DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 1/29/2024. Claims 1-21 are pending. All pending claims are currently under examination.
Information Disclosure Statement
No Information Disclosure Statement has been provided with the present application, therefore no IDS has been considered. 37 CFR 1.98(a)(1) requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The references cited in the specification have not been considered because they are not filed in an IDS.
Claim Objections
Claims 5, 7-8, 10, and 15 are objected to because of the following informalities:
Claim 5 recites “hybridize to bulge region of the decoy.” This claim should be amended to recite either “hybridize to the bulge region” or “hybridize to a bulge region.”
Claims 7-8, 10 recite “the composition claim 1” which should be amended to read “the composition of claim 1.”
Claim 15 recites “decoy sequence present” which should be amended to read “decoy sequence is present.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-6 and 10-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 3, claim 3 recites “said sequence” which lacks proper antecedent basis because no “sequence” is previously recited in the claim or the claim from which claim 3 depends (claim 1). Claim 3 further recites “said decoy sequence” which also lacks proper antecedent basis as the term “decoy sequence” is not recited previously in the claims.
Regarding claim 4, claim 3 recites “said sequence” which lacks proper antecedent basis because no “sequence” is previously recited in the claim or the claim from which claim 4 depends (claim 1). Additionally, claim 4 recites that the additional nucleotides are complementary to nucleotides present in the BCRNA 200 region bound by said BCRNA200 decoy. It is unclear what the requirements of the additional nucleotides are meant to be, as SEQ ID NO: 7 is a single-stranded piece of RNA which does not itself “bound” a region.
Regarding claim 5, claim 5 recites “bulge region of the decoy.” However, the bulge region and/or bulge regions of SEQ ID NO: 7 or the BCRNA200 molecules are not specified in the specification. It is therefore unclear which nucleotide residues can be modified in the limitations recited in claim 5 because there is no defined or identified bulge region in the specification.
Regarding claim 6, claim 6 recites “said modification.” Claim 6 depends from claim 1, which does not recite a modification. Claim 6 therefore lacks proper antecedent basis by reciting “said modification.”
Regarding claim 10, claim 10 recites “said BC200 decoy.” Claim 10 depends from claim 1, which recites “a BC RNA200 decoy;” recitation of “said BC200 decoy” therefore lacks proper antecedent basis. Claim 10 should be amended to read “said BC RNA200 decoy.”
Claims 11-14 depend from claim 10 and do not resolve this 112(b) issue and are therefore also rejected.
Regarding claim 15, claim 15 recites “said decoy sequence.” Claim 15 depends from claim 1 which does not recite the term “decoy sequence.” Claim 15 therefore lacks proper antecedent basis.
Claims 16-18 depend from claim 15 and do not resolve this 112(b) issue and are therefore rejected.
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.
Claim 2 is rejected under 35 U.S.C. 101 because it is directed to naturally occurring products of nature.
Regarding claim 2, claim 2 recites SEQ ID NO: 8, where the claim is in general drawn to a structure comprising SEQ ID NO: 8. As shown in CP124246 (NCBI Accession CP124426, Yersinia enterocolitica, genome of Y. enterocolitica, downloaded from NCBI BLAST database), SEQ ID NO: 8 is a 100% match for residues 2228593-2228608 of the Y. enterocolitica genome (see page 1 of CP124426 for alignment). Thus, claim 2 recites a naturally occurring product of nature, where the claim is broadly drawn to the DNA sequence comprising SEQ ID NO: 8 (Step 2A, prong I). Claim 2 further recites characteristics of the sequence; however recitation of these characteristics do not add structural significance to the sequence recited, where claim 2 is broadly drawn to SEQ ID NO: 8. Thus, there are no additional limitations which add structural characteristics to render markedly different characteristics on the recited sequence. Thus, claim 2 is drawn to the naturally occurring Y. enterocolitica genome and is not subject matter eligible.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states 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, reduction to drawings, 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. See Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claims 1 and 2, claims 1 and 2 recite “A composition for treating neuropsychiatric lupus comprising a BC RNA200 decoy of SEQ ID NO: 7,” (claim 1, or SEQ ID NO: 8 for claim 2), where “said decoy inhibiting SLE-anti- BC IgG mediated displacement of one or more of transport factors, hnRNP A2 and Pura, from BCRNA dendritic targeting elements.” Thus, claims 1 and 2 are drawn to decoy molecules comprising SEQ ID NOs 7 or 8, where these molecules are recited with the functionality of inhibiting SLE antibodies from displacing transport factors from BCRNA targeting elements. The claims broadly encompass embodiments of molecules which are limited only in that they comprise SEQ ID NOs 7 or 8, including sequences which consist only of either SEQ ID NOs 7 or 8, or nucleic acid sequences which comprise either SEQ ID NO 7 or 8 with the addition of any other nucleotides at the 5’ and 3’ ends. These claims are problematic because the specification does not show representative species commensurate in scope with what is being claimed, where 1) sequences as short as either SEQ ID NOs 7 or 8 alone were not demonstrated with the recited function, where the specification shows that such sequences would likely be non-functional as recited (see below) and 2) the specification has not shown representative species to show possession of the genus of molecules encompassed by the claims because the claims encompass any sequence of nucleic acid which comprises SEQ ID NOs 7 or 8 where the specification has not demonstrated that this region is a minimal sequence region to perform the recited function of the claims (i.e., to inhibit SLE antibodies from displacing transport factors, see below).
Guidance Provided in the Specification
Regarding the guidance provided in the specification, the experimental approaches and results will be briefly summarized. The Applicant offers Examples 1-4 in the specification. Examples 1-4 recite experimental methods which identify nucleic acid, specifically RNA, targets of auto-antibodies derived from patients with Systemic lupus erythematosus (SLE). Through experiments such as electrophoretic mobility shift assays (EMSAs), the Applicants have identified RNA epitope targets of the auto-antibodies taken from SLE patients, and found that one such target is a transport domain of the native RNA BC00. The Applicants propose a pathogenic mechanism of neuropsychiatric lupus, where autoantibodies of lupus patients bind to the transport domain of the native BC200 RNA molecule, preventing the proper localization of the RNA molecules in the cell, where such inhibition renders pathogenic phenotypes manifested in some lupus patients (e.g., seizures). The Applicant proposes the administration of RNA decoys which would bind to the autoantibodies to prevent the pathogenic manifestations caused by the autoantibodies binding to native RNA molecules (see Figure 12 for proposed disease model). The Applicant has identified key domains of native RNA molecules to which the lupus autoantibodies bind:
“We investigated whether any of the three BC1 RNA 5' architectural motifs are
recognized as antigenic epitopes by SLE anti-BC abs. SLE anti-BC IgGs were used with WT BC1 RNA and with BC1 RNA derivatives in which one of these motifs had been altered by point mutations (see Fig. 1 for structures of the mutants used). We found that in BC1 RNA, the 5' domain noncanonical GA motif and unpaired U22 were both indispensable for SLE autoantibody recognition (Fig. 4C). The 5' domain basal internal loop, in contrast, was recognition irrelevant (Fig. 4C),” (page 41, second paragraph).
Note that BC1 is the rat homologue of the human BC200 RNA. Thus, the Applicant has established critical epitope domains to which SLE autoantibodies bind (page 41, second paragraph). Regarding the human BC200RNA, the Applicant has similarly tested functional domains, finding that the GA1 domain is a critical domain for autoantibody recognition and binding, where mutations in critical domains such as GA1 render the RNA molecules non-reactive to SLE antibody binding (see Figure 14B). In short, the Applicant establishes that certain domains of the RNA molecule are required for SLE autoantibodies to bind to the BC200 RNA.
Regarding the identification of “minimal” domains of the BC200 RNA which could bind to SLE antibodies, the Applicant recites that:
“We will employ BC200 RNA and the BC200 5' domain as decoys but will in addition use a minimal BC200 decoy that comprises the apical GA motif (GAl) and adjacent unpaired U-residues, flanked by G=C base-pair clamps. A minimal structure is desirable because of administration considerations. Examples of the minimal structure for BC200 Decoys are shown in Fig. 15,” (page 59, final paragraph, where the ”minimal BC200 decoy” referenced here is shown in Figure 15, which is the combination of SEQ ID NOs 7 and 8.)
and
“We will establish a minimal BC200 DTE, comprising the structural attributes that are necessary and sufficient to specify transport factor binding which are also targeted by SLE anti-BC abs and thereby develop new therapeutic approaches. We have proof-of-principle evidence that the seizure phenotype that is observed after introduction of SLE anti-BC abs into wild-type (WT) mice fails to materialize with the same SLE anti-BC abs coinjected with BC200 RNA or the BC200 5' domain (Table 2),” (page 59, fourth paragraph).
Thus, the Applicant recites that they will establish a minimal decoy domain effective for binding SLE autoantibodies (page 59, fourth and fifth paragraphs). However, the minimal domain was not in fact tested or established. For instance, as stated on page 59, fourth paragraph, with regards to Table 2, Table 2 depicts an in vivo experiment where pathogenic SLE antibodies are injected into mice, where the mice are also injected with BC200 RNA (i.e., full length RNA) or the “5’ domain” of BC200 RNA (see Table 2 on page 65). Table 2 is reproduced, below:
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As seen in Table 2, the presence of “decoys” prevented seizures in the model (above, “SLE sera + decoys”). However, per the description of the “decoys” in paragraphs 4 and 5 of page 59, the “decoys” included BC200 RNA and the “5’ domain” of BC200 RNA. Thus, a “minimal” decoy is not established which includes only SEQ ID NO 7 or 8, as presently recited in claims 1 and 2, respectively, because the “decoys” tested in Table 2 included a combination of BC200RNA and the 5’ domain, where the “5’ domain” is not clearly defined.
Furthermore, the specification offers experimental data which indicate that either SEQ ID NOs 7 or 8, by themselves, would not function with the recited functionality, where SEQ ID NOs 7 or 8 would be required to interact with the SLE antibodies. For example, the Applicant teaches the structure of BC200 RNA (Figure 13, reproduced in part, below, shown in comparison with the combination of SEQ ID NOs 7 and 8 from Figure 15):
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Fig. 13 Fig. 15
As discussed previously, the GA1 region of the BC200RNA is a critical domain for SLE antibody binding (Figure 14B). As shown above, the COMBINATION of SEQ ID NOs 7 and 8 render the GA1 structural motif. SEQ ID NO: 7 by itself is “GCGGCUUGAGCCCG,” i.e., SEQ ID NO: 7 is only half of proposed “minimal” domain (compare GCGGCUUGAGCCCG to the nucleotides in the left vertical half of Figure 15 shown above). SEQ ID NO: 7 by itself would not render the GA1 structural motif, as SEQ ID NO: 7 alone is a single-stranded RNA molecule. Given that the GA1 motif is required for SLE antibody binding (Figure 14B of the specification), the specification itself teaches that either SEQ ID NOs 7 or 8 alone are insufficient to act as SLE antibody decoys, as presently recited. Furthermore, even the minimal domain comprising the combination of SEQ ID NOs 7 and 8 (i.e., the full molecule represented in Figure 15) was not tested and reduced to practice. Therefore, a minimal decoy comprising either SEQ ID NOs 7 or 8, or their combination, was not shown to be in possession by the inventors because only full length “5’ domains” of the BC200RNA decoys were tested. The Applicant’s establishment of the GA1 motif as a required domain for SLE binding is not sufficient to claim that it is the ONLY element required SLE antibody binding, which is required by the claim.
Furthermore, the Applicant was not in possession of the genus of molecules which comprise SEQ ID NO: 7 and includes additional nucleotides . The proposed structure of the “decoy” comprising SEQ ID NO: 7 in Figure 15 also includes SEQ ID NO: 8 to render a double-stranded GA1 motif to be recognized by the SLE antibodies. However, presently recited in claim 1 are embodiments that include SEQ ID NO: 7 and mutations in SEQ ID NO: 8, which can remove the GA1 motif. Such embodiments are non-functional with regards to their ability to bind SLE antibodies, per Figure 14B. Thus, the Applicant is not in possession of the genus of molecules which “comprise” SEQ ID NO: 7 or 8 alone, which operate with the recited functionality, as the specification does not demonstrate that either of the core structures recited (SEQ ID NO: 7, claim 1, or SEQ ID NO: 8, claim 2) are alone sufficient to render the functionality recited in the claims.
Claims 3-21 depend from claim 1 and do not resolve these 112(a) issues and are therefore also rejected.
Regarding claim 4, while claim 4 recites that additional nucleotides complementary to BC 200 are added to SEQ ID NO: 7, claim 4 recites minimal nucleotide additions such as 1 nucleotide, where such an addition of one nucleotide to either the 5’ or 3’ end of SEQ ID NO: 7 would not yield the required GA1 motif to satisfy the required functionality recited in claim 1. Claim 4 is therefore also rejected.
Furthermore, regarding the state of the art, it is known that unpredictability exists in the ability of an antibody to bind to an RNA epitope. For instance, Shao (Shao Y et al. J Mol Biol. 2016 Oct 9;428(20):4100-4114) is a research article that focuses on the recognition of antibodies with RNA target epitopes (Title, Abstract, and throughout). Shao teaches that RNA epitopes and their minimal recognition sequences must be identified empirically through acquiring experimental results to map minimal epitope regions (Figure 1A). Shao teaches that:
“biological systems also possess a highly complex and dynamic cellular RNA population, collectively known as the transcriptome, and antibodies that target RNA could provide equally valuable reagents for medicine and research,” (page 3, first paragraph).
and
“The limitations of currently available libraries underscore the need to investigate structural and energetic principles of Fab:RNA complexes for a range of RNA types in order to elucidate the principles and minimum requirements underlying protein-RNA recognition and to inform future library design,” (page 4, first paragraph)
Thus, Shao teaches that RNA are highly complex and unpredictable molecules which can bind antibodies, where further characterization is required to identify minimal requirements underpinning the interactions of antibodies and RNA (above). Shao teaches that determining minimal binding epitopes requires experimental validation to identify the epitope through deletions and binding experiments (Figure 1B, page 5, third paragraph). Thus, the Applicant has not shown possession of either SEQ ID NOs 7 or 8 alone with the recited functionality, as these sequences alone were not tested as minimal regions for antibody binding.
Furthermore, it is known in the art that RNA can adopt complex secondary 3D structures. For instance, Schroeder (Schroeder SJ. RNA. 2018 Dec;24(12):1615-1624) is a review article that focuses on challenges when predicting higher order RNA structure (Title, Abstract, throughout). Schroeder teaches that “approaches to predicting RNA structures with multiple conformations and complex folding landscapes
will benefit from more experimentally well-defined test cases,” (page 1620, right column, first paragraph). Schroeder teaches that “with new metrics and more experimentally defined examples of multiconformation RNA ensembles, RNA structure prediction will continue to improve,” and “a single minimum free energy structure for an RNA sequence will change to a deeper appreciation for the many possible diverse structures encoded in an RNA sequence,” (page 1621, right column, second paragraph). Thus, Schroeder teaches that RNA folding landscapes are complex and need to be experimentally defined and validated, and further that RNA can adopt many diverse structures upon folding, where such structures require experimental validation and new metrics to predict (above). Given that RNA are known to adopt complex structural motifs, the Applicant has also not shown possession of the genus of molecules recited, which includes SEQ ID NOs 7 or 8 as part of larger, undefined nucleic acid chains which can adopt any sequence or 3D structure. Given that there is no restriction of what additional nucleotides SEQ ID NOL 7 or 8 could comprise in claims 1 or 2, the structural motifs can not be predicted (i.e., random addition of nucleotides will not predicably form the required GA1 motif required for SLE antibody binding). The Applicant has therefore not shown possession of the claimed genera of nucleic acids in claims 1 and 2. The Applicant has only tested full-length or complete 5’ domains of BC200RNA, and has not shown that either SEQ ID NOs 7 or 8 alone or with the addition of any additional random nucleotides will function as recited in claims 1 and 2.
112(a) - Enablement
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating neuropsychiatric lupus by administration BC200 RNA comprising the 5’ domain as shown in SEQ ID NO: 6 , does not reasonably provide enablement for treatment of neuropsychiatric lupus by the administration of minimal RNAs consisting of SEQ ID NO: 7, or minimal domains surrounding SEQ ID NO: 7. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of the Invention/Breadth of Claims
Regarding claim 21, claim 21 is drawn to a method of treating neuropsychiatric lupus by delivering an effective amount of the molecule recited in claim 1 (i.e., an RNA comprising SEQ ID NO: 7). Thus, the method recites a category of molecule, RNA which comprises SEQ ID NO: 7, to be administered to treat neuropsychiatric lupus. The claim broadly encompasses embodiments of the composition to be administered, including embodiments as short as SEQ ID NO: 7 itself, as wells as molecules which merely comprise SEQ ID NO: 7 without other structurally defined motifs or sequences. This claim language is problematic because the specification has not reduced to practice a composition which simply consists of SEQ ID NO: 7 shown to have efficacy in any treatment, nor does the specification enable a practitioner to reliably predict what additional nucleotides could be added to SEQ ID NO 7 to render required binding motifs to be effective in the recited method.
Guidance in the Specification
A complete discussion of the guidance provided in the specification is given in the Written Description above, and incorporated herein in its entirety. For the sake of brevity, the full summary of the guidance in the specification will not be duplicated here. To briefly summarize the guidance in the specification, the Applicant has tested a method of treating a neuropsychiatric lupus seizure model by administering BC200 RNA in combination with the “5’ domain” and shown that such administration abolishes seizure progression in the model (see Table 2 on page 65). However, RNA molecules as short as SEQ ID NO: 7 alone were not tested, and it was not shown that this is a minimal RNA domain to have the overall effect of treating neuropsychiatric lupus, as presently claimed. Furthermore, the specification indicates that the GA1 motif of BCRNA200 is required for SLE antibody binding (see Figure 14B). SEQ ID NO: 7 in itself does not contain the GA1 motif, where SEQ ID NO: 7 would need to be complemented to SEQ ID NO: 8 in order to comprise the required motif for SLE antibody binding (Figures 13 and 15). Thus, the Applicant has demonstrated the SEQ ID NO: 7 alone would likely not function with the effect of treating neuropsychiatric lupus because it lacks the required GA1 motif. Furthermore, the Applicant has not offered guidance with respect to what additional nucleotides can be added to SEQ ID NO: 7 to have the effect of treating lupus. For instance, the claims broadly include a nucleic acid molecule which comprises SEQ ID NO: 7 and any combination or number or additional nucleotides without restriction. The specification does not provide guidance for what structure of nucleic acid sequences would have the effect of being effective at treating lupus.
Unpredictability in the Art
Regarding the state of the art, it is known that unpredictability exists in the ability of an antibody to bind to an RNA epitope. For instance, Shao (Shao Y et al. J Mol Biol. 2016 Oct 9;428(20):4100-4114) is a research article that focuses on the recognition of antibodies with RNA target epitopes (Title, Abstract, and throughout). Shao teaches that RNA epitopes and their minimal recognition sequences must be identified empirically through acquiring experimental results to map minimal epitope regions (Figure 1A). Shao teaches that:
“biological systems also possess a highly complex and dynamic cellular RNA population, collectively known as the transcriptome, and antibodies that target RNA could provide equally valuable reagents for medicine and research,” (page 3, first paragraph).
and
“The limitations of currently available libraries underscore the need to investigate structural and energetic principles of Fab:RNA complexes for a range of RNA types in order to elucidate the principles and minimum requirements underlying protein-RNA recognition and to inform future library design,” (page 4, first paragraph)
Thus, Shao teaches that RNA are highly complex and unpredictable molecules which can bind antibodies, where further characterization is required to identify minimal requirements underpinning the interactions of antibodies and RNA (above). Shao teaches that determining minimal binding epitopes requires experimental validation to identify the epitope through deletions and binding experiments (Figure 1B, page 5, third paragraph). Thus, the Applicant has not demonstrated SEQ ID NO 7 alone with the recited functionality, as this sequence alone was not tested as a minimal region for antibody binding.
Furthermore, it is known in the art that RNA can adopt complex secondary 3D structures. For instance, Schroeder (Schroeder SJ. RNA. 2018 Dec;24(12):1615-1624) is a review article that focuses on challenges when predicting higher order RNA structure (Title, Abstract, throughout). Schroeder teaches that “approaches to predicting RNA structures with multiple conformations and complex folding landscapes
will benefit from more experimentally well-defined test cases,” (page 1620, right column, first paragraph). Schroeder teaches that “with new metrics and more experimentally defined examples of multiconformation RNA ensembles, RNA structure prediction will continue to improve,” and “a single minimum free energy structure for an RNA sequence will change to a deeper appreciation for the many possible diverse structures encoded in an RNA sequence,” (page 1621, right column, second paragraph). Thus, Schroeder teaches that RNA folding landscapes are complex and need to be experimentally defined and validated, and further that RNA can adopt many diverse structures upon folding, where such structures require experimental validation and new metrics to predict (above). Given that RNA are known to adopt complex structural motifs, the Applicant has a higher burden to offer guidance concerning what additional nucleic acid residues are compatible with the recited method,, which includes SEQ ID NO 7 as part of larger, undefined nucleic acid chain which can adopt any sequence or 3D structure. Given that there is no restriction of what additional nucleotides SEQ ID NO 7 could comprise in claims 1 or 2, the structural motifs can not be predicted (i.e., random addition of nucleotides will not predicably form the required GA1 motif required for SLE antibody binding).
Undue Experimental Burden
The practitioner is burdened with undue experimentation in order to practice the method and its breadth as claimed. The practitioner would be required to identify minimal additions to SEQ ID NO 7 which would function as recited, as well as what additional sequences can be added to SEQ ID NO 7 in order to be used as a treatment for lupus. The practitioner would be burdened by being required to identify what additional nucleotides could generate the required epitope/GA1 motif required for the composition of claim 1 to function as an RNA decoy, where such molecules would need to be experimentally validated and tested individually, where furthermore it is unpredictable what additional residues presently encompassed by the recited genus of molecule would adopt a suitable conformation to function to bind SLE antibodies to function as a treatment for neuropsychiatric lupus.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(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 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Metsky (US 2018/0340215 A1).
Regarding claim 1, claim 1 is broadly drawn to SEQ ID NO: 7, where the other limitations recited in the claim are inherent characteristics of the decoy (i.e., SEQ ID NO: 7). Metsky teaches a nucleic acid molecule comprising a 100% match of SEQ ID NO: 7 (SEQ ID NO: 240,722 of Metsky, shown below in alignment, paragraph 79 of Metsky):
1 – gcggcttgagcccg – 14 -instant SEQ ID NO: 7
49- gcggcttgagcccg – 62, Metsky, SEQ ID NO: 240,722
Thus, Metsky anticipates the molecule recited in claim 1 because Metsky recites the same structure and therefore the same inherent features.
Claim 2 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pan (CN1712532, published 2006, original Chinese and Machine Translation in English provided).
Regarding claim 2, claim 2 is broadly drawn to a nucleic acid sequence comprising SEQ ID NO: 8, where the other limitations recited in the claim are inherent characteristics of the decoy (i.e., SEQ ID NO: 8). Pan teaches a nucleic acid molecule comprising a 100% match of SEQ ID NO: 8 (SEQ ID NO: 1 of Pan, shown below in alignment with SEQ ID NO: 8, taken from page 10 of original Pan):
SEQ ID NO: 8 (instant) 1 CGGGCAATATAGCCGC 16
SEQ ID NO: 1 (Pan) 10 CGGGCAATATAGCCGC 25
Thus, SEQ ID NO: 1 of Pan anticipates SEQ ID NO: 8 as instantly recited because Pan teaches the same structure and therefore the same inherent features.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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.
Claims 1-2, 4, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Tiege (US 10,234,455 B2, published 3/22/2018, issued 3/19/2019) in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang). The rejection is evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human).
Regarding claim 1, claim 1 is most broadly drawn to a nucleic acid molecule comprising SEQ ID NO: 7. Per the specification, “BC200 decoy that comprises the apical GA motif (GA1) and adjacent unpaired U-residues, flanked by G=C base-pair clamps. A minimal structure is desirable because of administration considerations. Examples of the minimal structure for BC200 Decoys are shown in Fig.15,” (page 59, final paragraph). Figure 15 of the specification depicts SEQ ID NOs 7 and 8. Thus, SEQ ID NO: 7 is a GA motif of BC200 RNA flanked by GC residues.
Regarding BC200 RNA GA motifs which bind anti-SLE antibodies to prevent hnRNP binding, Tiege is a patent that teaches “hnRNP A2 recognizes a DTE, in the form of a noncanonical GA motif, that is located in the BC RNA 5' region,” (column, 2, first paragraph). Tiege teaches “The epitopes for the anti-BC Abs were identified to be
localized in the 5' region of the BC RNAs. Anti-BC Abs specifically targeted the GA motif,” (column 4, second paragraph). Tiege teaches “These findings indicate that anti-BC Abs targeting BC RNA GA motifs can displace hnRNP A2, interfering with
dendritic RNA delivery,” (column 4, third paragraph). Tiege teaches:
“A method of inhibiting the binding of an anti-BC RNA (regulatory brain specific cytoplasmic RNA) autoantibody or fragment thereof to BC RNA, said method comprising contacting the anti-BC RNA autoantibody or fragment thereof with a composition comprising an anti-autoimmune reagent that specifically binds to an anti-BC RNA autoantibody or fragment thereof, wherein the anti-autoimmune
reagent is one or more GA motifs of BC RNA,” (claim 1)
where furthermore Tiege teaches that “the anti-BC RNA autoantibody or fragment thereof is associated with the pathology of neuropsychiatric lupus,” (claim 2). Tiege teaches BC200 RNA, and that it binds to lupus antibodies (e.g., Figure 4, and throughout). As evidenced by GenBank U01308, BC200RNA is identical to instant SEQ ID NO: 6, the wildtype form of human BC200 RNA (see GenBank U01308, pages 1-2 for alignment and description). Thus, Tiege inherently teaches the sequence of BC200 RNA and its structure by teaching BC200 RNA, which has a known sequence. Tiege teaches that the GA-motif containing BC RNAs are useful for treating lupus (column 13, second paragraph). Thus, Tiege teaches the concept of using GA motifs derived from BC200 RNA to act as a therapeutic to treat lupus by affecting the binding of SLE antibodies and their disruption of transport factors such as hnRNP. Tiege teaches that the GA motifs that are important for lupus autoantibody reaction are in the 5’ domain of BC RNA molecules (column 12, second paragraph)
Tiege, while teaching the BC200 RNA, and its inherent sequence and structure, and teaches that the GA motif is useful for therapeutic administration to treat lupus by interacting with pathogenic lupus autoantibodies (column 13, second paragraph, claims 1-2 of Tiege), does not teach that the bases in the region of SEQ ID NO: 7 at the 5’ and 3’ ends are modified to be GCs, as described in the present specification.
Zhang is a research article focused on engineering RNA for stability for various biotechnology applications (Title, Abstract, and throughout). Zhang and Tiege therefore overlap in subject matter and field of endeavor because both focus on RNA applications in biotechnology and the preserving/using of structural motifs in such RNA applications. Zhang teaches that it is known that increasing the GC content in stem structures of RNAs improves their stability, where stem structures with higher GC content are more structurally stable (page 829, right column, second paragraph, Figure 2B). Thus, Zhang teaches a motive to introduce GC basepairings into RNA molecules, with the overall predictable effect of improving their structural stability (above).
Furthermore, as evidenced by Jang, the structure of human BC200 RNA was already known (Figure 1a). As seen in Figure 1A of Jang, and reproduced below, the GC clamp modifications presently recited in SEQ ID NO: 7 fall within the stem region immediately adjacent to the bulge/loop structure in BC200 RNA (see below, Jang Figure 1A in part):
PNG
media_image4.png
302
519
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Greyscale
With respect to SEQ ID NO: 7 compared with the above portion of 5’ BC200 RNA, the 5’ “AUA” region and 3’ regions in SEQ ID NO: 7 are converted to GC clamps relative to wildtype BC200RNA, which as shown above are in a stem structure (see Figure 1A of Jang), with additional GC pairings are in the stem region on the other side of the loop (above). Thus, the recited GC modifications fall within a known stem region of BC200RNA, as evidenced by Jang.
It would have been obvious to a person of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the GA motif/antibody binding strategy and BC200RNA molecules taught by Tiege to include GC residues in the stem region as taught by Zhang, because such a combination is the simple combination of known prior art elements with predictable success. Furthermore the combination is not simply the combination of two elements – the practitioner would be motivated to modify the stem region of the BC200RNA because Zhang teaches that such modifications lead to improved structural stability. Given that the Tiege methods involve the in vivo administration of GA motifs from BC RNAs to treat lupus (column 13, second paragraph), and specifically teaches BC200 RNA, the practitioner would understand that structural stability and motif integrity would be important for the design and methods of Tiege, who also already taught that GA motifs are key binding domains and active sites for lupus antibody binding.
Regarding claim 2, claim 2 recites SEQ ID NO: 8. As shown in instant Figure 15, SEQ ID NO: 8 is simply the complementary portion of SEQ ID NO: 7, comprising complementary GC mutations with respect to SEQ ID NO: 7. Thus, SEQ ID NO: 8 is rendered obvious for the same reasons given in the rejection of claim 1, where claims 1-2 are broadly drawn to RNA molecules which comprise either SEQ ID NOs 7 or 8 (i.e., the 5’ domain of BC200RNA, where Tiege teaches that the GA motifs within this domain are the active sites for lupus autoantibody binding, see rejection of claim 1, above).
Regarding claim 4, Tiege teaches that the entirety of the 5’ domain functionally binds lupus antibodies (e.g., column 12, second paragraph). Thus, it would be obvious that the RNA molecules taught by Tiege could further comprise additional portions of the 5’ domain including the region bounded by SEQ ID NO: 7, to include the entire 5’ domain region, as Tiege taught and reduced to practice that the 5’ domain was effective at binding the pathogenic lupus antibody (column 12, second paragraph, Figure 3C).
Regarding claims 20-21, Tiege teaches that agents that inhibit the binding of lupus autoantibodies to their target , specifically comprising GA motif elements, are useful for treating lupus (column 13, second paragraph, and claims 1-2). Given that Tiege already teaches the therapeutic benefits of using their GA-motif containing anti-autoimmune reagents (i.e., BC RNA with GA motifs that bind lupus autoantibodies), it would be obvious that such reagents would be formulated in a pharmaceutical carrier, to be used as a treatment of SLE (column 13, second paragraph, claims 1-2 of Tiege).
Claims 3, 5-9, 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Tiege (US 10,234,455 B2, published 3/22/2018, issued 3/19/2019) in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human), as applied to claims 1-2, above, and further in view of Chen (US 2011/0092739 A1).
The teachings of Tiege, Zhang, Jang, and GenBank U01308 are given above and incorporated here.
Regarding claim 3, Tiege, Zhang, Jang, and GenBank U01308 do not teach that the 5’ or 3’ ends have a phosphate to reduce degradation.
Chen is a patent document that teaches delivery methods for molecules such as double-stranded RNA (Abstract). Chen therefore directly overlaps with Tiege because both teach the delivery of RAN molecules as therapeutics. Chen teaches 5’ addition of a phosphate to reduce exonuclease degradation, specifically with RNA decoy molecules such as those taught by Tiege (paragraphs 522-523).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the RNA decoy molecules taught by Tiege to include a terminal phosphate group to reduce degradation, as taught by Chen, as such a combination is the application of a known technique to improve a similar product in the same way. In the present case, a practitioner would be motivated to include the phosphate at the terminal end of the molecules taught by Tiege because Chen already teaches the benefits of using terminal phosphates.
Regarding claims 5-6, Chen teaches that beneficial modifications such as locked nucleic acids can be added to the 5’ or 3’ end of a given RNA molecule, which would not be in the “bulge” region as evidenced by Figure 1A of Jang (paragraph 244).
Regarding claim 7, Chen teaches phosphorothioate linkages to improve the stability of RNA molecules (paragraph 512).
Regarding claims 8-9, Chen teaches liposomes for the delivery of RNA agents (paragraph 11).
Regarding claims 15-18, Chen teaches that nucleic acids can be formulated and delivered in such vectors as adeno-associated viral vectors (paragraph 372).
Claims 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Tiege (US 10,234,455 B2, published 3/22/2018, issued 3/19/2019) in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human), as applied to claims 1-2, above, and further in view of Moss (Moss KH et al. Mol Pharm. 2019 Jun 3;16(6):2265-2277).
A discussion of the teachings of Tiege, Zhang, Jang, and GenBank U01308 are given above and incorporated here.
Regarding claims 10-14, Tiege, while teaching the delivery of BC200RNA RNA as decoys in vivo (column 13, second paragraph), does not teach that the decoy is bound to a lipid nanoparticle via an organic polymer spacer that is water soluble.
Moss is a research article that focuses on lipid nanoparticles for the delivery of RNA therapeutics (Title, Abstract, and throughout). Moss and Tiege therefore overlap in subject matter because both concern the delivery of therapeutic RAN molecules. Moss teaches that lipid nanoparticles which are conjugated to organic spacer polymers such as PEG are known in the art (page 2272, right column, second paragraph). Moss teaches that the organic water soluble PEG is a known ligand for decorating LNPs (page 2272, right column, second paragraph, where furthermore PEG is listed as one such embodiment of the recited polymers in the present specification at page 29, fourth paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the delivery of BC200RNAs as taught by Tiege to include LNPs comprising polymer moieties/ligands such as PEG because Moss teaches that such LNP and ligand formulations are already known in the art. The combination is the simple combination of known prior art elements with predictable success. Furthermore, the results are predictable because Moss and Tiege both use the same reagent types (i.e., therapeutic RNAs).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Tiege (US 10,234,455 B2, published 3/22/2018, issued 3/19/2019) in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human), as applied to claims 1-2, above, and further in view of Ostensen (Ostensen M et al. Lupus. 2000;9(8):566-72).
The teachings of Tiege, Zhang, Jang, and GenBank U01308 as they relate to claims 1-2, 4, and 20-21 are incorporated here.
Tiege teaches that their GA-motif containing BC RNAs are useful for treating lupus (column 13, second paragraph). Tiege does not mention that the BC RNAs compositions further comprise anti-inflammatory drugs.
Ostensen is a research article focused on anti-inflammatory drugs and their use in treating lupus (Title, Abstract, throughout). Tiege and Ostensen therefore directly overlap because they are both focused on treating the same disease (lupus). Ostensen teaches that lupus is an inflammatory disease, and that it is commonly treated with anti-inflammatory drugs (e.g., Abstract, and throughout).
It would have been obvious to a person of ordinary skill in the art to include anti-inflammatory drugs in the composition rendered obvious by Tiege, Zhang, Jang, and GenBank U01308, as taught by Ostensen, because Ostenses teaches that anti-inflammatory drugs are routinely given in order to treat lupus (Abstract). The practitioner would therefore be motivated to include anti-inflammatory drugs along with the composition of claim 1, so as to effectively treat lupus.
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 1-2, 4, and 20-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No 10,234,455 B2 (hereafter ‘455). in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human).
Regarding instant claims 1-2, claims 1-2 of ‘455 recite:
1. A method of inhibiting the binding of an anti-BC RNA
(regulatory brain specific cytoplasmic RNA) autoantibody
or fragment thereof to BC RNA, said method comprising
contacting the anti-BC RNA autoantibody or fragment
thereof with a composition comprising an anti-autoimmune
reagent that specifically binds to an anti-BC RNA autoantibody
or fragment thereof, wherein the anti-autoimmune
reagent is one or more GA motifs of BC RNA.
2. The method of claim 1, wherein the anti-BC RNA
autoantibody or fragment thereof is associated with the
pathology of neuropsychiatric lupus.
The teachings of ‘455, i.e., Tiege, as they are applied in the 103 rejection above are incorporated here in there entirety.
‘455 further teaches that the anti-autoimmune reagent that is a GA motif of a BCRNA can be BC200 RNA (e.g., Figure 4A), and further that such GA-motif containing BC RNA molecules are useful for treating lupus (column 13, second paragraph).
‘455, while teaching the BC200 RNA, and its inherent sequence and structure, and teaches that the GA motif is useful for therapeutic administration to treat lupus by interacting with pathogenic lupus autoantibodies (column 13, second paragraph claims 1-2), does not teach that the bases in the region of SEQ ID NO: 7 at the 5’ and 3’ ends are modified to be GCs, as described in the present specification.
Zhang is a research article focused on engineering RNA for stability for various biotechnology applications (Title, Abstract, and throughout). Zhang and ‘455 therefore overlap in subject matter and field of endeavor because both focus on RNA applications in biotechnology and the preserving/using structural motifs in such RNA applications. Zhang teaches that it is known that increasing the GC content in stem structures of RNAs improves their stability, where stem structures with higher GC content are more structurally stable (page 829, right column, second paragraph, Figure 2B). Thus, Zhang teaches a motive to introduce GC basepairings into RNA molecules, with the overall predictable effect of improving their structural stability (above).
Furthermore, as evidenced by Jang, the structure of human BC200 RNA was already known (Figure 1a). As seen in Figure 1A of Jang, and reproduced below, the GC clamp modifications presently recited in SEQ ID NO: 7 fall within the stem region immediately adjacent to the bulge/loop structure in BC200 RNA (see below):
PNG
media_image4.png
302
519
media_image4.png
Greyscale
With respect to SEQ ID NO: 7 compared with the above portion of 5’ BC200 RNA, the 5’ “AUA” region and 3’ regions in SEQ ID NO: 7 are converted to GC clamps relative to wildtype BC200RNA, which as shown above are in a stem structure (see Figure 1A of Jang), with additional GC pairings are in the stem region on the other side of the loop (above). Thus, the recited GC modifications fall within a known stem region of BC200RNA, as evidenced by Jang.
It would have been obvious to a person of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the GA motif/antibody binding strategy and BC200RNA molecules taught by ‘455 to include GC residues in the stem region as taught by Zhang, because such a combination is the simple combination of known prior art elements with predictable success. Furthermore the combination is not simply the combination of two elements – the practitioner would be motivated to modify the stem region of the BC200RNA because Zhang teaches that such modifications lead to improved structural stability. Given that the ‘455 methods involve the in vivo administration of GA motifs from BC RNAs (column 13, second paragraph), and specifically teaches BC200 RNA, the practitioner would understand that structural stability and motif integrity would be important for the design and methods of ‘455, who also already taught that GA motifs are key binding domains and active sites for lupus antibody binding.
Regarding claim 2, claim 2 recites SEQ ID NO: 8. As shown in instant Figure 15, SEQ ID NO: 8 is simply the complementary portion of SEQ ID NO: 7, comprising complementary GC mutations with respect to SEQ ID NO: 7. Thus, SEQ ID NO: 8 is rendered obvious for the same reasons given in the rejection of claim 1, where claims 1-2 are broadly drawn to RNA molecules which comprise either SEQ ID NOs 7 or 8 (i.e., the 5’ domain of BC200RNA, where ‘455 teaches that the GA motifs within this domain are the active sites for lupus autoantibody binding, see rejection of claim 1, above).
Regarding claim 4, ‘455 teaches that the entirety of the 5’ domain functionally binds lupus antibodies (e.g., column 12, second paragraph). Thus, it would be obvious that the RNA molecules taught by ‘455 could further comprise additional portions of the 5’ domain including the region bounded by SEQ ID NO: 7, to include the entire 5’ domain region, as ‘455 taught and reduced to practice that the 5’ domain was effective at binding the pathogenic lupus antibody (column 12, second paragraph, Figure 3C).
Regarding claims 20-21, ‘455 teaches that agents that inhibit the binding of lupus autoantibodies to their target , specifically comprising GA motif elements, are useful for treating lupus (column 13, second paragraph, and claims 1-2). Given that ‘455 already teaches the therapeutic benefits of using their GA-motif containing anti-autoimmune reagents (i.e., BC RNA with GA motifs that bind lupus autoantibodies), it would be obvious that such reagents would be formulated in a pharmaceutical carrier, to be used as a treatment of SLE (column 13, second paragraph, claims 1-2 of ‘455).
Claims 3, 5-9, 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No 10,234,455 B2 (hereafter ‘455). in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human) as applied to claims 1-2, above, and further in view of Chen (US 2011/0092739 A1).
The teachings of ‘455, Zhang, Jang, and GenBank U01308 are given above and incorporated here.
Regarding claim 3, ‘455, Zhang, Jang, and GenBank U01308 do not teach that the 5’ or 3’ ends have a phosphate to reduce degradation.
Chen is a patent document that teaches delivery methods for molecules such as double-stranded RNA (Abstract). Chen therefore directly overlaps with ‘455 because both teach the delivery of RAN molecules as therapeutics. Chen teaches 5’ addition of a phosphate to reduce exonuclease degradation, specifically with RNA decoy molecules such as those taught by ‘455 (paragraphs 522-523).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the RNA decoy molecules taught by ‘455 to include a terminal phosphate group to reduce degradation, as taught by Chen, as such a combination is the application of a known technique to improve a similar product in the same way. In the present case, a practitioner would be motivated to include the phosphate at the terminal end of the molecules taught by ‘455 because Chen already teaches the benefits of using terminal phosphates.
Regarding claims 5-6, Chen teaches that beneficial modifications such as locked nucleic acids can be added to the 5’ or 3’ end of a given RNA molecule, which would not be in the “bulge” region as evidenced by Figure 1A of Jang (paragraph 244).
Regarding claim 7, Chen teaches phosphorothioate linkages to improve the stability of RNA molecules (paragraph 512).
Regarding claims 8-9, Chen teaches liposomes for the delivery of RNA agents (paragraph 11).
Regarding claims 15-18, Chen teaches that nucleic acids can be formulated and delivered in such vectors as adeno-associated viral vectors (paragraph 372).
Claims 10-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No 10,234,455 B2 (hereafter ‘455). in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human) as applied to claims 1-2, above, and further in view of Moss (Moss KH et al. Mol Pharm. 2019 Jun 3;16(6):2265-2277).
A discussion of the teachings of ‘455, Zhang, Jang, and GenBank U01308 are given above and incorporated here.
Regarding claims 10-14, ‘455, while teaching the delivery of BC200RNA RNA as decoys in vivo (column 13, second paragraph), does not teach that the decoy is bound to a lipid nanoparticle via an organic polymer spacer that is water soluble.
Moss is a research article that focuses on lipid nanoparticles for the delivery of RNA therapeutics (Title, Abstract, and throughout). Moss and ‘455 therefore overlap in subject matter because both concern the delivery of therapeutic RAN molecules. Moss teaches that lipid nanoparticles which are conjugated to organic spacer polymers such as PEG are known in the art (page 2272, right column, second paragraph). Moss teaches that the organic water soluble PEG is a known ligand for decorating LNPs (page 2272, right column, second paragraph, where furthermore PEG is listed as one such embodiment of the recited polymers in the present specification at page 29, fourth paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the delivery of BC200RNAs as taught by ‘455 to include LNPs comprising polymer moieties/ligands such as PEG because Moss teaches that such LNP and ligand formulations are already known in the art. The combination is the simple combination of known prior art elements with predictable success. Furthermore, the results are predictable because Moss and ‘455 both use the same reagent types (i.e., therapeutic RNAs).
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No 10,234,455 B2 (hereafter ‘455). in view of Zhang (Zhang Q et al. Nat Chem Biol. 2021 Jul;17(7):828-836, published June 2021 online per page 1 of Zhang) as evidenced by Jang (Jang S et al. BMB Rep. 2020 Feb;53(2):94-99) and GenBank U01308 (GenBank accession number U01308, published 2008, BC200 RNA gene, human), as applied to claims 1-2, above, and further in view of Ostensen (Ostensen M et al. Lupus. 2000;9(8):566-72).
The teachings of ‘455, Zhang, Jang, and GenBank U01308 as they relate to claims 1-2, 4, and 20-21 are incorporated here.
‘455 teaches that their GA-motif containing BC RNAs are useful for treating lupus (column 13, second paragraph). ‘455 does not mention that the BC RNAs compositions further comprise anti-inflammatory drugs.
Ostensen is a research article focused on anti-inflammatory drugs and their use in treating lupus (Title, Abstract, throughout). ‘455 and Ostensen therefore directly overlap because they are both focused on treating the same disease (lupus). Ostensen teaches that lupus is an inflammatory disease, and that it is commonly treated with anti-inflammatory drugs (e.g., Abstract, and throughout).
It would have been obvious to a person of ordinary skill in the art to include anti-inflammatory drugs in the composition rendered obvious by ‘455, Zhang, Jang, and GenBank U01308, as taught by Ostensen, because Ostenses teaches that anti-inflammatory drugs are routinely given in order to treat lupus (Abstract). The practitioner would therefore be motivated to include anti-inflammatory drugs along with the composition of claim 1, so as to effectively treat lupus.
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights