DETAILED ACTION
The present application is a national stage entry of PCT/US21/63759, filed 16 December 2021, which claims priority to US Provisional Application No. 63/182,147, filed 30 April 2021.
The preliminary amendment filed 27 October 2023 is acknowledged. Claims 1-23 are pending in the current application and are examined on the merits herein.
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 .
Claim Rejections - 35 USC § 112(b)
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 22 and 23 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.
Claim 1 recites “-20 mV or lower”, and claim 21 recites “-10 mV or greater negative charge”. It is assumed that “lower” encompasses -21, -22, etc., while “greater” encompasses -9, -8, etc. But here, “greater negative charge” might mean -11, -12, etc. The claims should use consistent language to avoid confusion.
Thus, not only does the range in claim 21 fail to include all the limitations of the claim upon which it depends, but it is unclear if it is directed to a completely different range of values.
The scope of present claims 22 and 23 are similarly unclear as to whether they are encompassing different ranges of zeta potential.
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.
Claims 20-23 are 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.
The recitation “wherein the membrane has a negative surface charge” in present claim 20 fails to further limit claim 1, which already recites “membrane having…a negatively charged surface”.
The recitation “wherein the sulfonated polyether sulfone surface layer of the membrane has a zeta potential of approximately -10 mV or greater negative charge” in present claim 21 fails to include all the limitations of the claim upon which it depends, because claim 1 requires “a membrane having…a negatively charged surface with a zeta potential of -20 mV or lower”.
Furthermore, claim 1 recites “-20 mV or lower”, and claim 21 recites “-10 mV or greater negative charge”. It is assumed that “lower” encompasses -21, -22, etc., while “greater” encompasses -9, -8, etc. But here, “greater negative charge” might mean -11, -12, etc. The claims should use consistent language to avoid confusion.
Thus, not only does the range in claim 21 fail to include all the limitations of the claim upon which it depends, but it is unclear if it is directed to a completely different range of values.
The scope of present claims 22 and 23 are similarly unclear as to whether they are encompassing different ranges of zeta potential.
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 § 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) 1-5, 7 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Pearce et al. (EP 1533020, cited in IDS submitted 12 February 2024) in view of Gronke et al. (WO 2021/168306, cited in IDS submitted 12 February 2024) and further in view of Burns et al. (Journal of Membrane Science, 2000, vol. 172, pp. 39-48, cited in IDS submitted 07 January 2025) and Degen et al. (US Patent No. 5,128,041, cited in PTO-892).
Pearce et al. teach a method for separating a desired synthetic molecule from a solution containing a mixture of synthetic biomolecules, impurities and a carrier fluid, comprising the steps of providing a solution comprising the mixture, contacting the mixture with a charged ultrafiltration membrane, having a nominal molecular weight cutoff (NMWCO) of from about 0.5 to about 10 kDa, wherein the synthetic molecule and membrane have like net negative charges, wherein the desired synthetic molecule is retained in the retentate solution, and the impurities are contained in the permeate solution (claims 4-9). The membrane has a negative charge (claim 5). The synthetic biomolecules includes oligonucleotides (para [0014]). The method allows for the use of larger pored membranes, thereby increasing flux, processing speed and greater yield of product (para [0012]). Pearce et al. teach smaller molecules can be passed through regardless of their charge (para [0019]-[0020]). The charge of the membrane can be adjusted by changing the pH of the feed solution (abstract). Suitable membranes include polyethersulfone membranes such as BIOMAX® membranes (para [0032]).
Pearce et al. do not expressly disclose diafiltering the retentate solution with a buffer to produce a concentrated oligonucleotide solution (present claim 1). Pearce et al. do not expressly disclose a zeta potential of the membrane (present claim 1).
Gronke et al. teach purifying oligonucleotides by subjecting an aqueous solution of a oligonucleotide to ultrafiltration/diafiltration (UF/DF) to form a retentate, wherein the UF/DF is carried out using an aqueous buffer solution containing one or more salts (abstract). The aqueous buffer solution comprises at least one salt selected from sodium acetate, potassium acetate and ammonium acetate (claims 4-6). The UF/DF is carried out with a permeate flux of 5 L/h/m2 to 25 L/h/m2 (equivalent to 83 mL/min/m2 to 416 mL/min/m2 claim 12). The concentration of the oligonucleotide in the retentate is 50 g/L to 125 g/L (claim 14). The membrane has a MWCO of from 1 to 7 kDa, 2 to 4kDa, or 3 kDa (claim 15). The UF/DF is carried out by tangential flow filtration (claim 16). The oligonucleotide has 16-30 nucleotides, or 16-20 nucleotides (claim 22). Gronke et al. found adding salt to the diafiltration buffer was an effective way to increase permeate flux (p.16, example 2). Gronke et al. teach setting the conductivity to about 5.1 mS/cm, about 9.8 mS/cm and about 18.9 mS/cm (p.17:3-17). They found permeate flux was directly proportional to conductivity of the aqueous buffer solution, such that the increase in permeate flux is linearly related to the increase in buffer conductivity (p.17:3-17). The concentration was carried out using a transmembrane pressure of 35 psi and a crossflow of 3.0 liters/minute/meter2 (example 2). The method includes adjusting the pH of the aqueous buffer solution to range from 4.0 to 10.0 (p.10:13-17).
Burns et al. measured the zeta potential for standard polyethersulfone UF membranes in the presence of various buffers (abstract). With respect to the standard membrane, Burns et al. teach the membrane surface is ionizable with weakly acidic carboxylic or phenolic groups, where the extent of ionization is a strong function of the local hydrogen ion concentration (i.e. the solution pH), (p.47, first para). The zeta potential without any buffer was -5.6±0.3 at pH 5, and -15.1±0.8 at pH 7 (Table 1). The zeta potential for the acetate buffer was -4.9±0.2 mV at pH 5, and -14.0±0.3 at pH 7 (Table 1).
Degen et al. is concerned with the preparation and use of polymeric membranes for filtration (abstract). Degen et al. teach “colloid stability theory can be used to predict the interactions of electrostatically charged particles and surfaces. If the charges of suspended particle and the filter membrane surface are of like sign and with zeta potentials of greater than about 20 mV, mutual repulsive forces will be sufficiently strong to prevent capture by adsorption.” (col.2:35-42).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to subject the permeate solution of Pearce et al. to diafiltering with a buffer to produce a concentrated oligonucleotide solution.
Starting from Pearce et al., the ordinary artisan would have looked to the teaching of Gronke et al., because they are both concerned with forming a retentate having an oligonucleotide. The ordinary artisan would have included a step of diafiltration because Gronke et al. expressly teach it can be performed in combination with ultrafiltration.
The ordinary artisan would have known modifying pH is an effective means to affect the charge and zeta potential of the membrane. Since both Pearce et al. and Gronke et al. are concerned with obtaining the oligonucleotide in the retentate using a membrane having the same net charge as the desired oligonucleotide, the ordinary artisan would have been motivated to increase the overall pH of the buffer.
The ordinary artisan would have additionally been motivated to lower the overall zeta potential to -20 mV or lower (by increasing the pH), because Degen et al. teach “colloid stability theory can be used to predict the interactions of electrostatically charged particles and surfaces. If the charges of suspended particle and the filter membrane surface are of like sign and with zeta potentials of greater than about 20 mV, mutual repulsive forces will be sufficiently strong to prevent capture by adsorption”.
While Gronke et al. reported obtaining a permeate flux of 83 mL/min/m2 to 416 mL/min/m2 (reported as 5 L/h/m2 to 25 L/h/m2), the ordinary artisan would have known this is a result-effective variable. Both Pearce et al. and Gronke et al. are concerned with filtering through a membrane at a high flux. Gronke et al. found diafiltering with an acetate buffer was an effective way to increase permeate flux. The ordinary artisan would have also been motivated to modify pH and surface charge to optimize flux. The ordinary artisan would have been motivated to increase permeate flux to increase the speed of purification and obtaining the desired product.
As noted above, Gronke et al. found the concentration of the oligonucleotide in the retentate is 50 g/L to 125 g/L. The concentration limitation of present claims 11 and 12 are a latent property of performing the positively recited steps.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Pearce et al., Gronke et al., Burns et al. and Degen et al. as applied to claims 1-5, 7 and 9-13 above, and further in view of Smith (US Patent No. 11,564,893, cited in PTO-892).
Pearce et al. teach as discussed above.
Pearce et al. do not expressly disclose “wherein the negatively charged oligonucleotides have a zeta potential of from about -1 to -500 mV” (present claim 6).
Gronke et al., Burns et al. and Degen et al. teach as discussed above.
Smith is concerned with preparing polynucleotide particles, wherein the method includes one or more filtration steps (abstract). The particles have a surface charge, which may be modified via pH (abstract). Smith et al. teach the average zeta potential of the particles may be negative, and includes -2 to about -40 mV (col.8: 17-39).
As discussed above, Pearce et al. teach filtering oligonucleotides having the same negative charge as the membrane, which ensures the oligonucleotides are retained in the retentate. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to purify an oligonucleotide having a negative zeta potential of -2 mV to about -40 mV, because it would ensure they are the same negative charge as the membrane used to filter them.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 8 and 14-23 are rejected under 35 U.S.C. 103 as being unpatentable over Pearce et al., Gronke et al., Burns et al. and Degen et al. as applied to claims ) 1-5, 7 and 9-13 above, and further in view of Felo et al. (WO 2007/056191, cited in IDS submitted 12 February 2024) and Ikeda et al. (EP 0165077, cited in IDS submitted 07 January 2025).
Pearce et al. teach as discussed above.
Pearce et al. do not expressly disclose flushing the membrane with water prior to circulating the solution through the UF or NF unit (present claim 8). Pearce et al. do not expressly disclose the type of membrane (present claims 14-16), or the thickness of the membrane (present claim 17).
Felo et al. is concerned with the purification of nucleotides using membranes (title). Suitable membranes can be flat, plate and frame, tubular, spiral wound, hollow fiber, and the like (para [0071]). The membranes can be employed in a cross-flow configuration. The desired carbohydrate is separated into a retentate stream, while the permeate stream contains the removed contaminants. Exemplary membranes include polysulfones, and sulfonated polysulfones (para [0065]). The membrane is also selected to have a surface charge that is appropriate for the ionic charge of the carbohydrate and contaminants (para [0066]). The MWCO of the membrane is chosen based on the MW of the desired target carbohydrate (para [0064]). Felo et al. teach removing residual salts from the solution by concentration and diafiltration (see e.g. para [0227]; [0232]). The solution is purified using tangential flow filtration (para [0244]), or cross-flow filtration (para [0071). The cross-flow rate is 20 mL/min at 12 psi (para [0244]). Felo et al. teach conductivity values of 2 mS/cm (para [0170], 0.755-1.93 mS (para [0244]), 0.389-23.9 mS (para [0247]). Felo et al. teach the concentration of contaminant is about 1% or less of the pre-purification contaminant concentration (para [0044]). Felo et al. teach using filters having 0.2 µm thickness (para [0191]).
Ikeda et al. teach composite semipermeable membrane comprising a sulfonated polyether polysulfone on a ultrafiltration membrane as a support (p.2:1-6). The ultrafiltration support is also a polysulfone (para [0020]-[0021], claim 4). The thickness of the membrane ranges from 0.01 to 5 µm (p.5:33-40). Ikeda et al. exemplifies a membrane having a thickness of 0.3 µm (p.6:46-61). Ikeda et al. teach varying the amount of additive affects the % rejection and flux (Table 8). Ikeda et al. teach flushing water through the membrane to remove any additives used to make the membrane, before using the membrane for purification purposes (p.5:41-44). Ikeda et al. teach flushing the membrane with water at a flux of around 2.4-2.5 m3/m2-day (example 15)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a composite semipermeable membrane comprising sulfonated polyether polysulfone on a polysulfone support in the form of a spiral wound cartridge, having a thickness of 0.3 µm, because Pearce et al. expressly teach polyethersulfone membranes are suitable for filtering oligonucleotides as taught above. The polyethersulfone membranes of Ikeda et al. and Felo et al. are exemplary filtration membranes known before the effective filing date of the claimed invention.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699