DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 1-12-24.
Claims 1-10, 12-14, 16, 17, 22, 23, 26, 27, and 33 are pending in the instant application.
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 1-10, 12-14, 16, 17, 22, 23, 26, 27, and 33 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the concise conditions described in the paragraphs below for generating and using the plurality of conjugates claimed, does not reasonably enable methods of making and using the large genus of components claimed.
. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The claims are drawn to methods of purifying a ribonucleic acid (RNA) transcript comprising a poly-adenosine tail, the method comprising obtaining a first sample comprising the RNA transcript comprising at least 5% impurities; contacting the first sample with the composition comprising a plurality of conjugates comprising the structure of Formula I:
A-L-B
Formula I,
wherein: A is a surface comprising a polystyrene divinylbenzene (PSDVB) particle; L is a linker comprising the structure:
PNG
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m is 1, 2,3,4,5,6,7,8, 9, or 10; and B is an oligomer comprising a poly-deoxythymidine oligonucleotide optionally comprising 5 to 200 deoxythymidines; which plurality of conjugates has an epoxide density of from about 30 to about 60 pmol/mL; a poly-deoxythymidine oligonucleotide density of from about 0.1 to about 0.5 pmol/mL;(iii) a dT/resin charge of less than about 5 mg/mL;(iv) an ionic capacity of greater than about 5 pmol/mL; and/or (v) a dynamic binding capacity of greater than about 1.5 pmol/mL, under conditions such that the RNA transcript binds to a conjugate in the composition; (c) eluting the RNA transcript from the composition; and (d) collecting the RNA transcript in a second sample, wherein the second sample comprises less than 5% impurities.
Claim 1 recites the terms “about 30 to about 60 umol/mL” (regarding epoxide density); “from about 0.1 to about 0.5 umol/mL” (regarding poly-deoxythymidine (poly dT) density); “less than about 5 mg/mL” (regarding dT/resin); “greater than about 5 umol/mL (regarding ionic capacity); and “greater than about 1.5 umol/mL” (regarding dynamic binding capacity).
Claim 5 recites the term “of about” (with respect to poly-T density).
Claim 23 recites the term “about 50 um” (with respect to mean particle size).
Claim 27 recites the term “of about 2000 angstroms” (with respect to mean pore size).
Claim 33 recites the terms “at least 5%” (with respect to impurities; and “under conditions such that” (with respect to the binding between an RNA transcript and a conjugate).
Teachings in the specification.
The specification teaches the following definitions:
[0092] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described.
[0093] As used herein, “binding capacity” refers to the amount of RNA that can bind to a surface per unit volume of the surface as measured in 0.5 M NaCl 10 mM Tris HCl 1 mM EDTA pH 7.4 at 25° C. In particular embodiments of measuring binding capacity, RNA is preheated to 65° C. for 15 minutes and is then adjusted with binding buffer to contain 0.5M NaCl, 10 mM Tris HCl, 1 mM EDTA, pH 7.4, at less than 1.5 mg RNA/mL; the RNA solution is contacted with the surface, heated with the surface as a slurry to 65° C. for 15 minutes, and then allowed to cool and hybridize under continuous mixing in a batch reactor for 30 minutes at 20° C.; the resin is washed, with 0.5 M NaCl, 10 mM Tris HCl, 1 mM EDTA, followed by a subsequent wash with 0.1 M NaCl, 10 mM Tris HCl, 1 mM EDTA; and RNA is eluted at 65° C. in 10 mM Tris HCl and 1 mM EDTA and then quantified by UV spectrophotometry at 260 nm, using 1 OD=40 μg at 1 cm pathlength as the conversion factor for OD to mass (mg) for, where binding capacity equals the total mg of eluted RNA (mg)/volume of surface (mL).
The specification teaches the following examples:
[0195] Results: Sample No. 8-1 (dT/resin charge of 3 mg/mL) maintained about 90% of 40mer dA binding capacity. Sample No. 8-9 (dT/resin charge of 4.5 mg/mL) immobilized at 45° C. and had about 30% higher 40mer dA binding capacity.
TABLE-US-00009 TABLE 9 Resin No.* Pore size (Å) Particle size (μm) R1 2000 50.0 R2 1000 40.0 R3 1200 50.0 R4 400 40.0 R5 300 30.0 R6 100 35.0 *All resins carry epoxy functions on surfaces with epoxy density of about 20-30 μmol/mL
Example 7—Epoxy Density Level, Coupling Kinetics, Coupling Temperature
[0210] Procedure: Poros OH150 beads/resins were epoxy functionalized with five levels of base content (NaOH concentrations) to generate EP 150 resins. A concentration of 0.83% NaOH (% w) leads to the highest epoxy level (about 50 μmol/mL). Decreasing base content leads to lower epoxy density. Higher NaOH concentration facilitates the epoxy hydrolysis as a competitive side reaction, which leads to lower functions levels. The base concentration up to 1.5% triggers the crosslinking between b-epoxy molecules in reaction mixture, which causes the failure of epoxy functionalization (FIG. 25).
[0211] EP 150 resins with four levels of epoxy densities ranging from 34 up to 51 μmol/mL were prepared to examine the effect of epoxy functions on coupling and resin performance (FIG. 25). The four resins were coupled with dT ligands and evaluated through ionic capacity test and 40mer dA HTP assay.
[0212] Results: The process for EP150/dT resins was studied by investigating the effect of epoxy density on bead surfaces, coupling kinetics, coupling dT ligand charge and temperature, as well as blocking time. The process tolerance window for epoxy density on bead surfaces was identified from 40 to 52 μmol/mL. This epoxy range can be realized by controlling the base content from 0.6% to 1.0% during the preparation EP 150 beads. The coupling time at 24±2 hours, coupling temperature at 65±2° C., dT/bead charge at 3±0.2 mg/mL and blocking time at 18±3 hours, are determined as the process tolerance windows to prepare EP150/dT resins.
[0213] Epoxy density level: As epoxy density decreases from 51 to 40 μmol/mL, both ionic capacity and 40mer dA binding capacity values remain at the same level (FIG. 26). Decreasing the epoxy density to 34 μmol/mL leads to both ionic capacity and 40mer dA binding capacity values decreasing about 10% (FIG. 26). About 0.5% epoxy functions are used for dT ligand coupling (coupled dT ligand density is <0.3 μmol/mL). An epoxy level higher than 40 μmol/mL is achieved by adjusting the base content to between 0.6% and 1.0%, but this epoxy level higher than 40 μmol/mL will not significantly impact the coupling process and resin performance.
[0226] Results: The pore size of the base bead was measured using Prosimetery, and the results were expressed in terms of Pore Mode (Table 19 and FIG. 34). The pore size distribution widens as the pore mode is increased, and the range of pore modes is >2000 Å. The particle size of the base bead was measured via Coulter method. The mean particle size for all three samples were about 50 μm. All samples sized to remove fines <25 μm (Table 19).
[Emphases added].
The examples provided in the instant specification, of the concise conditions for generating the plurality of conjugates, including conditions listed in para 0093 for defining binding capacity, Sample No. 8-1 comprising a dT/resin charge of 3 mg/mL, immobilized at 45o C, maintaining about 90% of 40mer dA binding capacity, the pore and particle sizes listed in Table 9 and para 0226, the conditions for coupling kinetics to achieve the epoxy density levels between 34-51 umol/mL, are not representative or correlative of ability to make and use the large genus of components claimed.
In light of the teachings in the art and the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure, and summarized above, as being correlative or representative of the ability to make and use the large genus of components claimed. Since the specification fails to provide the requisite guidance for making and using the large genus of components claimed, and since determination of the factors required for providing the concise proper conditions for generating the large genus is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For the aforementioned reasons, the instant rejection under 35 U.S.C. 112, first paragraph is proper.
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.
Claim(s) 1-10, 12-14, 16, 17, 22, 23, 26, 27, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Issa et al (US 2016/0024140) and Varady et al (USPN 5,030,352), the combination in view of Gmachl et al (US 2019/0358230).
Issa et al (US 2016/0024140) teach methods of purification of poly-adenosine RNA transcripts (see the abstract, para 0002-0008, 0049-0053, 0092-0101) utilizing compositions comprising a plurality of conjugates comprising the core structure of Formula I comprising compositions of surfaces linked to poly T oligonucleotides and a linker, which surface comprises polystyrene divinylbenzene (see esp. para 0048-0050, 0078), and which compositions further comprise epoxy crosslinkers (see esp. para 0082, 0088, 0113, 0114) See also claims 1, 6, 14-17 and 20.
Varady et al (USPN 5,030,352) teach compositions comprising a plurality of conjugates comprising a surface comprising a polystyrene divinylbenzene (PSDVB) particle, and an epoxide density between 30-60 umol/mL (see esp. the abstract, Figures 1 and 2, examples 1, (col. 9-11, col. 12), example 4 (col. 13-14), claims 14, 15, 17, 23, 24).
The primary references do not teach the linkers recited in claim 1 and 13.
Gmachl et al (US 2019/0358230) teach the linkers recited in claim 1 and 13. (2-propanol, 1-(methylamino)-2-, (2S)- and (2-propanol, 1-(methylamino)-2-, (2R)- (See accompanying structure search, RN 70377-76-3, and RN 131101-46-7) .
It would have been obvious to generate and optimize the conjugate compositions as claimed because the purification of poly-A mRNA had been routinely utilized in the prior art, as evidenced in the teachings of Issa. The routine use of PSDVB and epoxide crosslinking was disclosed in the teachings of both Issa and Varady. The routine use of the common linker set forth in claims 1 and 13 for generating multicomponent structures was also clearly disclosed in the teachings of Gmachl. One of skill in the art would have reasonably expected that the instantly claimed compositions would provide for efficient purification of poly-A RNA, relying on the combined teachings of Varady, Issa and Gmachl.
For these reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
2-9-26
/JANE J ZARA/Primary Examiner, Art Unit 1637