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
Applicant’s election without traverse of Group I (Claims 1-6; drawn to a method of protecting RNA from degradation by contacting the RNA with a boron compound) in the reply filed on November 16, 2025, is acknowledged.
Claims 7-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 7, 2024.
Applicant further elected the following species:
a. N- [(5aR,6aS,7S,10aS)-9-carbamoyl-4,7-bis(dimethylamino)-1,8,10a,11-tetrahydroxy-10,12- dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]-1-hydroxy-3,3-dimethyl-1,3-dihydro- 2,1-benzoxaborole-6-carboxamide as the boron compound
Rejoinder
The species election requirement for the species of boron has been reconsidered in view of the prior art and has been withdrawn.
DETAILED ACTION
The claims filed on November 16, 2025, have been acknowledged. In light of the Applicant’s elected invention, claims 7-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-6 are pending and examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 63/072,778, filed August 31, 2020 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This provisional application provides information related to 14 of the boron compounds identified in claim 6 (see Table 1 on pages 33-35 of the provisional application). However, Application No. 63/227,098, filed on July 29, 2021, did provide information for the remaining boron compounds found in claim 6. Therefore, claims 1-6 (only including the compounds identified in Application No. 63/072,778) receive domestic benefit from US provisional application 63/072,778, filed August 31, 2020, while the compounds of claim 6 not included in Application No. 63/072,778 receive domestic benefit from Application No. 63/227,098, filed on July 29, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on May 9, 2023, has been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 are 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 protecting specific RNA sequences (Chi-18, HCV IRES, and Fgen1 depending on the boron compound) using specific boron compounds with an EC50 below 300 μM for the specific RNA sequence in a specific buffer, does not provide enablement for using any boron compound to protect any RNA sequence in any solution at any concentration at any pH. 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. The prior art provides enablement for using Jeremejevite, Ludwigite, and Hambergite at low concentrations (10 μg/mL) in water and Rhodizite and Elbaite in formamide to protect RNA, using boron metal as a lyoprotectant to stabilize RNA during storage, and modifying siRNAs with a lipophilic boron cluster (C2B10H11, CB) which increased the resistance to enzymatic degradation. The applicant’s disclosure does not provide enough information for any person skilled in the art to protect any RNA sequence with any boron compound in any solution at any concentration.
The factors to be weighed to evaluate whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is undue are set forth in MPEP 2164.01(a).
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Although all the factors have been considered, the relevant factors will be addressed below.
Breadth of the claims: Claim 1 recites the following claim language, “A method of protecting RNA from degradation by contacting the RNA with a boron compound.” The broadest reasonable interpretation is that this method could be used to protect any RNA sequence with any boron compound in any type of solution at any concentration. Furthermore, Claim 6 recites multiple born compounds and the broadest reasonable interpretation is that any of these compounds protect any RNA sequence in any type of solution at any concentration.
Nature of the invention: The subject matter of the invention relates to a method of protecting RNA with boron compounds.
State of the prior art: The prior art teaches multiple boron compounds that protect or degrade RNA and that this can depend on the solution containing the boron compound and RNA and the concentration of the born compound, as identified by Cossetti (Polymers 2: 211-228. 2010).
Cossetti teaches that they examined the effects of borate minerals on RNA in water and in formamide at 80 °C. This particular physical-chemical setting was selected because RNA degradation in these conditions takes reasonable experimental time span (page 213, paragraph 1). As can be seen in Table 3, a multitude of borate minerals either had no effect or caused degradation of the RNA. Of the tested borate minerals, only Jeremejevite, Ludwigite, and Hambergite had a protective effect in water and Rhodizite and Elbaite had a protective effect in formamide. Furthermore, it is important to note that this protective effect was dependent on the solution as Ludwigite and Hambergite caused degradation when placed in formamide, Rhodizite and Elbaite caused degradation when placed in water, and Jeremejevite had no effect when placed in formamide.
Furthermore, Cossetti teaches that the three minerals whose interaction with RNA in water increased stability (jeremejevite, ludwigite, hambergite) display a common behaviour: stabilization is observed only at low mineral concentration (10 μg/mL) while at high mineral concentration (103 μg/mL) degradation is stimulated (page 220, paragraph 1).
Therefore, Cossetti teaches multiple boron compounds that have a protective effect on RNA but that this protective effect is dependent on the solution the mineral is in and the concentration of the boron compound as degradation occurs in when placed in a different solution at high concentrations of the boron compound.
Furthermore, the prior art teaches that boron metals can be used as lyoprotectants to stabilize mRNAs for long-term storage as identified by United States Patent Application No. 20180243219 (Ketterer) and stabilize siRNA using a lipophilic boron cluster, as identified by Kwiatkowska et al. (Bioconjugate Chem. 24: 1017−1026. 2013).
Ketterer teaches that lyophilization of RNA in the presence of a lyoprotectant,
and under controlled conditions, preferably under controlled freezing and/or drying conditions as defined herein, results in a composition comprising RNA, which is characterized by an outstanding integrity of the RNA after completion of the lyophilization process and which is further characterized by increased storage stability, in particular with respect to storage for extended periods and/or under non-cooling conditions. Ketterer teaches that the lyophilized RNA can include mRNA encoding a viral antigen. Ketterer teaches that the lyoprotectant can be boron metal (paragraphs 0035, 0060, and 0182-0195).
Kwiatkowska teaches that they modified siRNAs targeted against the BACE1 gene at various positions with a lipophilic boron cluster (C2B10H11, CB) which increased the resistance to enzymatic degradation of the modified oligomers compared to the unmodified counterparts (abstract).
Kwiatkowska teaches that a set of RNA strands was synthesized to prepare thirteen siRNAs (I-XIII), directed toward mRNA of human BACE1 protein (Table1). The modified thymidine unit bearing the boron cluster at N3 was introduced at the position 3 or 20 of the siRNA sense strand, counting from the 5′-end [oligomers (CB3)s and (CB20)s]. The antisense strand was modified at position 20 [the oligomer (CB20)as]. These three modified RNA strands allowed us to obtain siRNA duplexes listed in rows II-VI in Table 1. siRNA duplexes I-XIII (Table 1) were assembled in phosphate saline buffer (PBS, without Ca2+ and Mg2+) by mixing equimolar amounts of complementary oligonucleotides, heating the mixture at 95 °C for 2 min, and slow cooling down to room temperature (ca. 2 h). Formation of the resulting duplexes was confirmed by 4% agarose gel electrophoresis (Figure 1) (page 1022, column 1, paragraph 2 and page 1023, column 1, paragraph 3).
Therefore, Ketterer and Kwiatkowska teach that boron can be used as a lyoprotectant to protect mRNA and lipophilic boron clusters can be used to protect siRNA from degradation.
Level of predictability in the art: The prior art successfully reduces to practice that multiple boron compounds can be used to prevent degradation of RNA, such as certain boron containing minerals and lipophilic boron clusters, and that mRNA and siRNA can be protected from degradation. However, the prior art teaches that these protective effects are dependent on the boron containing compound, concentration and solution. Otherwise, degradation or no effect occurs. As such, this results in unpredictability about how someone can use any boron compound to protect RNA and would require a trial-and-error test to examine the efficacy of each boron compound at different concentrations in different solutions at protecting RNA.
Amount of direction provided by the inventor and existence of working examples: The specification teaches they examined 50 boron containing compounds (1 of the compounds tested does not contain boron) in Table 1 for their efficacy at preventing degradation of Chi18, HCV IRES, FgenI, and a random 30 nt RNA oligonucleotide using multiple assays to assess RNA protection (RNA FP protection screen, syto-9 dye intercalation, and droplet digital PCR). Applicant discloses that in the FP protection assay, the y-axis percent activity represents the ability of the boron compound to protect the RNA from degradation, the syto-9 assay will produce a signal if there is an EC50- <300 μM and produce no signal if EC50 >300 μM, and the ddPCR assay will determine the EC50 for protecting degradation.
Figures 2, 4, and 6 correspond to FP protection screens for PF-07230998, PF-06967658, and PF-06966741 using a random 30 nt RNA sequence. As can be seen in these figures RNA protection is concentration dependent for each compound.
Figures 9-12 correspond to syto-9 assays for PF-06963078, PF-06962739, PF-06863029, and PF-06962691 using a FgenI and Chi-18 RNA. As can be seen in these figures, protection is dependent on concentration and the RNA sequence. For example, PF-06963078 has an EC--50 of 74 with Chi-18 RNA but has an EC50 of >300 for FgenI which is also found in the negative control counterscreen whereas PF-06863029 has an EC50 of >300 with Chi-18 RNA but has an EC50 of 63 for FgenI.
Figures 13-15 correspond to ddPCR assays assessing the EC50 of PF-06957640, PF-01499456, and PF-06959336 with either CHI-18 RNA at pH 10.4 or 11.4 or HCV IRES RNA at pH 11.4. As can be seen in the figures, the EC50 is dependent on the compound, pH (EC50 at pH 10.4 for PF-06957640 was 370.6 but 266.4 at pH 11.4), and RNA sequence dependent (EC50 for PF-06957640 was 266.4 with Chi-18 RNA but 388.2 for HCV IRES RNA).
Furthermore, Table 2 identifies the EC50 of 38 of the 50 compounds using ddPCR. However, it is unclear whether these are EC50 for Chi-18, HCV IRES RNA, a combination of the two as the methods identify that both RNAs were examined using ddPCR (as can be seen in Figures 13-15, the EC50 is dependent on the RNA) but Table 2 does not identify what RNA the EC50 was determined with (pages 2-4 and 38-55 and Figures 2-15).
Therefore, the Applicant has shown that 38 of their compounds have a concentration dependent protective effect that is dependent on the RNA sequence being protected and the pH during protection.
Quantity of experimentation needed: In light of the above factors, the applicant provides enablement for using the 38 compounds with an identified EC50 specific to the RNA being protected (either Chi-18, FgenI, or HCV IRES) at specific pHs. The prior art provides enablement for using Jeremejevite, Ludwigite, and Hambergite at low concentrations (10 μg/mL) in water and Rhodizite and Elbaite in formamide to protect RNA, using boron metal as a lyoprotectant to stabilize RNA during storage, and modifying siRNAs with a lipophilic boron cluster (C2B10H11, CB) which increased the resistance to enzymatic degradation. The Applicant does not provide enablement for using any boron compound nor any of the 50 boron containing compounds identified in Table 1 to protect any RNA sequence at any concentration in any solution at any pH. As such, there would be undue experimentation related to using any boron compound or any of the 37 boron containing compounds identified in claim 6 to protect any RNA sequence at any concentration in any solution at any pH to practice the full scope of the claim.
Claims 2-6 are also rejected because of their dependency on claim 1.
The following is a quotation of 35 U.S.C. 112(d):
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.
Claim 6 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 6 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
As can be seen in Table 1, although 50 of the 51 compounds contain a boron compound, there are a multitude of different core structures for incorporating the boron. For example, many structures contain an oxaborol structure but many do not, such as those with a diazaborinin or benzodioxaborepin structure. Furthermore, it is not clear what core structure is important for the function of protecting RNA from degradation. Although the top 3 compounds by EC50 in Table 2 have oxaborol structures, the 4th lowest comprises a benzodioxaborepin structure but does comprise a similar octahydrotetracene structure. Relatedly, many oxaborol containing compounds have significantly lower EC50 levels compared to the top 10 compounds, such as PF-04009301 with an EC50 of 474.164, and those with an oxaborol structure and an octahydrotetracene structure (PF-06968126) has an EC50 of 392.858. Therefore, it is not clear what is the core structure that has the function of protecting RNA from degradation.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 is dependent on claim 1 which requires a boron compound be used to protect RNA from degradation. N-[(3-methyl-1,2-oxazol-5-yl)methyl]-2-[(3S)-3-(2-methylphenyl)piperidin-1-yl]-7H- pyrrolo[2,3-d]pyrimidin-4-amine does not contain a boron.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kwiatkowska et al. (Bioconjugate Chem. 24: 1017−1026. 2013).
Kwiatkowska teaches that they modified siRNAs targeted against the BACE1 gene at various positions with a lipophilic boron cluster (C2B10H11, CB) which increased the resistance to enzymatic degradation of the modified oligomers compared to the unmodified counterparts (abstract).
Kwiatkowska teaches that a set of RNA strands was synthesized to prepare thirteen siRNAs (I-XIII), directed toward mRNA of human BACE1 protein (Table1). The modified thymidine unit bearing the boron cluster at N3 was introduced at the position 3 or 20 of the siRNA sense strand, counting from the 5′-end [oligomers (CB3)s and (CB20)s]. The antisense strand was modified at position 20 [the oligomer (CB20)as]. These three modified RNA strands allowed us to obtain siRNA duplexes listed in rows II-VI in Table 1. siRNA duplexes I-XIII (Table 1) were assembled in phosphate saline buffer (PBS, without Ca2+ and Mg2+) by mixing equimolar amounts of complementary oligonucleotides, heating the mixture at 95 °C for 2 min, and slow cooling down to room temperature (ca. 2 h). Formation of the resulting duplexes was confirmed by 4% agarose gel electrophoresis (Figure 1) (page 1022, column 1, paragraph 2 and page 1023, column 1, paragraph 3).
Therefore, Kwiatkowska modifies the antisense strand as a single RNA strand before assembling it into an siRNA duplex and that this modification protects the RNA from degradation.
Claims 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cossetti (Polymers 2: 211-228. 2010; referenced in IDS).
Cossetti teaches that they examined the effects of borate minerals on RNA in water and in formamide at 80 °C. This particular physical-chemical setting was selected because RNA degradation in these conditions takes reasonable experimental time span (page 213, paragraph 1). Of the tested borate minerals, only Jeremejevite, Ludwigite, and Hambergite had a protective effect in water and Rhodizite and Elbaite had a protective effect in formamide.
Therefore, Cossetti teaches multiple boron compounds that have a protective effect on RNA
Claims 1 and 4-5 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20180243219 (Ketterer).
Ketterer teaches that lyophilization of RNA in the presence of a lyoprotectant,
and under controlled conditions, preferably under controlled freezing and/or drying conditions as defined herein, results in a composition comprising RNA, which is characterized by an outstanding integrity of the RNA after completion of the lyophilization process and which is further characterized by increased storage stability, in particular with respect to storage for extended periods and/or under non-cooling conditions. Ketterer teaches that the lyophilized RNA can include mRNA encoding a viral antigen. Ketterer teaches that the lyoprotectant can be boron metal (paragraphs 0035, 0060, and 0182-0195).
Therefore, Ketterer teaches that boron metals can be used as a lyoprotectant to stabilize RNA in a lyophilized storage for long term storage and prevent degradation of the RNA during storage.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631