equate to a zeta potential of about 50 mV one skilled in the art would have been motivated to utilize this zeta potential. Furthermore, one skilled in the art would manipulate the zeta potential and the relative positive charge on the surface to ensure a stable lipoplex but not too stable a lipoplex that the DNA or RNA cannot be delivered as suggested by Caracciolo et al.
Regarding claim 12, all samples in Caracciolo et al. were prepared with the same cationic lipid/DNA ratio (mol/mol) of 3.2 (section 2.2, page 2281).
Regarding claim 18 and 23, Table 1 of Heirtlein et al. discloses proteins which include stimulating proteins and antigens suggesting that depending on the desired end use one skilled in the art would have been motivated to manipulate the mRNA to produce the desired protein.
Regarding claim 19, as shown in table 1 of Heirtlein et al., a variety of proteins are suggested including those not expressed by a tumor cell.
Regarding claims 40 and 43, taught is incubating cells with lipoplexes in Optimem (carrier/excipient) to permit transient transfection. This reads on cells with the nanoparticles and a pharmaceutical composition with a plurality of nanoparticles and a carrier/excipient.
Response to Arguments
Applicants’ arguments filed January 26 2026 have been fully considered but they are not persuasive.
Applicants argue that the combination of Caracciola, Heartlein and Betker do not render the claimed subject matter obvious. The instant claims require that the nanoparticle does not comprise a neutral lipid. The Office cited no reason as to how or why one of ordinary skill would deviate from the teachings of the cited reference in the manner required to arrive at the subject matter of claim 1. At best the Office suggests one skilled in the art would mix-and-match lipids as deemed necessary in order to form a lipopolex with the desired level of stability. Yet, the cited references suggest that neutral lipids are desirable, leading one of ordinary skill in the rt to include neutral lipids. Applicants point to page 2282 of Caracciola et al. in which Caracciolo teaches the critical role of neutral lipids. One of ordinary skill in the art would not be motivated to remove the neutral lipid form the lipoplex as it would have a detrimental effect on the structure and behavior of the lipoplex. Betker also teaches the importance of cholesterol within the lipoplexes pointing to page 3. It is argued that one skilled in the art would not have been motivated to generate nanoparticles that lack neutral lipids. Applicants argue that the references teach away from the non-inclusion of a neutral lipid and the office has provided no reasonable rationale as why one skilled in the art would depart from the teachings.
Regarding Applicants arguments, the examiner cannot agree that Betker teaches that cholesterol is required. Claim 1 recites a lipoplex formulation comprising a. at least one cationic amphiphile, b. at least one C18-30 saturated fatty acid and c. at least one nucleic acid. Cholesterol, a neutral lipid, isn’t required until claim 2. Thus, Betker clearly contemplates lipoplexes without a neutral lipid. As pointed to by the examiner previously, page 18, teaches “Polyanionic therapeutic compounds (e.g., one or more nucleic acids or RNAi agents) may be combined with one or more lipid molecules (e.g., cationic, anionic, or neutral lipids) to produce a lipoplex formulation of this disclosure. The formulation can also include one or more components (e.g., cholesterol, cholesterol-iRGD conjugates, cationic amphiphiles, etc.). “. This clearly suggests that while it can be included, neutral lipids are not required. Then Betker goes on to state that: “ These lipoplexes may include any useful combination of lipid molecules (e.g., a cationic lipid (optionally including one or more cationic lipids, e.g., one or more cationic lipids of this disclosure as described herein and/or optionally including one or more cationic lipids known in the art), a neutral lipid, an anionic lipid, including polypeptide- lipid conjugates and other components that aid in the formation or stability of a lipoplex, as described herein. A person of skill in that art will know how to optimize the combination that favor encapsulation of a particular agent, stability of the lipid formulation, scaled-up reaction conditions, or any other pertinent factor. The formulations of this disclosure may include other components that aid in formation or stability.”. Thus while the examiner did indicate that one skilled in the art would manipulate (or mix-and-max) the lipid components of lipoplex, this is based on the express teaching of Betker. Furthermore, on page 5, Betker teaches that cholesterol may be included in the lipoplexes. If present, the lipoplexes may include a cholesterol content greater than 5% (page 5). Which again suggest that cholesterol is not required. Betker teaches that cholesterol reduces toxicity of the delivery vehicle (page 3) which is the same reason that Caracciola et al. (page 2282 as pointed to by Applicants). But Betker in many instances throughout indicates that the cholesterol is not required. Therefore, Applicants arguments are not persuasive because, based on the express teaching in Betker, one skilled in the art would optimize the combination that favor encapsulation of a particular agent, stability of the lipid formulation, scaled-up reaction conditions, or any other pertinent factor. Since cholesterol is not required to be present, one skilled in the art would recognize that it can be excluded and lipoplexes can still be formed as taught by Betker.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, 7-8, 10-15, 17, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18268725 (US PGPUB NO. 20240299516). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant application claims a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer and wherein the nanoparticle does not comprise a neutral lipid.
Copending ‘725 claims a method for treating cancer comprising administering to a human subject a dose of nanoparticles wherein the nanoparticles comprises a positively charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers each nucleic acid layer being positioned between a cationic lipid bilayer. The nucleic acids are delivered form a cancer cell reading on instant claim 40. The same zeta potential is claimed. The same cationic lipids is claimed. The same ratio of nucleic acid molecules and cationic lipid is claimed. mRNA is claimed. Overlapping concentrations of nucleic acids are claimed. Claimed are nanoparticles in a composition comprising the nanoparticles per mL suggesting a carrier reading on instant claim 43.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15, 17, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-8, 13-19, 27-28 and 30 of copending Application No. 17797810 (US PGPUB NO. 20230096704). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘810 claims a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two ribonucleic acid (RNA) layers, wherein each RNA layer is positioned between a cationic lipid bilayer, wherein the RNA binds to or encodes an epitope of a nucleic acid encoding a fusion protein expressed by a tumor. The same particle size and zeta potential is claimed. The same ratio of nucleic acid molecules and cationic lipid is claimed. The same cationic lipid is claimed. A cell comprising the nanoparticles and a composition with a carrier is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15 and 17-19, 23, 25-28, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of copending Application No. 17800687 (US PGPUB NO. 20230346700). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘687 claims a method of increasing sensitivity of a tumor to treatment with an immune checkpoint inhibitor (ICI) in a subject, the method comprising administering to the subject a composition comprising a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer, optionally, wherein the composition is systemically administered to the subject. A PD-L1 inhibitor is claimed. The same concentration of nucleic acid is claimed. The same diameter and zeta potential is claimed. The same ratio of nucleic acid and cationic lipid is claimed. The same cationic lipid is claimed. mRNA is claimed. The mRNA encodes a protein. siRNA are claimed. Intravenous administration is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15, 17 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 14, 36-41 of copending Application No. 17268408 (US PGPUB NO. 20210170005; issued as US Patent No. 12514930). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Copending ‘408 claims a method of treating a subject with an immune checkpoint inhibitor (ICI)-resistant tumor, comprising administering to the subject (i) a composition comprising a liposome comprising a cationic lipid and mRNA complexed with the cationic lipid via electrostatic interactions, and (ii) an ICI, wherein the liposome is systemically administered to the subject and the composition does not comprise cells, and wherein the mRNA does not encode a tumor antigen. A PD-L1 inhibitor is claimed. Cationic DOTAP is claimed. Overlapping zeta potential is claimed. Overlapping diameter is claimed. The mRNA encodes a protein not expressed by the tumor is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15, 17 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8- 10, 12-13, 22-23, 26, 35, 38-39, and 50-51 of copending Application No. 17275399 (US PGPUB NO. 20220054610). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘399 claims a composition comprising a liposome comprising a cationic lipid and at least 10 different RNA consisting essentially of slow cycling cell (SCC) transcriptome RNA, wherein the RNA comprises RNA molecules encoded by at least 10 of the following genes. DOTAP is claimed. Overlapping zeta potential is claimed. Overlapping diameter is claimed. Electrostatic interactions are claimed. The same ratio is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 11-12, 16, 18-19 and 24-26 of copending Application No. 18289705 (US PGPUB NO. 20240238418). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘705 claims a method of preconditioning a subject for chimeric antigen receptor (CAR) T cell therapy, the method comprising administering to the subject a first composition comprising a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer, at least one day prior to administering CAR T cell therapy to the subject. At least three nucleic acid layers positions between a cationic lipid bilayer is claimed. The outermost layer is cationic. An overlapping zeta potential is claimed. DOTAP is claimed. mRNA is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15, 17, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3,5,7-13, 16-20, 32,35,37, 45 and 49-51 of copending Application No. 17914894 (US PGPUB NO. 20230226169). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘894 claims a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer, wherein the nanoparticle comprises RNA molecules encoding a SARS-CoV-2 protein. As claimed the outermost layer is a cationic lipid. The same concentration of the nucleic acid is claimed. Overlapping diameter and zeta potential is claimed. The same ratio of nucleic acid to cationic lipid is claimed. DOTAP is claimed. mRNA encoding a protein are claimed. A cell and a pharmaceutical composition with a carrier is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-8 and 10-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 17, 20-21, 27, 29-31, 33 and 36-37 of copending Application No. 18854015 (US PGPUB NO. 20250231177). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘015 claims a method of identifying a tumor for immunotherapy, the method comprising: a) culturing tumor cells obtained from a subject; b) exposing the tumor cells to nanoparticles comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer; and c) measuring interferon-alpha and interleukin 6 (IL-6) produced by the tumor cells. Overlapping zeta potential is claimed. The same ratio is claimed. DOTAP is claimed. mRNA is claimed.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both recite nanoparticles comprising the same structure.
Claims 1, 5, 7-15, 17-19, 23, 25-28, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 17, 20-21, 27, 29-31, 33 and 36-37 of copending Application No. 18854015 (US PGPUB NO. 20250231177); claims 1,3,5,7-13, 16-20, 32,35,37, 45 and 49-51 of copending Application No. 17914894 (US PGPUB NO. 20230226169); claims 1-6, 8, 11-12, 16, 18-19 and 24-26 of copending Application No. 18289705 (US PGPUB NO. 20240238418); claims 1-4, 6, 8- 10, 12-13, 22-23, 26, 35, 38-39, and 50-51 of copending Application No. 17275399 (US PGPUB NO. 20220054610); claims 1-7, 14, 36-41 of copending Application No. 17268408 (US PGPUB NO. 20210170005); claims 1-3, 6-8, 13-19, 27-28 and 30 of copending Application No. 17797810 (US PGPUB NO. 20230096704); OR claims 1-18 of copending Application No. 18268725 (US PGPUB NO. 20240299516) in view of Caracciolo et al., Heirtlein et al. and/or Betker et al.
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The claims of copending ‘015, ‘894, ‘705, ‘399, ‘408, ‘810 and ‘725 are set forth above.
The copending applications do not claim all the limitations instantly claimed. However, any deficiency is cured by Caracciolo et al., Heirtlein et al. and/or Betker et al.
The teachings of by Caracciolo et al., Heirtlein et al. and Betker et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of any of the copending applications, Caracciolo et al., Heirtlein et al. and/or Betker et al. and utilize RNA with the lipoplexes of Caracciolo et al. One skilled in the art would have been motivated to utilize RNA in place of DNA as it is substantially safer as taught by Heirtlein et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caracciolo et al. and Heirtlein et al. and utilize mRNA that encodes proteins in the lipoplexes. One skilled in the art would have been motivated to utilize mRNA that encodes therapeutic proteins in order to treat a desired condition as taught by Heirtlein et al. Since Heirtlein et al. teaches delivery of mRNA in lipoplexes there is a reasonable expectation of success.
Regarding claim 18 and 23, Heirtlein et al. teaches in Table 1 discloses proteins which include stimulating proteins and antigens suggesting that depending on the desired end use one skilled in the art would have been motivated to manipulate the mRNA to produce the desired protein. Regarding claim 19, as shown in table 1 a variety of proteins are suggested including those not expressed by a tumor cell.
Regarding claim 8, Heirtlein et al. teaches following administration the protein produce encoded by the mRNA is detectable at concentrations of at least 0.25-1.5 µg/ml and compositions are formulated to provide at least 0.1 mg mRNA. Therefore, depending on the mRNA utilized and the desired therapeutic effect, one skilled in the art would manipulate the concentration in order to achieve the desired effect. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results. The amount of an active ingredient is a parameter that a person of ordinary skill in the art would routinely optimize based on the condition being treated, severity of the condition and desired dosing frequency, among other factors. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where 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, 105 USPQ 233 (CCPA 1955). NOTE: MPEP 2144.05.
Regarding claim 9, Heirtlein et al. teaches an overlapping diameter.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the copending applications, Caracciolo et al., Heirtlein et al. and/or Betker et al. and utilize an siRNA which inhibits the expression of PD-L1. One skilled in the art would have been motivated to utilize this nucleic acid as PD-L1 is a protein which results in the ability of tumors to evade the immune system. Therefore, the use of an siRNA which inhibits expression of this protein would allow for a chemotherapeutic or immunotherapeutic effect as suggested by Betker et al. Since Betker et al. teaches the siRNA with lipoplexes there is a reasonable expectation of success.
Response to Arguments
Applicants’ arguments filed January 26 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) Patent ‘930 does not define the nanoparticles as comprising a positively charged surface and an interior comprising a core and at least two nucleic acids wherein each nucleic acid layer is position between a cationic lipid bilayer and does not comprise a neutral lipid.
Regarding Applicants’ first argument, firstly, Patent ‘930 does not claim a neutral lipid, thus the broadest reasonable interpretation is that the liposome does not include a lipid. As claimed the liposome is made from the same cationic lipid (DOTAP) and mRNA which are complexed by electrostatic interactions. The liposome is claimed as having a positive zeta potential and therefore must have a cationic surface. The same diameter of the liposome is claimed and thus is a nanoparticle. Thus, the examiner cannot agree that the same structure is not suggested. With regards to the arguments about domination, the instant claims are the broader claims. Even if there are limitations missing, the claims were additionally rejected as obvious in view of Caracciolo, Heartlein and Betker and the arguments are not persuasive for the reasons set forth above.
Applicants argue that (2) the examiner states scopes overlap and thus are obvious variants of one another between ‘399 and the instant claims. Mere alleged overlap in scope is not sufficient to sustain a double patenting rejection. Caracciolo, Heartlein and Betker do not supplement the rejection.
Regarding Applicants’ second argument, the claims recites a liposome comprising a cationic lipid and RNA. The same cationic lipid is claimed (DOTAP), the same zeta potential about 30 mV to about 60 mV is claimed. Since a positive zeta potential is claimed the liposome must have a cationic surface. The same diameter is claimed indicating a nanoparticle. The RNA and the cationic lipid are complexed via electrostatic interactions with an overlapping ration of cationic lipid to nucleic acid. Thus, the examiner cannot agree that the claimed liposome is not the same as the instantly claimed nanoparticle. Even if there are limitations missing, the claims were additionally rejected as obvious in view of Caracciolo, Heartlein and Betker and the arguments are not persuasive for the reasons set forth above.
Applicants argue that (3) copending ‘725, ‘810, ‘687, ‘705, ‘904 and ‘015 all have an later patent term filing date than the instant claims July 17 2020.
Regarding Applicants’ third argument, firstly, Applicants have correctly identified the instantly claimed patent term filing date. Copending ‘725, ‘810, ‘687, 705, ‘904 and ‘015 are all later filed. So the examiner agrees, when the instant application becomes allowable, if these applications are still copending, the double patenting rejection can be dropped.
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.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636