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 .
Claims Status
Claims 1-6, 8-16, and 20-24 are pending.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-6, 8-16, and 20-24 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 the limitation "DNA”. It is not clear if this refers to “host cell DNA” or a different DNA. There is insufficient antecedent basis for this limitation in the claim. Claims 2-6, 8-16, and 20-24 are rejected as well since they depend on claim 1 and do not rectify the indefinites issues.
Claim Rejections - 35 USC § 103
Claims 1-6, 8-12, 14-16, 20-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Improved purification of recombinant adenoviral vector by metal affinity membrane chromatography by Lee et al. (Lee).
In regard to claim 1, Lee teaches a method for removal of host cell DNA from a sample containing a desired species of a protein, a virus, or an extracellular vesicle (abstract, adenovirus, host cell; pg. 641, Materials and methods, DNA). Lee teaches a step of loading a substrate bearing an anionic exchange chromatography resin (abstract). Lee teaches a further step of loading the metal-loaded anionic metal affinity substrate bearing a metal affinity ligand with a metal ion (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands). Lee does not explicitly teach the substrate is an anionic metal affinity ligand with a metal ion; however, making elements integral is generally recognized as being within the level of ordinary skill in the art. In re Larson, 340 F.2d 965, 968, 144 USPQ 347, 349 (CCPA 1965). Additionally, one of ordinary skill in the art at the time the invention was made would have been led by the applied references to forgo use of separate modules, along with their function and benefit, where doing so is technically feasible and would reduce cost. See In re Thompson, 545 F.2d 1290, 1229, 188 USPQ 365, 367 (CCPA 1976). It would have been obvious for one of ordinary skill in the art before the effective filing date to combine the anionic chromatography substrate and metal affinity ligand substrate in the method of Lee in order to create a streamlines system and method, reduce operating costs, reduce space and material requirements, and tune chromatographic resolution.
Lee teaches equilibrating the substrate with a buffer having a pH in the range of pH 4 to pH 10, and a salt concentration in a concentration range of 50 mM to 1 M (pg. 641, Materials and methods, Metal affinity membrane chromatography, pH 8, 2 mM MgCl2, 500 mM NaCl).
Lee teaches the buffer is adjusted to a combination of pH and salt conditions that prevents binding of the desired species but permits binding of DNA (pg. 641, Materials and methods, Metal affinity membrane chromatography, pH 8, 2 mM MgCl2, 500 mM NaCl).
Lee teaches contacting the sample with the metal-loaded anionic metal affinity substrate (abstract). Lee teaches separating the metal-loaded anionic metal affinity substrate from the sample, wherein the sample has a reduced content of host cell DNA (abstract).
Lee does not explicitly teach the salt does not form a chemical complex with the anionic metal affinity ligand; however, Lee teaches the same salt as in the instant specification and claimed, the same buffer pH (pH 8), the same salt concentration (sodium chloride with concentration less than 1M), and the same metal affinity ligand (Zn2+); therefore, regarding limitations recited in the claims which are directed to specific properties of the salt and metal affinity ligand, it is noted once a metal affinity ligand is disclosed to comprise Zn2+ metal ions and the salt is disclosed to comprise sodium chloride in a concentration range up to 1M, and therefore is the same as the metal affinity ligand and salt as claimed, it will, inherently, display recited properties. See MPEP 2112.
In regard to claim 2, Lee teaches the anionic metal affinity ligand is selected from the group consisting of amino-dicarboxylic acids and amino-tricarboxylic acids (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands).
In regard to claim 3, Lee teaches the anionic metal affinity ligand is iminodiacetic acid (IDA) or nitriloacetic acid (NTA) (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands).
In regard to claim 4, Lee teaches the substrate bearing an anionic metal affinity ligand is in the form of particles, nanofilaments, porous membranes, monoliths, hydrogels, depth filtration media, or soluble polymer media (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands).
In regard to claim 5, Lee teaches the substrate bearing an anionic metal affinity ligand is in the form of a flow-through chromatography device (abstract, chromatography).
In regard to claim 6, Lee teaches equilibrating the substrate is performed by means of a buffer having a pH in the range of pH 7.0 to 9.5 (pg. 641, Materials and methods, Metal affinity membrane chromatography, pH 8, 2 mM MgCl2, 500 mM NaCl)).
In regard to claim 8, Lee teaches the buffer used for equilibrating the substrate is adjusted with the salt selected from the group consisting of an inorganic salt, an organic salt, a chaotropic salt, and combinations thereof (pg. 641, Materials and methods, Metal affinity membrane chromatography, pH 8, 2 mM MgCl2, 500 mM NaCl).
Lee does not explicitly teach the buffer used for equilibrating the substrate provides salt conditions that prevent binding of a virus or extracellular vesicle but permit binding of DNA; however, Lee teaches the same salt as in the instant specification and claimed, the same buffer pH (pH 8), the same salt concentration (sodium chloride with concentration less than 1M), and the same virus particle (adenovirus type 5); therefore, regarding limitations recited in the claims which are directed to specific properties of the salt, it is noted once a species is disclosed to comprise adenovirus and the salt is disclosed to comprise sodium chloride in a concentration range up to 1M, and therefore is the same as the species and salt as claimed, it will, inherently, display recited properties. See MPEP 2112.
In regard to claim 9, Lee teaches the metal-loaded anionic metal affinity substrate is loaded with metal ions having at least two positive charges (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands).
In regard to claim 10, Lee teaches the sample is selected from the group consisting of a cell harvest, cell lysate, and a partially purified preparation thereof (pg. 641, Materials and methods, cells were lysed). Lee teaches the desired species is selected from the group consisting of non-lipid-enveloped protein capsid virus particles, lipid-enveloped virus, bacteriophages, extracellular vesicles, proteins, and combinations thereof (abstract, adenovirus).
In regard to claim 11, Lee teaches the AAV capsid is selected from the group consisting of AAV serotypes AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV 11, a recombinant hybrid serotype, a synthetic recombinant serotype and combinations thereof (pg. 641, Materials and methods, adenovirus type 5).
In regard to claim 12, Lee teaches after the separating step the sample is processed by biological affinity chromatography after the metal affinity step of claim 1, cation exchange after the metal affinity step of claim 1, hydrophobic interaction chromatography after the metal affinity step of claim 1, tangential flow filtration after the metal affinity step of claim 1 or combinations thereof (pg. 641, Materials and methods, particle number and overall purity were determined by anion-exchange HPLC).
In regard to claim 14, Lee teaches the sample having a reduced content of DNA is further processed by anion exchange chromatography (pg. 641, Materials and methods, particle number and overall purity were determined by anion-exchange HPLC).
In regard to claim 15, Lee teaches the sample containing the desired species is a cell harvest or cell lysate (pg. 641, Materials and methods, cells were lysed).
In regard to claim 16, Lee teaches the sample did not undergo any chromatographic step prior to the step of contacting the sample with the metal-loaded anionic metal affinity substrate (abstract).
In regard to claim 20, Lee teaches the sample has alkaline conditions (abstract).
In regard to claim 21, Lee discloses all of the claim limitations as set forth above, but the reference does not explicitly disclose a buffer having a concentration of the salt in the range of 125 mM to 250 mM. As the method cost of construction, separation resolution, and efficiency of operation are variables that can be modified, among others, by adjusting said buffer salt concentration, the buffer salt concentration would have been considered a result effective variable by one having ordinary skill in the art at the time the invention was made. As such, without showing unexpected results, the claimed buffer salt concentration cannot be considered critical. Accordingly, one of ordinary skill in the art at the time the invention was made would have optimized, by routine experimentation, the buffer salt concentration in the method of modified Lee to obtain the desired balance between the construction cost, operation efficiency, and separation resolution (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223).
In regard to claim 23, Lee teaches the metal ions having at least two positive charges are selected from the group consisting of iron(II), manganese(II), calcium(II), magnesium(II), copper(II), zinc(II), barium(II), nickel(II), cobalt(II), and combinations thereof (abstract, Sartobind IDA membrane unit charged with Zn2+ ions as affinity ligands).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Improved purification of recombinant adenoviral vector by metal affinity membrane chromatography by Lee et al. (Lee), as noted above, in view of WO2020023612 by Cardinal et al. (Cardinal).
In regard to claim 22, Lee teaches the limitations as noted above. Further, Lee teaches the inorganic salt is sodium chloride, (pg. 641, Materials and methods, Metal affinity membrane chromatography, pH 8, 2 mM MgCl2, 500 mM NaCl).
Lee does not teach an organic salt selected from the group consisting of arginine-HCl, lysine-HCl, a salt based on an imidazolium, histidyl, and histaminyl cation; Lee does not teach a chaotropic salt is selected from a guanidinium cation and a thiocyanate anion.
Cardinal teaches separating adenovirus with metal affinity chromatography ([0061]; [0284]; [0388]). Cardinal teaches buffers include pharmaceutically acceptable salts ([1126]). Cardinal teaches salts include thiocyanate ([1126]). Cardinal teaches arginine-HCL salts ([0349]). It would have been obvious for one of ordinary skill in the art before the effective filing date to incorporate arginine-HCL salt and thiocyanate, as taught by Cardinal, in the method of modified Lee as they are both known salts utilized in metal affinity chromatography with adenovirus sample. One of ordinary skill in the art would have been motivated to choose a pharmaceutically acceptable salt to achieve desired elution and separation.
Claims 13 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Improved purification of recombinant adenoviral vector by metal affinity membrane chromatography by Lee et al. (Lee), as noted above, in view of U.S. Patent Publication No. 20200101136 by Schreiber et al. (Schreiber).
In regard to claim 13, Lee teaches all the limitations as noted above. Lee does not teach the tangential flow filtration is using a membrane with pore size cutoffs in the range of 30 kDa to 1 MDa.
Schreiber teaches chromatographic separation ([0239]). Schreiber teaches a membrane with pore size cutoffs in the range of 30 kDa to 1 MDa (abstract; Table 1, pore membrane glycoprotein 210 kDa).
It would be obvious to one of ordinary skill in the art before the effective filing date to incorporate a membrane with a pore size cutoff in the range of 30 kDa to 1 MDa, as taught by Schreiber, as it is a known pore size cutoff range for chromatographic separation. One of ordinary skill in the art before the effective filing date would be motivated to chose a pore size cutoff range to achieve the desired separation, purity, and system effectiveness.
In regard to claim 24, Lee teaches all the limitations as noted above. Lee does not teach influenza or corona virus. Lee teaches virus separations (abstract).
Schreiber teaches chromatographic separation ([0239]). Schreiber teaches influenza virus ([0130]).
It would be obvious to one of ordinary skill in the art before the effective filing date to separation influenza virus, as taught by Schreiber, as it is a known virus separated by chromatography.
Response to Arguments
Applicant's arguments filed 3/20/2026 have been fully considered but they are not persuasive.
The 112b rejections are removed in light of Applicant’s amendments.
In regard to the Applicant’s argument Lee does not teach “a buffer that has been adjusted to a combination of pH and salt conditions that prevents binding of the desired species but permits binding of DNA”; the instant specification discloses three unexpected discoveries including 1) metal affinity methods are known where acidic pH elutes IgG and His-tag proteins but not the opposite situation, 2) non-chelating salts overcome stronger binding of viruses, and 3) conditions that weaken binding of viruses and extracellular vesicles permit binding of host cell DNA despite the prior art indicating DNA binds poorly; the Examiner does not find this persuasive.
The Examiner notes the rejection has been updated above in view of the claim amendments.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., IgG elution; His-tag proteins; non-chelating salts; weaken binding of viruses) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In regard to the Applicant’s argument Lee binds the target species to the membrane while NOT binding the host DNA; Lee fails to teach or suggest a method in which the buffer is adjusted to a combination of pH and salt conditions that prevents binding of the desired species but permits binding of DNA; the Examiner does not find this persuasive.
See updated rejection above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA M PEO whose telephone number is (571)272-9958. The examiner can normally be reached 9 to 5:30.
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/KARA M PEO/Primary Examiner, Art Unit 1777
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