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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-15) and species of PEG-8000, Fab, succinimidyl ester moiety and TCEP in the reply filed on 09/04/2026 is acknowledged.
Claims 16-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/04/2026.
Claim Objections
Claims 1 and 14 are objected to because of the following informalities:
In claim 1, the conjunction “and” should appear after part d).
In claim 14, the conjunction “and” should appear after part a).
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 5, 9 and 10 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 claims 5, 9 and 10, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In particular, it is not clear if these limitations following “preferably” limit the claims: for about 2 minutes limits claim 5, is about 40% (w/v) limits claim 9 and if about 200 mM limits claim 10. “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made.” MPEP 2173.05(d). Here, as set forth, it is not clear if the preferences set forth in the claims are limitations of the claim. For the purpose of rejections below, the features following “preferably” are not considered limitations of the claims for the broadest reasonable interpretation of claims 5, 9 and 10.
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.
Claim(s) 1-11, 14 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. (Oligonucleotide conjugated antibody strategies for cyclic immunostaining, Sci. Reports 11, 2021, 2384) further in view of Gagnon (U.S. 2015/0376231 A1) and Rauterberg (EP 0205643 A1). An English language translation of Rauterberg is provided and cited herein.
Jones reviews common and standard methods for producing antibody-nucleic acid conjugates known in the prior art.
“Two of the most common antibody conjugation methods, maleimide and NHS ester, were employed for antibody modification with the Cu-free click chemistry linker dibenzocyclooctyne (DBCO) permitting covalent attachment of the azide-modified oligos (Fig. 1A,B). While both methods are common and relatively simple, Ab-oligo conjugate production with maintained binding affinity and specificity had high variability. Two commercial kit-based approaches were investigated including the Solulink and SiteClick kits (Fig. 1C,D). The Solulink kit uses NHS ester modification of the antibody to add a succinimidyl-6-hydrazino-nicotinamide (S-HyNic) group and addition of an NHS ester-4-formylbenzamide (4FB) group to the 5’ end of the oligo. Once modified, the antibody and oligo were covalently attached through formation of a stable bis-arylhydrazone bond (Fig. 1C). The SiteClick kit enabled site-directed conjugation, where the antibody was modified to contain an azide moiety on the Fc region. Oligos containing an alkyne group in the form of a DBCO triethylene glycol (TEG) spacer modification on the 5′ end permitted Cu-free click chemistry-mediated covalent attachment (Fig. 1D).: Jones, page 2.
Specific procedures are described on pages 14-15 of Jones, “Non-specific maleimide or NHS ester antibody conjugation” and “Site-specific antibody conjugation,” which makes it clear that a first solution containing nucleic acids with a reactive group is contacted with a second solution containing antibodies to form antibody-nucleic acid conjugates as directly recited in claim 14. For example: “For both maleimide and NHS ester reactions, the antibody was modified at a molar ratio of 6:1 DBCO to antibody and ~ 30:1 oligo to antibody. The resultant DBCO-antibody products [second solution] were incubated with gentle shaking for 3 h at RT. Docking strands (DS) with an azide moiety on the 5′ end [first solution including nucleic acids with an azide moiety reactive group] were subsequently added to the DBCO-antibody product and the conjugation reaction was run overnight at 4 °C.
As such, Jone teaches the features of claims 14 and 15 except for purification of the antibody nucleic acid conjugates utilizing a method as recited in claim 1.
Gagnon, abstract, states:
A method for the purification of a desired protein from a protein preparation includes conditioning the protein preparation by treatment with soluble organic multivalent ions, immobilized organic multivalent ions, or both, optionally in the presence of supersaturated allantoin, thereby removing at least 90% of chromatin, then (1) precipitating the desired protein with a nonionic organic polymer in the presence of non-protein-precipitating salts at greater than physiological concentration to provide a precipitate of the desired protein; or (2) precipitating the desired protein with a nonionic organic polymer in the absence of non-precipitating salts at greater than physiological concentration to provide a precipitate and subsequently washing the precipitate with a nonionic organic polymer in the presence of non-protein-precipitating salts at greater than physiological concentration.
“In some aspects, embodiments disclosed herein relate to methods for the purification of a desired protein from a protein preparation comprising conditioning the protein preparation by treatment with soluble organic multivalent ions, immobilized organic multivalent ions, or both, optionally in the presence of supersaturated allantoin, thereby removing at least 90% of chromatin, then (1) precipitating the desired protein with a non-ionic organic polymer in the presence of non-protein-precipitating salts at greater than physiological concentration to provide a precipitate of the desired protein, or (2) precipitating the desired protein with a nonionic organic polymer in the absence of non-precipitating salts at greater than physiological concentration to provide a precipitate and subsequently washing the precipitate with a nonionic organic polymer in the presence of non-protein-precipitating salts at greater than physiological concentration, wherein the precipitating or washing step is optionally carried out in the substantial absence of a protein-precipitating salt, and optionally without adjusting the pH of the desired protein to a value within 0.5 pH units of the isoelectric point of the desired protein, and optionally washing the precipitate with a protein-precipitating salt in the absence of a non-ionic organic polymer, where in the precipitating salt is present at a sufficient concentration to keep the desired protein in a precipitated state.” Gagnon, para. [0005].
“A different approach to development of an IgG purification illustrates some of the alternatives that may be considered. As in the previous general example, development begins with selecting a clarification method to remove 90% or more of the chromatin from a cell culture harvest. One useful starting point is to add allantoin in an amount of 1% w/v to the harvest, followed by the addition of ethacrdine acid in an amount of 0.025% w/v. The pH of the mixture is adjusted to 7.5 and mixed for 2 hours at room temperature. Positively charged metal affinity particles, such as BioWorks TREN high, are equilibrated to pH 7.5 then added to the mixture in an amount of 4% v/v, while negatively charged hydrophobic particles such as Bio-Rad MacroPrep tbutyl are added in an amount of 1% v/v, and incubated stirring for 4 hours. Solids are then removed by any expedient method. The method may be followed by passing the supernatant through a depth filter, the fluid contact surfaces of which bear electropositive ligands. Conductivity, pH, and concentrations of reactants may be subsequently refined if desired. The clarified IgG preparation now substantially devoid of chromatin and chromatin catabolites, is precipitated by addition of PEG-6000 to a final concentration of 19%. NaCl is also added in an amount of about 850 mM, bringing the net salt concentration (sample+added NaCl) to a presumptive concentration of about 1M [i.e. contacting a solution containing IgG antibody and purification solution including polyethylene glycol (PEG) and sodium chloride (NaCl) to produce a mixture]. pH is about 7 (6.8 to 7.2) conferred and controlled by 20-50 mM Hepes, sodium or potassium phosphate, pH 7. These conditions can be further refined if desired. The precipitate is collected by centrifugation or filtration and the supernatant discarded [i.e. centrifuging the mixture to produce a supernatant and a pellet (i.e. precipitate), and discarding the supernatant is isolating the pellet from the supernatant]. The precipitate is suspended in 19% PEG-6000; 1 M NaCl, 20-50 mM Hepes or phosphate, pH 7 [i.e. resuspending the pellet with a resuspension solution to produce a purified solution], then the precipitate is re-sedimented and the supernatant discarded. The precipitate can then be re-solubilized, for example with 50 mM phosphate, 1 M NaCl, pH 7.2, and purified further by application to a column of Capto adhere equilibrated to the same conditions, if desired. The purified IgG may then be eluted by reducing the NaCl concentration to 300 mM. Alternative chromatography methods are known and it is within the purview of a person of ordinary skill in the art to choose a suitable method or methods, and develop the conditions to operate them.” Gagnon, para. [0135].
Regarding the concentration of PEG, Gagnon, para. [0135], indicates that 19% (understood to be w/v) PEG-6000 is sufficient concentration to precipitate an IgG antibody. Regarding concentration of NaCl, Example 1, para. [0139], of the specification describes “Selection of NaCl concentration for conducting precipitation” wherein “In a parallel experiment, NaCl was added to the original sample to create a salt concentration equivalent to 200 mM. 200 mM NaCl was also added to the resuspension buffer. In additional parallel experiments, the NaCl concentrations were raised to 400, 800, and 1000 mM NaCl. The concentration of contaminating host cell proteins was measured in the resolubilized antibody from each experiment. Those levels were as follows: no added NaCl, 16,544 ppm; 200 mM NaCl, 1,984 ppm; 400 mM NaCl, 605 mM NaCl; 800 mM NaCl, 50 ppm; 1000 mM NaCl, 32 ppm.”
As such, Gagnon teaches that increased NaCl concentration is increasingly effective to remove cellular contamination. However, Gagnon teaches that no particular NaCl concentration is required for precipitation to occur and teaches that 200 mM NaCl causes a marked decrease in contamination as compared to employment of no salt. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II)(A). In view of Gagnon teaching the effectiveness of a range of NaCl concentrations in a purification/precipitation solution including 200 mM NaCl, it is not inventive to discover that a concentration of 200 mM NaCl is workable.
Further, as far as Gagnon makes clear that both PEG and NaCl need to be added to the antibody, an ordinarily skilled artisan at the time of filing would have been motivated to combined PEG and NaCl into the same purification solution in order to achieve the convenience of adding only one solution to reach the needed concentration of PEG and NaCl.
As such, Gagnon suggests the following method:
A method for purifying an antibody from a solution including the antibody, the method comprising: a) contacting the solution and a purification solution including polyethylene glycol 6000 (PEG-6000) and sodium chloride (NaCl) to produce a mixture including antibody, PEG and NaCl such that the concentration of PEG in the mixture is 19% (w/v) and the concentration of NaCl in the mixture is about 200 mM; b) centrifuging the mixture to produce a supernatant and a pellet; c) isolating the pellet from the supernatant; and d) resuspending the pellet with a resuspension solution to produce a purified solution.
However, Gagnon does not teach a method for purifying antibody-nucleic acid conjugates from a solution including the antibody-nucleic acid conjugates and unconjugated nucleic acid, by contacting the solution and a purification solution including polyethylene glycol (PEG) and sodium chloride (NaCl) to produce a mixture including antibody-nucleic acid conjugates, unconjugated nucleic acids, PEG and NaCl.
As discussed above in regards to Jones, page 14, antibody and oligonucleotides are reacted at a molar ratio of 30:1 such that the result of such reaction is a solution including the antibody-nucleic acid conjugates and unconjugated nucleic acids that are in large molar excess. In one embodiment, Jones (page 15) describes that “Excess unbound oligo was removed with a 0.5 ml 30 kDa Amicon spin filter.”
An ordinarily skilled artisan at time of filing would have recognized that Amicon™ spin filters are a commercial product that is associated with substantial cost. As discussed above, Ganon teach that it is possible to purify and recover an antibody from a mixture by precipitation using common reagents (PEG and NaCl) and common laboratory equipment (centrifuge). As such, in order to avoid the use of a commercial product associated with significant cost (i.e. spin filters), an ordinarily skilled artisan would have been motivated to utilize other known methods in the prior art for purifying an antibody from a mixture including the PEG and NaCl precipitation methods as taught by Gagnon as taught above.
Gagnon describes purification of antibodies from a cell culture supernatant (see Example 1) that is a complex milieu containing many impurities such that an ordinarily skilled artisan at time of filing would have expected that PEG and NaCl precipitation as taught by Gagnon would be effective to separate an antibody-nucleic acid conjugate from a simpler reaction mixture as described by Jones including unreacted/unconjugated DNA and other reaction components.
Gagnon does not describe use of PEG precipitation for specific purification of an antibody-nucleic acid conjugate. However, there is no technical reason for an ordinarily skilled artisan at time of filing to believe that an antibody will cease to be precipitated with PEG and NaCl due to conjugation to a nucleic acid. For example, Rauterberg, para. [0008], states: Instead of precipitation with ammonium sulfate, . . . also proposed precipitation of the double-stranded DNA antibody conjugates by polyethylene glycol (PEG). This method also detects weakly vivid anti-DNA antibodies.” The double-stranded DNA antibody conjugates of Rauterberg is understood as an anti-DNA antibody non-covalently bound to DNA as an antigen. Regardless, Rauterberg teach that an antibody bound or associated to DNA is fully expected by an ordinarily skilled artisan at time of filing to be precipitated with PEG.
An ordinarily skilled artisan would have been motivated to utilize other known methods in the prior art for purifying an antibody from a mixture including the PEG precipitation methods as taught by Gagnon in order to avoid the cost of commercial products such as spin filters. Upon applying the PEG precipitation methods to a mixture including an antibody-nucleic acid conjugate and unconjugated nucleic acid as taught by Jones, the following method is reached:
A method for purifying an antibody-nucleic acid conjugate from a solution including the antibody-nucleic acid conjugate and unconjugated nucleic acid, the method comprising: a) contacting the solution and a purification solution including polyethylene glycol 6000 (PEG-6000) and sodium chloride (NaCl) to produce a mixture including antibody, PEG and NaCl such that the concentration of PEG in the mixture is 19% (w/v) and the concentration of NaCl in the mixture is about 200 mM; b) centrifuging the mixture to produce a supernatant and a pellet; c) isolating the pellet from the supernatant; and d) resuspending the pellet with a resuspension solution to produce a purified solution.
Regarding further recitation in claim 1 of “repeating steps (a) - (d) at least once using the purified solution of step (d) to produce a purified solution that is at least 90% [or 95%] pure for the antibody-nucleic acid conjugates, as measured by size exclusion (SEC) high performance liquid chromatography (HPLC),” “the precipitate is collected by centrifugation or filtration and the supernatant discarded. The precipitate is suspended in 19% PEG-6000; 1 M NaCl, 20-50 mM Hepes or phosphate, pH 7, then the precipitate is re-sedimented and the supernatant discarded. The precipitate can then be re-solubilized, for example with 50 mM phosphate, 1 M NaCl, pH 7.2.” Gagnon, para. [0135].
That is, Gagnon states that the precipitation/sedimentation with PEG should be performed twice. Gagnon states that the second precipitation is done by resuspending the precipitate/pellet in a solution already containing PEG and NaCl such that a solution containing the antibody-nucleic acid conjugate is not contacted with a purification solution as recited in step a) of claim 1 upon repetition. However, “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.” 2144.04(IV)(C). Here, suspending the precipitate/pellet having the antibody conjugate in a buffer such as 50 mM phosphate, 1 M NaCl, pH 7.2, prior to reperformance of the precipitation steps meets the features of steps a) through (d) of claim 1 as discussed above is a prima facie obvious selection of order of performing steps in the absence of new or unexpected results.
Regarding the specific recitation to produce a purified solution that is at least 90% [or 95%] pure for the antibody-nucleic acid conjugates, as measured by size exclusion (SEC) high performance liquid chromatography (HPLC), the claim language does not require actually performance of HPLC chromatography but only that the recited purity is present if measured. “[U]sing this method, antibody loss due to SiteClick Conjugation [which employs oligo with an alkyne reactive group] was estimated to be 10–25% and conjugation ratio was found to be 1–1.5 oligos per antibody, which indicates that the antibody is substantially all conjugated without unconjugated antibody.” Jones, page 11. The conjugation reactions described by Jones are understood to use substantially pure antibodies without other contaminating proteins present. Since unreacted DNA would not be expected be precipitated by PEG and NaCl, an ordinarily skilled artisan at time of filing would have actively expected that recovered antibody-DNA conjugate would be substantially pure with unreacted DNA removed including greater than 90% or 95% purity as measured by HPLC as recited. Further, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." 2145(II). The level of purity recited in claims 1 and 4 is recognition of another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious by performing recovery of an antibody-nucleic acid conjugate by precipitation with PEG and NaCl as suggested by the discussed prior art above.
For these reasons, the cited prior art suggests the features of claims 1-4, 7, 14 and 15.
Regarding 5, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II)(A). As discussed, Gagnon teaches formation of a precipitate or pellet by centrifugation but does not discuss a specific centrifugal force. An ordinarily skilled artisan at time of filing would have recognized that a minimum amount of centrifugal force is required to separate a precipitate/pellet and a supernatant wherein it is not inventive to discover that a workable amount of centrifugal force is more than 1,000 RCF (xg).
Regarding claim 6, Gagnon is silent regarding a specific incubation time or temperature for step (a) or step (d) as recited in claim 6. Upon combination of an antibody solution with the PEG/NaCl purification solution (step (a)), the same is necessarily at some temperature and remains combined for some non-zero period of time prior centrifugation as in step (b). Similarly, upon resuspension of a formed precipitate/pellet the same is at some temperature for a period of time before repeating precipitation as discussed. In the absence of any criticality of incubation time periods from about 20-40 minutes at 20[Symbol font/0xB0]C and/or about 20-40 minutes at about 37[Symbol font/0xB0]C as recited in claim 6, it is not inventive to discover workable ranges of incubation times and temperature. See MPEP 2144.05(II)(A).
Regarding claims 8-10, “The clarified IgG preparation now substantially devoid of chromatin and chromatin catabolites, is precipitated by addition of PEG-6000 to a final concentration of 19%. NaCl is also added in an amount of about 850 mM, bringing the net salt concentration (sample+added NaCl) to a presumptive concentration of about 1M.” Gagnon, para. [0135]. The solution added to supply the PEG-6000 and NaCl (purification solution) must necessarily be more concentrated that the final concentration after combination/contact with the antibody solution. As discussed, Agnon suggests a final concentration of 19% (w/v) PEG and 200 mM NaCl (in addition to lower concentrations of NaCl). Further, as far as Gagnon makes clear that both PEG and NaCl need to be added to the antibody, an ordinarily skilled artisan at the time of filing would have been motivated to combined PEG and NaCl into the same purification solution in order to achieve the convenience of adding only one solution to reach the needed concentration of PEG and NaCl.
Gagnon does not discuss either the concentration or volume of solution containing PEG and NaCl combined with an antibody solution. Regardless, in view of MPEP 2144.05(II)(A) cited above, Gagnon teaches the general condition that such solution to added NaCl and PEG must be more concentrated than the desired concentrations of PEG and NaCl after combination such that it cannot be considered to be inventive to discover that contacting the antibody solution and purification solution at a 1:1 (v/v) ratio as recited in claim 8, for the PEG concentration to be higher than 19%(w/v) including falling within the range of about 35%-45% (w/v) as recited in claim 9, and NaCl at a higher concentration as desired such as 250 mM as recited in claim 10.
Regarding claim 11, “the site-specific SiteClick conjugation kit was used to attached azide moieties directly to the carbohydrate domains present only in the Fc region of the antibody, preventing labeling in the Fab region and minimizing disruption of the antibody binding site.” Jones, page 11. As such, the antibodies described by Jones has an Fab region and a Fc region that is understood to meet the “antibodies comprise a Fab” as recited in claim 11.
Claim(s) 1-15 (all non-withdrawn claims) is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. (Oligonucleotide conjugated antibody strategies for cyclic immunostaining, Sci. Reports 11, 2021, 2384), Gagnon (U.S. 2015/0376231 A1) and Rauterberg (EP 0205643 A1) as applied to claims 1-11, 14 and 15 above, and further in view of Scannell et al. (Revisit PEG‑Induced Precipitation Assay for Protein Solubility Assessment of Monoclonal Antibody Formulations, Pharm. Res. 38, 2021, 1947-60).
Regarding claims 12 and 13, Jones in reference to Fig. 1 discusses the performance of at least 4 reactions to form an antibody nucleic acid conjugate. An ordinarily skilled artisan at time of filing would have readily understood that some sort of container must be used for performance of reach reaction to form a conjugate, although Jones does not make the nature of such a container explicit. Regardless, Scannell, abstract, teaches processing plural monoclonal antibody (MAb) in a PEG-induced precipitation assay. Scannell, page 1949, left col.:
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That is, Scannell teaches that multi-well plates (i.e. 96-well Deep Well plates) are a known container in the prior art to process multiple antibody samples in parallel including the ability to precipitate the same antibodies in PEG by centrifuging the multi-well plates. As far as Jones teaches the need to produce plural antibody nucleic acid conjugates, an ordinarily skilled artisan at time of filing would have been motivated to employ a multi-well plate as a container to produce such conjugates and precipitate the same with PEG and NaCl, since Scannell teaches that such multi-well plates are a suitable container for processing multiple antibody samples including for PEG precipitation. An ordinarily skilled artisan at time of filing would understand that each of a plurality of antibodies as taught by Jones can be placed in a separate, distinct well of a multi-well plate and that the same is a suitable container for simultaneous performance of both a conjugation reaction of plural antibody samples with nucleic acid to produce plural antibody nucleic acid conjugates and to precipitate the same with PEG and NaCl (as discussed above) as to meet the features of claims 12 and 13.
Conclusion
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
