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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 31, 2025 has been entered.
Claims 1, 10 and 14-17 are pending.
Claims 14-16 stand withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1, 10 and 17, drawn to a composition comprising a lipid nanoparticle that read on (A) therapeutic agent as the species of agent and (B) antibody as the species of targeting domain are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/091,010, filed Oct 13, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 1, 2025 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Rejection Withdrawn
The rejection of claims 17-18 under 35 U.S.C. 103 as being unpatentable over Parhiz et al (of record, J Control Release 291: 106-115, published December 10, 2018 online, PTO 892) in view of Foster et al., (of record, human Gene Therapy 30(2): 168-178, 2018; PTO 892) and Ramishetti et al (of record, ACS Nano 9(7): 6706-6716, 2015; PTO 892) as applied to claims 1 and 10 and further in view of Scharenber (of record, US20180327781, published November 15, 2018; PTO 892), Finn et al (of record, Cell Reports 22: 2227-2235, 2018; PTO 892), Mali et al (of record, Science 339(6121): 823-826, 2016; PTO 892) and Ren et al (of record, Oncotarget 8: 17002-17011, 2017; PTO 892) is withdrawn in view of the claim amendment.
The rejection of claims 1, 10, 17 and 18 under 35 U.S.C. 102 (a)(1) or (a)(2) as being anticipated by Peer et al (US20180142261, published May 24, 2018; PTO 892) is withdrawn in view of the claim amendment.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 10 and 17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or 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 function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claims are drawn to a composition for transfecting CD4 expressing T cells in vivo comprising a lipid nanoparticle (LNP) comprising at least an ionizable cationic lipid, phosphatidylcholine, cholesterol and a pegylated lipid conjugated to a targeting domain, wherein the LNP encapsulates any one or more nucleoside-modified guide RNA or nucleoside-modified RNA encoding any therapeutic agent, wherein the nucleoside-modified RNA comprises at least one modified nucleoside selected from the group consisting of pseudouridine, I1-methyl pseudouridine, 2-thiouridine, 5-methyluridine, 1 -methyt-3 -(3 -amnino-3 -carboxypropyl) pseudouridine, 3-methylpseudouridine, 5 ,2'-O-dimethyluridine, 4-thiouridine, dihydrouridine, 5-methyl-2-thiouridine, 2-thio-2'-O-methyluridine, 3 -(3 -amino-3 - carboxypropyl)uridine, 5-hydroxyuridine, 5-methoxyuridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5-(carboxyhydroxymethyl)uridine), 5-(carboxyhydroxymethyl)uridine methyl ester, 5-methoxycarbonylmethyluridine, 5- methoxycarbonylmethyl-2'-O-methyluridine, 5 -methoxycarbonylmethyl-2-thiouridine, 5-aminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylaminomethyl-2- thiouridine, 5-methylaminomethyl-2-selenouridine, 5-carbamoylmethyluridine, 5- carbamoylmethyl-2'-O-methyluridine, 5-carboxymethylaminomethyluridine, 5- carboxymethylaminomethyl-2'-O-methyluridine, 5 -carboxymethylaminomethyl-2- thiouridine, 5 -carboxymethyluridine, 3 ,2'-O-dimethyluridine, 5-taurinomethyluridine, 5- taurinomethyl-2-thiouridine and 5-methyldihydrouridine, and further wherein the targeting domain comprises any anti-CD4 antibody.
This encompass a huge genus of functionally and structurally distinct nucleoside modified guide RNA or nucleoside-modified RNA encoding any and all therapeutic agents encompassed within the pegylated lipid nanoparticle comprising at least an ionizable cationic lipid, phosphatidylcholine, and cholesterol wherein the pegylated LNP is conjugated to any anti-CD4 antibody for transfecting T cells in vivo.
Regarding any therapeutic agent, the specification discloses:
[0541] In some embodiments, the therapeutic agent is an agent for the treatment or prevention of an infection or an infectious disease. In one embodiment, the therapeutic agent is an agent for the treatment or prevention of a bacterial infection or a disease or disorder associated therewith. The bacterium can be from any one of the following phyla: Acidobacteria, Actinobacteria, Aquificae, Bacteroidetes, Caldiserica, Chlamydiae, Chlorobi, Chloroflexi, Chrysiogenetes, Cyanobacteria, Deferribacteres, Deinococcus-Thermus, Dictyoglomi, Elusimicrobia, Fibrobacteres, Firmicutes, Fusobacteria, Gemmatimonadetes, Lentisphaerae, Nitrospira, Planctomycetes, Proteobacteria, Spirochaetes, Synergistetes, Tenericutes, Thermodesulfobacteria, Thermotogae, and Verrucomicrobia.
[0542] The bacterium can be a gram-positive bacterium or a gram-negative bacterium. The bacterium can be an aerobic bacterium or an anerobic bacterium. The bacterium can be an autotrophic bacterium or a heterotrophic bacterium. The bacterium can be a mesophile, a neutrophile, an extremophile, an acidophile, an alkaliphile, a thermophile, a psychrophile, a halophile, or an osmophile.
[0543] The bacterium can be an anthrax bacterium, an antibiotic resistant bacterium, a disease-causing bacterium, a food poisoning bacterium, an infectious bacterium, Salmonella bacterium, Staphylococcus bacterium, Streptococcus bacterium, or tetanus bacterium. The bacterium can be a mycobacteria, Clostridium tetani, Yersinia pestis, Bacillus anthracis, methicillin-resistant Staphylococcus aureus (MRSA), or Clostridium difficile.
[0544] In one embodiment, the therapeutic agent is an agent for the treatment or prevention of a viral infection, or a disease or disorder associated therewith. In some embodiments, the virus is from one of the following families: Adenoviridae, Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae (including SARS and SARS-CoV-2), Filoviridae, Hepadnaviridae, Herpesviridae, Orthomyxoviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Picornaviridae, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, or Togaviridae. The viral antigen can be from human immunodeficiency virus (HIV), Chikungunya virus (CHIKV), dengue fever virus, papilloma viruses, for example, human papilloma virus (HPV), polio virus, hepatitis viruses, for example, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV), smallpox virus (Variola major and minor), vaccinia virus, influenza virus, rhinoviruses, equine encephalitis viruses, rubella virus, yellow fever virus, Norwalk virus, hepatitis A virus, human T-cell leukemia virus (HTLV-I), hairy cell leukemia virus (HTLV-II), California encephalitis virus, Hanta virus (hemorrhagic fever), rabies virus, Ebola fever virus, Marburg virus, measles virus, mumps virus, respiratory syncytial virus (RSV), herpes simplex 1 (oral herpes), herpes simplex 2 (genital herpes), herpes zoster (varicella-zoster, a.k.a., chickenpox), cytomegalovirus (CMV), for example human CMV, Epstein-Barr virus (EBV), flavivirus, foot and mouth disease virus, lassa virus, arenavirus, or a cancer causing virus.
[0545] In one embodiment, the therapeutic agent is an agent for the treatment or prevention of a parasitic infection, or a disease or disorder associated therewith. In some embodiments, the parasite is a protozoa, helminth, or ectoparasite. The helminth (i.e., worm) can be a flatworm (e.g., flukes and tapeworms), a thorny-headed worm, or a round worm (e.g., pinworms). The ectoparasite can be lice, fleas, ticks, and mites.
[0546] The parasite can be any parasite causing any one of the following diseases: Acanthamoeba keratitis, Amoebiasis, Ascariasis, Babesiosis, Balantidiasis, Baylisascariasis, Chagas disease, Clonorchiasis, Cochliomyia, Cryptosporidiosis, Diphyllobothriasis, Dracunculiasis, Echinococcosis, Elephantiasis, Enterobiasis, Fascioliasis, Fasciolopsiasis, Filariasis, Giardiasis, Gnathostomiasis, Hymenolepiasis, Isosporiasis, Katayama fever, Leishmaniasis, Lyme disease, Malaria, Metagonimiasis, Myiasis, Onchocerciasis, Pediculosis, Scabies, Schistosomiasis, Sleeping sickness, Strongyloidiasis, Taeniasis, Toxocariasis, Toxoplasmosis, Trichinosis, and Trichuriasis.
[0547] The parasite can be Acanthamoeba, Anisakis, Ascaris lumbricoides, Botfly, Balantidium coli, Bedbug, Cestoda (tapeworm), Chiggers, Cochliomyia hominivorax, Entamoeba histolytica, Fasciola hepatica, Giardia lamblia, Hookworm, Leishmania, Linguatula serrata, Liver fluke, Loa loa, Paragonimus—lung fluke, Pinworm, Plasmodium falciparum, Schistosoma, Strongyloides stercoralis, Mite, Tapeworm, Toxoplasma gondii, Trypanosoma, Whipworm, or Wuchereria bancrofti.
[0548] In one embodiment, the therapeutic agent is an agent for the treatment or prevention of a fungal infection, or a disease or disorder associated therewith. In some embodiments, the fungus is Aspergillus species, Blastomyces dermatitidis, Candida yeasts (e.g., Candida albicans), Coccidioides, Cryptococcus neoformans, Cryptococcus gattii, dermatophyte, Fusarium species, Histoplasma capsulatum, Mucoromycotina, Pneumocystis jirovecii, Sporothrix schenckii, Exserohilum, or Cladosporium.
[0549] By way of a non-limiting example, in one embodiment, the invention provides a CD4.sup.+ T cell-targeted delivery vehicle comprising or encapsulating a nucleoside-modified 1086C Env mRNA, encoding the clade C transmitted/founder human immunodeficiency virus (HIV)-1 envelope (Env) 1086C, for the treatment or prevention of HIV infection or a disease or disorder associated therewith.
However, the specification does not describe the structure, e.g., nucleoside sequence of the guide RNA or mRNA that encode any and all therapeutic agent above for treating or preventing any bacterial infection or viral infection or parasitic disease above. It cannot be envisioned which nucleoside modified guide RNA or nucleoside-modified RNA encoding which therapeutic agent out of the entire universe would be capable of treating or preventing which disease when transfecting T cell in vivo.
Regarding nucleoside modified guide RNA or nucleoside modified RNA, the specification exemplifies:
[0579] Coding sequences of Cre recombinase or firefly luciferase were codon-optimized, synthesized and cloned into the mRNA production plasmid (pUC-ccTEV-Cre-A101 and pUC-ccTEV-Luc2-A101, respectively). mRNAs were produced using T7 RNA polymerase (Megascript, Ambion) on linearized plasmids. mRNAs were transcribed to contain 101 nucleotide-long poly(A) tails. m1Ψ-5′-triphosphate (TriLink) instead of UTP was used to generate modified nucleoside-containing mRNA. Capping of the in vitro transcribed mRNAs was performed co-transcriptionally using the trinucleotide cap1 analog, CleanCap (TriLink). mRNA was purified by cellulose purification, as described (Baiersdorfer et al., 2019, Mol Ther Nucleic Acids, 15:26-35). All mRNAs were analyzed by native agarose gel electrophoresis and were stored frozen at −20° C.
[0580] m1Ψ-containing mRNAs were encapsulated in LNP using a self-assembly process in which an aqueous solution of mRNA at pH=4.0 is rapidly mixed with a solution of lipids dissolved in ethanol (Maier et al., 2013, Mol Ther, 21:1570-1578). LNP used in this study were similar in composition to those described previously (Maier et al., 2013, Mol Ther, 21:1570-1578; Jayaraman et al., 2012, Angew Chem Int Ed Engl, 51:8529-8533), which contain an ionizable cationic lipid (Acuitas)/phosphatidylcholine/cholesterol/PEG-lipid (50:10:38.5:1.5 mol/mol) and were encapsulated at an RNA to total lipid ratio of ˜0.04 (wt/wt). The diameter of the nanoparticles was ˜80 nm as measured by dynamic light scattering using a Zetasizer Nano ZS (Malvern Instruments Ltd., Malvern, UK) instrument. mRNA-LNP formulations were stored at −80° C. at a concentration of mRNA of ˜1 μg/μl.
[0581] Monoclonal Antibody-Conjugated Lipid Nanoparticles
[0582] LNP were conjugated with mAbs specific for CD4. Purified NA/LE Rat anti-mouse CD4 (BD Pharmingen™), purified rat anti-human CD4 antibody, clone A161A1 (BioLegend), and control isotype-matched IgG were coupled to LNP via SATA-maleimide conjugation chemistry, as described earlier 18. Briefly, LNP were modified with DSPE-PEG-maleimide by a post-insertion technique. The antibody was modified with SATA (N-succinimidyl S-acetylthioacetate) (Sigma-Aldrich) to introduce sulfhydryl groups allowing conjugation to maleimide. SATA was deprotected using 0.5 M hydroxylamine followed by removal of the unreacted components by G-25 Sephadex Quick Spin Protein columns (Roche Applied Science, Indianapolis, Ind.). The reactive sulfhydryl group on the antibody was then conjugated to maleimide moieties using thioether conjugation chemistry. Purification was performed using Sepharose CL-4B gel filtration columns (Sigma-Aldrich). mRNA content was calculated by performing a modified Quant-iT RiboGreen RNA assay (Invitrogen). Size and surface charge of the targeted lipid nanoparticles were determined using dynamic light scattering (DLS) and laser doppler velocimetry (LDV), respectively on a Malvern Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Both size and zeta potential measurements were carried out in PBS pH 7.4 at 25° C. in relevant disposable capillary cells. A non-invasive back scatter system (NIBS) with a scattering angle of 173° was used for size measurements. Diameters of unconjugated and antibody-modified mRNA-LNP were interpreted as normalized intensity size distribution as well as z-average values for particle preparations.
Other than the m1Ψ-modified mRNA encoding Cre recombinase or firefly luciferase, the specification does not describe the structure of all nucleoside modified guide RNA or nucleoside-modified RNA encoding any and all therapeutic agent, wherein the nucleoside-modified pseudouridine, 11-methyl pseudouridine, 2-thiouridine, 5-methyluridine, 1 -methyt-3 -(3 -amnino-3 -carboxypropyl) pseudouridine, 3 -methylpseudouridine, 5 ,2'-O-dimethyluridine, 4-thiouridine, dihydrouridine, 5-methyl-2-thiouridine, 2-thio-2'-O-methyluridine, 3 -(3 -amino-3 - carboxypropyl)uridine, 5-hydroxyuridine, 5-methoxyuridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5-(carboxyhydroxymethyl)uridine), 5-(carboxyhydroxymethyt)uridine methyl ester, 5-methoxycarbonylmethyluridine, 5- methoxycarbonylmethyl-2'-O-methyluridine, 5 -methoxycarbonylmethyl-2-thiouridine, 5-aminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylaminomethyl-2- thiouridine, 5-methylaminomethyl-2-selenouridine, 5-carbamoylmethyluridine, 5- carbamoylmethyl-2'-O-methyluridine, 5-carboxymethylaminomethyluridine, 5- carboxymethylaminomethyl-2'-O-methyluridine, 5 -carboxymethylaminomethyl-2- thiouridine, 5 -carboxymethyluridine, 3 ,2'-O-dimethyluridine, 5-taurinomethyluridine, 5- taurinomethyl-2-thiouridine and 5-methyldihydrouridine and further encapsulated within the lipid nanoparticle (LNP) comprising ionizable cationic lipid, phosphatidylcholine, cholesterol and pegylated lipid, let alone conjugate to any anti-CD4 antibody for transfecting T cells in vivo.
However, this is not sufficiently representative of the broad range of nucleoside modified guide tRNA or nucleoside-modified RNA encoding any and all therapeutic agent encompassed by the claims. The specification does not provide any correlation between the structure of the guide tRNA or nucleoside-modified RNA encoding therapeutic agent for treating or preventing any disease or disorder such as cancer, infectious diseases or immunological disorder. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Thus one of skill in the art cannot "visualize or recognize" most members of the genus.
Regarding lipid nanoparticle (LNP) comprising any ionizable cationic lipid, phosphatidylcholine, cholesterol and pegylated lipid, the specification discloses ALC-0307 LNP and Acuitas LNP formulation containing ionizable lipid 0315 (ALC-0315 LNP). The list of ingredients in LNP formulation includes (hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) or ALC-3015 ionizable lipid 2[9polyethylene glycol-2000]-N,N-ditetradecylacetamide, 1,2-disteroyl-sn-glycero-3-phosphocholine and cholesterol, see p. 143. Thus, the application at best describes a roadmap for producing various combinations of anti-CD4 conjugated to pegylated LNP comprising at least an ionizable cationic lipid, phosphatidylcholine, cholesterol encapsulated any one or more nucleoside modified guide RNA or nucleoside-modified RNA encoding any and all therapeutic agent, and then determining which actually can treat or prevent which disease such as cancer, infectious disease or immunological disorder as claimed. See Novozymes A/S v. DuPont Nutrition Biosciences. 107 USPQ2d 1457 (Fed. Cir. 2013). In Novozymes the court held that the problem is that “the specification failed to inform the reader which member of that group was the right one.” See Abbvie Deutschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc., and Abbvie Biotechnology, Ltd., v. Janssen Biotech In. And Centocor Biologics, LLC, Case No. 2013-1338 and 2013- 1346, C.A.Fed. ("Abbvie").
A “patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”), see Noelle v. Lederman, 69 USPQ2d 1508 1514 (CAFC 2004), (citing Enzo Boichem II, 323 F. 3d at 965; Regents, 119 F.3d at 1568), MPEP 2163.IIAii
Section 112 states that “[t]he specification shall contain a written description of the invention . . . in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains . . . to make and use the same . . . .” This requirement ensures “that the inventor actually invented the invention claimed.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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).
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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
In light of the number of representative number of species provided and in light of the lack of structural features common to the members of the genus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Parhiz et al (of record, J Control Release 291: 106-115, published December 10, 2018 online, PTO 892) in view of Ramishetti et al (of record, ACS Nano 9(7): 6706-6716, 2015; PTO 892) and Foster et al., (of record, human Gene Therapy 30(2): 168-178, 2018; PTO 892).
Regarding claim 1, Parhiz teaches a composition comprising lipid nanoparticles (LNP) which contain an ionizable cationic lipid, phosphatidylcholine, cholesterol and PEG lipid conjugated to a targeting domain, e.g., a monoclonal antibody (mAb) that binds to PECAM-1, wherein the LNPs encapsulated the nucleoside-modified RNA comprises m1pseudouridine modified nucleoside, see p. 3, mRNA production and formulation into lipid nanoparticles, see p. 3, Preparation and characterization of targeted lipid nanoparticles, in particular. The antibody-coupled nucleoside-modified mRNA-LNPs provides highly effective vascular immunotargeting to target organ such as the lungs within 4.5 to 24 hours. Parhiz teaches that the uses of modified nucleosides decrease immune activation, and increase protein translation from mRNA in vivo, see p. 9, conclusion, in particular. The advantages of nucleoside-modified mRNA include it does not require nuclear entry, it cannot induce insertional mutagenesis, and it results in both very rapid and highly controllable protein expression. Thus, the non-integrating and transient character of mRNA therapy is extremely well suited for using mRNA for expressing proteins and applying it for replacement therapies. To make mRNA a potent therapeutic, stable, highly translatable and non-immunogenic mRNA, HPLC-purification and incorporation of modified nucleosides e.g. 1-methylpseudouridine and stabilizing elements, including 5′ cap, optimized 5′- and 3′-UTRs and poly(A)-tail into the mRNA sequence was necessary, see p. 8, in particular.
Parhiz does not teach the antibody is anti-CD4 antibody for transfecting CD4 expressing T cells in vivo as per claim 1.
However, Ramishetti teaches a novel strategy to specifically deliver siRNAs to murine CD4+ T cells using anti-CD4 antibody to target lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4+ T lymphocytes. Systemic intravenous administration (aka in vivo) of these particles led to efficient binding and uptake into CD4+ T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow, see entire document, abstract, in particular. The anti-CD4 monoclonal antibody conjugated siRNA-LNPs permit delivery of the lipid nanoparticle encapsulated siRNA (siRNA-LNPs) specifically to CD4 T cells ex vivo (Figure 2) and in vivo (Figure 3), see entire document, p. 6707, right col, in particular. The results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases, see abstract, in particular.
Foster teaches the use of nucleoside modified mRNA over unmodified mRNA by incorporating a 1-methyl pseudouridine (m1Ψ) modified mRNA encoding therapeutic protein, e.g., anti-CD19 expressing chimeric antigen receptor (CAR) on T cells to improve mRNA stability in T cells and increase translation capacity for treating cancer, see entire document, p. 169, p. 171, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to encapsulated Foster’s nucleoside modified m1Ψ-mRNA encoding chimeric antigen receptor in Parhiz’s lipid nanoparticle (LNP) comprising at least an ionizable cationic lipid, phosphatidylcholine, cholesterol and PEG lipid wherein the nanoparticle is conjugated to Ramishetti’s anti-CD4 monoclonal antibody to arrive at the claimed invention with a reasonable expectation success, e.g., targeting LNPs encapsulated pseudouridine modified mRNA encoding chimeric antigen receptor (CAR) to CD4+ expressing T cells.
The person of ordinary skill would have had a reasonable expectation of success in swapping Parhiz’s anti-PECAM1 antibody for another, e.g., Ramishetti’s anti-CD4 antibody conjugated to lipid nanoparticle (LNP) comprising encapsulated m1pseudouridine modified mRNA in order to target the lipid nanoparticle encapsulated pseudouridine modified mRNA to T cells that express CD4 in vivo as taught by Ramibshetti, see Figure 3.
One of ordinary skill in the art would have been motivated to substitute a known antibody for another, e.g., anti-CD4 monoclonal antibody because Ramishetti teaches that anti-CD4 monoclonal antibody conjugated siRNA-LNPs permit delivery of the lipid nanoparticle encapsulated siRNA (siRNA-LNPs) specifically to CD4 expressing T cells ex vivo (Figure 2) and in vivo (Figure 3), see entire document, p. 6707, right col, in particular.
One of ordinary skill in the art would have had a reasonable expectation of success to do so because Parhiz teaches that systemic mRNA delivery using antibody conjugated nucleoside-modified mRNA-LNPs provides one of the most efficient LNP-mRNA system developed, thus far, the uridine modified nucleosides decrease innate immune activation and increase protein translation from mRNA in vivo (see p. 9, in particular).
One of ordinary skill in the art would have been motivated to use nucleoside modified mRNA because Foster teaches that incorporation of 1-methylpseudouridine to mRNA can improve mRNA stability in T cells and increase translation capacity (see p. 169) and Parhiz teaches that the non-integrating and transient character of mRNA therapy is extremely well suited for using mRNA for expressing proteins and applying it for replacement therapies since mRNA does not require nuclear entry, it cannot induce insertional mutagenesis and the results are repaid and highly controllable protein expression. The nucleoside modification and HPLC purification of the mRNA increase protein production in vivo and eliminate inflammatory responses after administration. The LNPs containing ionizable cationic lipids can pack anionic mRNA by electrostatic interaction and protect cargo enroute to the site of action, see introduction, p. 8, in particular.
One of ordinary skill in the art would have been motivated to do so because Foster teaches nucleoside modified m1Ψ-mRNA encoding CD19 specific chimeric antigen receptor (CAR) can improve mRNA stability, improved efficacy in vivo and in vitro in the context of the CAR expression and nucleoside modification and purification increase protein expression and eliminate inflammatory response by reduced expression of checkpoint regulators and a differential pattern of Tumor necrosis factor superfamily genetic activation, see p. 174-175. in particular.
Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them."' See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Applicants’ arguments filed July 31, 2025 have been fully considered but are not found persuasive.
Applicant respectfully submits that prima facie obviousness must rest on more than a cursory conclusion that one of skill in the art would combine the teachings described by Parhiz, Foster, and Ramishetti to arrive at the presently claimed methods. “To have a reasonable expectation of success, one must be motivated to do more than merely to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result.” See In re Stepan at 1347 (quoting Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1365 (Fed. Cir. 2007), quoting Medichem, S.A. v. Rolabo, L.S., 437 F.3d 1157, 1165 (Fed. Cir. 2006)). The Office has failed to meet the requirement for the additional reasoning, as the Office’s rationale amounts merely to a skilled person varying any and all available parameters to arrive at a successful result. Applicant respectfully submits that the claims are not prima facie obvious based on the cited references.
Applicant submits that a skilled artisan would recognize the unpredictability associated with combining different constituents into a single composition. That is, a skilled artisan would understand that combining constituents from various teachings into a single composition may have unpredictable effects and consequences, even if the individual constituents may have similar function when used alone or in a different context (i.e., Applicant submits that a skilled artisan would recognize the unpredictability in the art of transfecting a CD4" T cell iv vivo using a targeted LNP comprising a nucleoside-modified RNA as recited in claim 1, upon which claim 10 depends.
Combinations of Unpredictable Elements Compounds the Unpredictability
While the Office has provided instances where combinations of a subset of the combined constituents of the claimed method exhibit one or more activities, Applicant submits that a skilled artisan would recognize the unpredictability that comes with combining all of the recited components into one method. The Office’s rationale is that a skilled artisan would expect that any known LNP could be combined with a known targeting agent to deliver a known nucleic acid agent comprising one or more modified nucleosides to produce method that would function to transfect a targeted T cell in vivo. However, Applicants submit that the present record and the knowledge in the field demonstrates the inherent unpredictability in attempting to do so.
Such unpredictability is demonstrated in the present application itself. Applicant submits that the person of skill in the art, armed with the disclosure of Ramishetti, would understand that the CD4" targeted LNPs of Ramishetti exhibited low uptake by CD4+ T cells, with only 30% of cells exhibiting uptake (as described on page 135, lines 26 through 29 of the Specification). In view of the low uptake of Ramishetti, Applicant submits that a person of skill in the art would not have been motivated to modify the LNP of Parhiz to encapsulate a nucleoside-modified RNA molecule encoding a therapeutic agent and further include a CD4* targeting molecule as recited in claim 1 for transfection of T cells. In contrast, in view of the low uptake of the targeted LNPs by Ramishetti, Applicant submits that a person of skill in the art would have been motivated to pursue alternative forms of delivery of agents to targeted LNPs to achieve a higher level of uptake.
Secondary Considerations
As described above, the test that must be met for a reference or a combination of references to establish obviousness includes an evaluation of evidence of secondary considerations. Importantly, “secondary considerations” may include evidence of commercial success, long-felt but unsolved needs, failure of others, industry praise, and unexpected results. Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. See MPEP §2145. Additionally, MPEP § 2143.01 provides: “The mere fact that references can be combined or modified does not render the resultant combination obvious unless the prior art also suggests the desirability of the combination.” In re Mills, 916 F.2d 680, 16 USPQ2d 1430 (Fed. Cir. 1990).
Failure of Others
Others have tried and failed to transfect T cells in vivo. For example, as described above, Ramishetti sought to transiently knock down expression in CD4" T cells using siRNA, however Ramishetti only achieved gene silencing in approximately 30% of CD4+ T cells. Other attempts have been made for lymphocyte targeting with other lipid- and polymer-based carriers. McKinlay et al. (McKinlay et al., 2018, Proceedings of the National Academy of Sciences 115:E5859-E5866) reported on a combinatorial chemical approach of mRNA delivery using hybrid lipid-based amphiphilic charge-altering releasable transporters (CARTs), but only achieved approximately 1.5% T lymphocyte transfection efficiency in mice.
Applicants submit that in vivo transfection of CD4" T cells is a long felt need that has been pursued by persons of skill in the art at length, but at the time of the invention remained unmet. Further, a person of skill in the art, having knowledge of the low transfection rate demonstrated by Ramishetti, would not have had an expectation of success for using LNP for transfection of T cells in vivo with nucleoside-modified mRNA molecules encoding a therapeutic agent. Unexpected Results In Crocs, Inc. v. U.S. Int’] Trade Commission, 598 F.3d 1294 (Fed. Cir. 2010), the Federal Circuit reaffirmed the requirements for a finding of non-obviousness in view of “unexpected results.” Rejecting the proposition that a combination of prior art elements is per se obvious, the Federal Circuit held that a claimed combination of prior art elements is non- obvious when the combination yields “more than predictable results.” In Crocs, testimony on record indicated that the combined elements in the shoe reduced wearer discomfort in ways that were not suggested or contemplated by the prior art. The Federal Circuit pointed out that this combination “yielded more than predictable results” and was thus patentable. Id. at 1310. This ruling affirmed prior holdings that inventions that have new and unexpected properties are patentable (In re Papesch, 315 F.2d. 381, 387 (C.C.P.A. 1963)). The determination that the result is “unexpected” depends upon what a person of ordinary skill in the art would have predicted based upon the prior art (Procter & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 997-98 (Fed. Cir. 2009); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367 (Fed. Cir. 2007)). Consistently, under MPEP § 2143 A(3), merely pointing to the presence of all claim elements in the prior art is not a complete statement of a rejection for obviousness. In accordance with MPEP § 2143 A(3), a rejection based on the rationale that the claimed invention is a combination of prior art elements is improper if it does not include a finding that results flowing from the combination would have been predictable to a person of ordinary skill in the art. MPEP § 2143 A(3). If results from the invention would not have been predictable, an obviousness rejection using the combination of prior art elements rationale is improper.
Applicants submit that the present application demonstrates the unexpected benefit of the composition comprising a CD4' targeted LNP, that the LNP was able to transfect 60% of the CD4" T cells in the spleen (see page 135, line 28-29 of the Specification). As described in the present application, the claimed method was discovered as result of an attempt to develop an improved method for delivery of therapeutic agents to T cells. Thus, experiments were devised to deliver nucleoside-modified mRNA molecules using a CD4" T cell targeted LNP that overcomes the limitations that were seen in prior studies with siRNA delivery to CD4" T cells (i.e., those seen with Ramishetti). Additionally, it was considered that if such a method could be identified it would need to display improved performance over known alternative delivery compositions.
It is demonstrated in Example 1 that T cell targeted LNPs were able to successfully genetically engineer a high percentage of T cells in vivo. Further, the targeted mRNA-LNP platform is the first report of an LNP-based mRNA delivery system for selective and functional CD4" targeting. Overall, the CD4'T cell-targeted mRNA-LNP platform presented offers tremendous opportunity for a wide range of in vivo T cell manipulations.
In sum, the present application details that the in vivo transfection properties of the CD4" T cell targeted LNP were unexpected in view of the results of Ramishetti, and therefore these results could not have been predicted or expected from the cited art. As described above, the in vivo effects of biological agents and therapeutics are unpredictable, and thus a skilled artisan would not have any expectation that the CD4" T cell targeted LNPs would be able to successfully transfect T cells in vivo, much less that they would be able to do so at the level demonstrated in the Specification before determining it empirically through experimentation.
For at least the foregoing reasons, Applicant respectfully requests reconsideration and withdrawal of the rejection of claims 1 and 10 under 35 U.S.C. 103.
In response, the amendment to claim 1 and cancelation of claim 18 is acknowledged.
In response to the argument of unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”, see MPEP 716.02(d).
In this case, the unexpected results are NOT commensurate in scope with the claims. The specification discloses just anti-CD4 targeted Cre mRNA-LNP. m1Ψ-5′-triphosphate (TriLink) instead of UTP was used to generate modified nucleoside-containing mRNA. However, claim 1 encompasses a composition for transfecting T cells in vivo comprising a lipid nanoparticle (LNP) comprising at least an ionizable cationic lipid, phosphatidylcholine, cholesterol and a pegylated lipid conjugated to a targeting domain, wherein the LNP encapsulates any one or more nucleoside-modified guide RNA or nucleoside-modified RNA encoding any therapeutic agent, wherein the nucleoside-modified RNA comprises at least one modified nucleoside selected from the group consisting of pseudouridine, I1-methyl pseudouridine, 2-thiouridine, 5-methyluridine, 1 -methyt-3 -(3 -amnino-3 -carboxypropyl) pseudouridine, 3 -methylpseudouridine, 5 ,2'-O-dimethyluridine, 4-thiouridine, dihydrouridine, 5-methyl-2-thiouridine, 2-thio-2'-O-methyluridine, 3 -(3 -amino-3 - carboxypropyl)uridine, 5-hydroxyuridine, 5-methoxyuridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5-(carboxyhydroxymethyl)uridine), 5-(carboxyhydroxymethyt)uridine methyl ester, 5-methoxycarbonylmethyluridine, 5- methoxycarbonylmethyl-2'-O-methyluridine, 5 -methoxycarbonylmethyl-2-thiouridine, 5-aminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylaminomethyl-2- thiouridine, 5-methylaminomethyl-2-selenouridine, 5-carbamoylmethyluridine, 5- carbamoylmethyl-2'-O-methyluridine, 5-carboxymethylaminomethyluridine, 5- carboxymethylaminomethyl-2'-O-methyluridine, 5 -carboxymethylaminomethyl-2- thiouridine, 5 -carboxymethyluridine, 3 ,2'-O-dimethyluridine, 5-taurinomethyluridine, 5- taurinomethyl-2-thiouridine and 5-methyldihydrouridine, and further wherein the targeting domain comprises an anti-CD4 antibody.
In response to the argument that the present application demonstrates the unexpected benefit of the composition comprising a CD4+ targeted LNP, that the LNP was able to transfect 60% of the CD4+ T cells in the spleen, the benefit of targeting CD4+ T cell using anti-CD4 antibody is expected because Ramishetti teaches anti-CD4 antibody conjugated siRNA-LNPs can be used to specifically targeted lipid nanoparticles encapsulated therapeutic agent (siRNA-LNPs) specifically to CD4 T cells ex vivo (Figure 2) and in vivo (Figure 3), see entire document, p. 6707, right col, in particular. There is no requirement that the composition must be able to transfect 60% of the CD4+ T cells in the spleen.
Note that Parhiz teaches a composition comprising lipid nanoparticles (LNP) which contain an ionizable cationic lipid, phosphatidylcholine, cholesterol and PEG lipid conjugated to a targeting domain, e.g., a monoclonal antibody (mAb) that binds to PECAM-1, wherein the LNPs encapsulated the nucleoside-modified RNA comprises m1pseudouridine modified nucleoside, see p. 3, mRNA production and formulation into lipid nanoparticles, see p. 3, Preparation and characterization of targeted lipid nanoparticles, in particular. Likewise, Foster teaches nucleoside modified m1Ψ-mRNA, the same nucleoside used by applicant in the working example as disclosed in the specification and reproduced below for Applicant’s convenient.
[0579] Coding sequences of Cre recombinase or firefly luciferase were codon-optimized, synthesized and cloned into the mRNA production plasmid (pUC-ccTEV-Cre-A101 and pUC-ccTEV-Luc2-A101, respectively). mRNAs were produced using T7 RNA polymerase (Megascript, Ambion) on linearized plasmids. mRNAs were transcribed to contain 101 nucleotide-long poly(A) tails. m1Ψ-5′-triphosphate (TriLink) instead of UTP was used to generate modified nucleoside-containing mRNA. Capping of the in vitro transcribed mRNAs was performed co-transcriptionally using the trinucleotide cap1 analog, CleanCap (TriLink). mRNA was purified by cellulose purification, as described (Baiersdorfer et al., 2019, Mol Ther Nucleic Acids, 15:26-35). All mRNAs were analyzed by native agarose gel electrophoresis and were stored frozen at −20° C.
Parhiz and Foster do not teach that the targeting domain is anti-CD4 antibody as per claim 1. However, this deficiency is remedy by the teachings of Ramishetti. Ramishetti teaches a novel strategy to specifically deliver siRNAs to murine CD4+ T cells using anti-CD4 antibody to target lipid nanoparticles (tLNPs) to T cells would have led one of ordinary skill in the art to substitute Parhiz or Foster’ antibody conjugated to Pegylated LNP encompassed nucleoside modified mRNA for another, e.g., anti-CD4 to arrive at the claimed composition.
Therefore, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
In response to applicant's argument that a composition for transfecting CD4 expressing T cells in vivo, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Further, Ramishetti teaches anti-CD4 antibody conjugated siRNA-LNPs can be used to specifically targeted lipid nanoparticles encapsulated therapeutic agent (siRNA-LNPs) specifically to CD4 T cells ex vivo (Figure 2) and in vivo (Figure 3), see entire document, p. 6707, right col, in particular.
For these reasons, the rejection is maintained.
Claims 1, 10 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Peer et al (US20180142261, published May 24, 2018; PTO 892) in view of Aneja (US20180163213, published June 14, 2018; PTO 892) and Smith et al (WO2018107028 publication, published June 14, 2018; PTO 892).
Peer teaches a composition for transfecting (see para. 0072]) CD4 expressing T cells in vivo (see para. [0049]) comprising a targeted lipid nanoparticle (LNP) comprising at least one ionizable cationic lipid (see para. [0027], [0028], [0087]), phosphatidylcholine (PC), see para. [0029], cholesterol (see para. [0029]), pegylated lipid (see para. [0031] to [0033]) conjugated to a targeting domain, e.g., anti-CD4 antibody (see para. , reference claims 50, 69), wherein the LNP encapsula