DDETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 1, 2, 4-8, 10-13, 17-20, 23, and 26-29 are pending. Applicant’s election without traverse of group I (Claims 1, 2, 4-8, 10-13, 17-20, and 29) is acknowledged. Applicant elects the species of a lipid nanoparticle (1 st species) and glutamic acid (2nd species). Claims 23 and 26-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Examiner notes that claim 29 is also withdrawn from consideration as being drawn to a method, i.e. a non-elected group.
Examination on the merits commences on claims 1, 2, 4-8, 10-13, and 17-20.
Claim Rejections - 35 USC § 101
`35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, 5-8, 10-13, and 17-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims are drawn to an oligonucleotide. However, the claims do not include elements, when considered separately and in combination, that are sufficient to amount to significantly more than the judicial exceptions as outlined below.
Subject Matter Eligibility Test for Products and Processes: Claim 1.
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES
Claims 61 is directed to composition comprising in solution: at least 1 mM of a free amino acid; and a capsule comprising isolated RNA.
Step 2A, Prong One - Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Natural phenomena have been identified by the courts by way of example, including products of nature. Claim 1 is drawn to a solution containing a free amino acid, a capsule, and an isolated RNA. Each of these is a product of nature. For natural products, products that are not “markedly different” than their naturally occurring counterparts, are judicial exceptions. See MPEP 2016.04((b). Free amino acids are not markedly different from amino acids in a cell used as components for protein assembly. Capsules are not markedly different from a cell’s phospholipid bilayer membrane. Isolated RNA is not markedly different from free complementary RNA ejected from the cell during exocytosis or apoptosis. MPEP 2106.04(c) outlines the markedly different analysis.
The claim limitations are not markedly different than their naturally occurring counterparts and constitutes a judicial exception.
Step 2A, Prong Two - Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. The phrase "integration into a practical application" requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. Claim 1 does not recite any additional elements that would integrate the natural product into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claim as a whole is evaluated as to whether it amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). In this case no additional elements are recited in claim 1. Therefore, the claim does not amount to something significantly more than the judicial exception.
Subject Matter Eligibility Test for Products and Processes – Dependent claims
Note that Claims 4 is not rejected under §101. Claim 4 discloses a synthetic 5 prime cap. Therefore, this claim is more than mere natural phenomenon.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 5, 10-13, 17, and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jones (Jones, M., WO2019246313A1).
Regarding claim 1, Jones teaches combinations of active agents in liquid formulations of a micelle carrier delivering TNF inhibitors to treat a disease of the gastrointestinal tract (title, pg 6 lines 5-8). Jones teaches the TNF-alpha inhibitor includes an RNA such as shRNA (pg 558 line 15) and other types of inhibitors such as antibody inhibitors (pg 62 line 10-29) used together in combination for enhanced TNF-alpha inhibition (claim 3). Jones teaches the inhibitors formulated within a nanoparticle (pg 214 line 12) such as a gold-nanoparticle (pg 496 line 12). Jones teaches antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., a lentivirus, a retrovirus, or an adenovirus vector) (pg 205 line 1). Jones further teaches the liquid formulation administered comprises at least about 60 mg/mL of an antibody, at least about 10% (w/v) of a non-reducing sugar, and at least about 175 mM of one or more free amino acids (pg 62 line 10-29). Jones teaches the formulation can include any desired free amino acid, a salt thereof, or a combination thereof, which can be in the L-form, the D-form or any desired mixture of these forms (pg 62 line 10-29). Jones teaches the free amino acids that can be included in the formulation include, for example, any one of the 20 essential amino acids, or more particular amino acids, such as histidine, alanine, arginine, glycine, glutamic acid, serine, lysine, tryptophan, valine, cysteine, methionine, and any combination thereof (pg 62 line 10-29). Jones teaches the amino acids stabilize an antibody against degradation during manufacturing, drying, lyophilization and/or storage, e.g., through hydrogen bonds, salt bridges antioxidant properties or hydrophobic interactions or by exclusion from the protein surface (pg 62 line 10-29). Jones teaches amino acids act as tonicity modifiers or can act to decrease viscosity of the formulation (pg 62 line 10-29). Jones teaches free amino acids, such as histidine and arginine, can act as cryoprotectants and lyoprotectants, and do not crystallize when lyophilized as components of the formulation and that free amino acids, such as glutamic acid and histidine, alone or in combination, can act as buffering agents in an aqueous formulation (pg 62 line 10).
Examiner interprets the teachings of Jones to anticipate the claimed composition comprising in solution at least 1 mM of a free amino acid; and a capsule comprising isolated RNA.
Regarding claim 5, Jones teaches the nucleic acid inhibitor can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (pg 204 line 5).
Regarding claim 10, Jones teaches the inhibitory nucleic acid formulated within a lipid nanoparticle (pg 214 line 24).
Regarding claims 11 and 12, Jones teaches the formulations, which include the free amino acid, may contained within a solution with the inhibitory RNA or contained within a nanoparticle along with the inhibitory RNA (pg 60, line 29-35 and pg 40 line 25-35).
Regarding claim 13, Jones teaches the formulation comprises an amino acid; optionally, the amino acid is a free amino acid selected from the group consisting of histidine, alanine, arginine, glycine, glutamic acid and methionine, and a combination of any two or more of the foregoing; preferably, the free amino acid is histidine, arginine, or a combination thereof (claim 57).
Regarding claim 17, Jones teaches the pharmaceutical formulation contains a sugar and an aqueous buffer system (pg 721 line 3, claims 49-57).
Regarding claims 20, Jones teaches the buffer and/or final solution formulation pH is about 7. (pg 47 line 13).
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.
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.
Claim(s) 1, 2, 4, 6-8, and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones (Jones, M., WO2019246313A1), as applied to claims 1 and 17, in view of Khan (Khan, O., US-20200155660-A1) and Wood (Wood, K., WO-2019067992-A1).
The teachings of Jones as applied above to claims 1 and 17 are incorporated here.
Regarding claims 2 and 4, Jones does not teach where in the RNA is an mRNA or saRNA or which contains the 5 prime cap of claim 4 with additional components: a 5' untranslated region; a coding region for a nonstructural protein derived from an alphavirus; a subgenomic promoter derived from an alphavirus; an open reading frame encoding a gene of interest; a 3' untranslated region; and
a 3' poly A sequence.
However, Khan teaches prophylactic and diagnostic agents encapsulated within modified dendrimer nanoparticles (MDNPs) which include one or more nucleic acids, such as expression vectors or mRNAs, where the vectors can encode one or more genic regions for expression within the recipient cell [0145]. Khan teaches heterologous sequences carried in the MDNP nanoparticle delivery system include mRNAs, antisense molecules, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, and external guide sequences. The functional nucleic acid molecules can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules can possess a de novo activity independent of any other molecules [0144-0149]. Khan teaches MDNP-delivered alphavirus derived replicons within nanoparticle delivery systems able to deliver a variety of payloads [0403]. Replicons are attenuated virus genomes lacking viral structural proteins required for the production of progeny virions [0128]. Kan teaches MDNPs with a broad range of amplifiable payloads which includes replicon subgenomic promoters [0341]. Khan teaches Alphaviral self-amplifying repRNA typically includes a 5′ Cap; 5′ untranslated region (5′UTR), non-structural genes (e.g., NSP1-4) encoded within a first open reading frame, a genomic promoter region (e.g., 26S sub-genomic promoter), a second open reading frame, a 3′ untranslated region (3′UTR) and a 3′ poly-adenylated tail (See FIGS. 1A-1C, [0129]).
Wood teaches lipid nanoparticle-based compositions having improved properties for the delivery of biologically active agents, modified cells, and methods for administering these agents (abstract). Wood discloses RNA with a 5 prime cap [083]. Wood teaches the use of a 5′ cap specifically as a CleanCap™ AG structure [085], identical to the 5 prime cap disclosed in claim 4, including adenine and guanine as the B1 and B2 attachments.
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It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Jones’ enhanced combination RNA nanoparticle delivery system to include the RNA payloads disclosed by Khan which are enhanced to deliver a therapeutic RNA to a target such as replicon modulated to encode TNF-alpha inhibitors. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Khan’s RNA payloads could be effectively delivered within Jones’ nanoparticle delivery system because Jones teaches a variety of effective RNA payloads for delivery within nanoparticles and because Khan teaches the replicons can code for heterologous nucleic acids which can act as inhibitors. It would have been predictable that Jones’ composition solutions would benefit the nanoparticle payload effectiveness because Jones teaches the free amino acids in the composition solution stabilize the nanoparticle delivery composition against degradation in a number of ways such as tonicity modifiers and cryoprotection. Furthermore, it would have been predictable that Wood’s 5′ synthetic cap could be effective within Khan’s RNA payload in place of Khan’s 5′cap because Woods discloses use of the CleanCap™ AG structure within the nucleic acid structure. Therefore, the skilled artisan would be motivated to combine the RNA delivering nanoparticle components of Khan and Woods into Jones’ combination nanoparticle inhibition system to enhance overall payload and anti-TNF-alpha effectiveness for the treatment of GI disease.
Regarding claims 6-8, Khan teaches the exogenous nucleic acid sequences of the invention can encode a vaccine antigen which includes a viral antigen [0162-164]. It would have been obvious to one skilled in the art to include Khan’s viral antigens and vaccine delivery vector within Jones’ nanoparticle nucleic acid delivery system to enhance payload and vector uptake in a subject.
Regarding claims 18 and 19, Jones is silent as to exact concentration of the sugar and buffer in solution, however, Examiner notes that the optimization of doses/concentrations (i.e. concentrations of sugar and buffer in solution) would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claims 18 and 19 are obvious and is properly rejected under 35 U.S.C. 103.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637