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 .
Priority
The instant application filed on 09/16/2022 is a 371 of PCT/JP2020/015698 filed on 04/07/2020, which claims priority to JP2020-047003 filed on 03/17/2020. The certified copy of foreign priority for JP2020-047003 is not filed in English; therefore, the effective filing date of the claimed invention is 04/07/2020.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Withdrawal of Rejections
The response and amendments filed on 11/24/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments. The previous claim rejections under 35 U.S.C. 102 for anticipation and 103 for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
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 13-22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Schmalz (US 2012/0172299; Date of Publication: July 5, 2012 – previously cited) in view of Gagnon (US 2009/0318674; Date of Publication: December 24, 2009 – previously cited) and Brierley (U.S. Patent No. 6,207,806; Date of Publication: March 27, 2001 – newly cited.
Schmalz’s general disclosure relates to a method for purifying erythropoietin, wherein the method comprises “steps i) the erythropoietin in a solution containing Calcium-ions is brought into contact with a stationary phase containing hydroxyapatite equilibrated with a solution containing Calcium-ions and namely under conditions under which the erythropoietin binds to the stationary phase containing hydroxyapatite, ii) a solution is passed over the stationary phase containing hydroxyapatite from i) which contains less Calcium-ions than the previous solution and the erythropoietin is not detached from stationary phase containing hydroxyapatite, and iii) a further solution which contains less than 0.5 mM Calcium-ions is passed over the stationary phase containing hydroxyapatite from ii) whereby the erythropoietin is detached from the stationary phase containing hydroxyapatite” (see, e.g., Schmalz, abstract).
Regarding claim 13 pertaining to the method of treating the hydroxyapatite filler, Schmalz teaches a liquid containing a concentration of 5 mM phosphate ions is brought into contact with the hydroxyapatite (see, e.g., Schmalz, [0015]). Schmalz teaches a stock solution with sodium hydroxide, which is a liquid containing alkali (see, e.g., Schmalz, [0112]). Additionally, Schmalz teaches bringing a low molecular weight alcohol solution into contact with the hydroxyapatite (see, e.g., Schmalz, [0093]). Schmalz teaches an aqueous alcohol solution that contains “20 mM TRIS-HCl, 5 mM CaCl2, 0.25 M NaCl, 9% (v/v) 2-propanol with a pH of 6.9±0.2 (see, e.g., Schmalz, [0082]); therefore, this solution is free of phosphate and alkali. Furthermore, Schmalz teaches that the alcohol solution is added to the hydroxyapatite for elution (see, e.g., Schmalz, [0093]); therefore, one of ordinary skill in the art would understand that elution of the protein by addition of the alcohol would come after treatment with the phosphate and alkali solutions.
Regarding claim 14 pertaining the hydroxyapatite filler, Schmalz teaches hydroxyapatite (see, e.g., Schmalz, abstract & [0008]).
Regarding claim 15 pertaining to the alcohol, Schmalz teaches that the alcohol is a lower molecular weight alcohol (see, e.g., Schmalz, [0093]).
Regarding claims 17-18 pertaining to the percentage of alcohol, Schmalz teaches 25% to 35% alcohol (see, e.g., Schmalz, [0093]).
Regarding claim 19 pertaining to supplementation with calcium, Schmalz teaches that the hydroxyapatite is equilibrated with a solution containing calcium ions before addition of erythropoietin in solution with calcium ions is brought into contact with a stationary phase of the hydroxyapatite (see, e.g., Schmalz, abstract).
Regarding claim 20 pertaining to the concentration of calcium ions, Schmalz teaches addition of calcium ions at a concentration of 0.5 mM to 20 mM for contact with a stationary phase containing hydroxyapatite (see, e.g., Schmalz, [0008], [0047], [0060], [0075], [0082]).
Regarding claim 21 pertaining to the calcium cions, Schmalz teaches “Calcium-ions are introduced into the solution as CaCl2”; therefore, the calcium ion is calcium chloride (see, e.g., Schmalz, [0082]).
Regarding claim 24 pertaining to the amount of the aqueous solution passed through the filler, Schmalz teaches “4 to 7 column volumes of the second solution are applied to the column”, wherein the second solution contains an 2-propanol (see, e.g., Schmalz, [0082]).
However, Schmalz does not teach: contacting the hydroxyapatite filler with an aqueous solution containing an alcohol for 48 hours or more (claim 13); or wherein the alcohol is ethanol (claim 16); or wherein the alcohol aqueous solution is brought into contact with the hydroxyapatite filler for 5 days or more in the second step (claim 22); or wherein the hydroxyapatite filler is kept in the aqueous solution (claim 24).
Gagnon’s general disclosure relates to “methods and compositions for purification of proteins, in particular, to methods and compositions for an antibody purification process that
includes aggregate removal and the use of solubility enhancing additives such as zwitterion-containing compositions to enhance antibody solubility and avoid aggregate formation or occlusion during ion exchange chromatography, yielding a high-purity protein product substantially free of aggregates” (see, e.g., Gagnon, abstract). Moreover, Gagnon discloses the use of hydroxyapatite chromatography for purification of antibodies because “aggregate removal using PEG-containing buffers during hydroxyapatite chromatography, especially using ceramic
hydroxyapatite, was found to be reliable and easy to achieve” (see, e.g., Gagnon, [0012], [0037]).
Regarding claim 16 pertaining to the alcohol, Gagnon teaches that the hydroxyapatite is contacted with a buffer that contains ethanol (see, e.g., Gagnon, [0081]).
Regarding claims 22 and 24 pertaining to contacting and storing the hydroxyapatite filler, Gagnon teaches that the hydroxyapatite is kept in Buffer F, which contains ethanol (see, e.g., Gagnon, [0081]); therefore, one of ordinary skill in the art would readily understand that the hydroxyapatite filler is kept in the aqueous alcohol solution.
Brierley’s general disclosure relates to “an improved process for obtaining purified, monomeric, intact, correctly-folded insulin-like growth factor-I (also known as somatomedin-C). The improvements, consisting primarily of the addition of an IGF-I unfolding/refolding step and the substitution of a reverse phase chromatography step for a gel filtration chromatography step result in a three-fold increase in final yield. The process includes the following steps, in order: first cation exchange, unfolding/refolding, hydrophobic interaction chromatography, second cation exchange, and reverse phase chromatography” (see, e.g., Brierley, abstract). Moreover, Brierley teaches recovering IGF-1 from chromatography column(s) by elution with ethanol (see, e.g., Brierley, col. 10, lines 52-63).
Regarding claim 13, 16, 22, and 24 pertaining to the treatment time and ethanol, Brierley teaches that “elution time will vary as a function of column dimensions, matrix material, and the like. Flow of eluent through the column is preferably about 10 to 300 cm/h” (see, e.g., Brierley, col 8, lines 10-12). Furthermore, Brierley teaches “These IGF-I forms include authentic IGF-I (approximately 18% of the total IGF-I) eluting at 7.3 minutes; misfolded monomeric IGF-I (approximately 15%) eluting at 5.08 minutes; degraded or amino-terminal clipped (des-2) monomer form (approximately 1% of total) eluting at 6.0 minutes; oxidized and glycosylated monomer forms (approximately 7% of total) eluting at 6.7 minutes; a variety of degraded or nicked monomer forms (approximately 7% of total) eluting between 8 and 11 minutes; and numerous multimeric forms (approximately 50% of total) eluting between 11 and 22 minutes” (see, e.g., Brierley, col. 10, lines 52-63). Moreover, Brierley teaches that “Authentic IGF-I is recovered through isocratic elution with an aqueous/organic buffer, followed by gradient elution. The isocratic elution is carried out with several column volumes of an aqueous/organic buffer, having an organic solvent concentration of between approximately 20% and 40%. Further IGF-I elution is carried out with an organic solvent gradient. Preferably, the isocratic elution is with four column volumes of 0.2 M acetic acid containing 19% ethanol, and the gradient (step or linear) from 19% to 25% ethanol (v/v), in 0.2 M acetic acid” (see, e.g., Brierley, col. 8, lines 26-35). Based on the teachings of Brierley, one of ordinary skill in the art would readily understand that the elution time, or flow rate, is correlated to the amount of time that the protein is in contact with the ethanol since ethanol is used for elution of proteins from the chromatography column. Moreover, based on the teachings of Brierley, the larger or more complex the protein, the longer the elution time is; therefore, elution time depends on protein size.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ Schmalz’s methods of treating a hydroxyapatite filler, wherein proteins introduced to the hydroxyapatite filler for chromatography are contacted with ethanol, as taught by Gagnon and Brierley, and wherein the column is contacted with ethanol for the purposed of eluting proteins, as taught by Brierley. . One would have been motivated to do so because Gagnon teaches that hydroxyapatite columns can be contacted with ethanol and Brierley was used as motivation to teach that ethanol can use used to elute proteins from chromatography columns, wherein the proteins can be eluted at various times based on the size of the protein and length/size of the column (see, e.g., Brierley, col. 8, lines 10-12 & 26-35 & col. 10, lines 52-63). Furthermore, Brierley teaches “authentic IGF-I (approximately 18% of the total IGF-I) eluting at 7.3 minutes; misfolded monomeric IGF-I (approximately 15%) eluting at 5.08 minutes; degraded or amino-terminal clipped (des-2) monomer form (approximately 1% of total) eluting at 6.0 minutes; oxidized and glycosylated monomer forms (approximately 7% of total) eluting at 6.7 minutes; a variety of degraded or nicked monomer forms (approximately 7% of total) eluting between 8 and 11 minutes; and numerous multimeric forms (approximately 50% of total) eluting between 11 and 22 minutes” (see, e.g., Brierley, col. 10, lines 52-63). see, e.g.,. Moreover, Schmalz teaches the addition of 2-propanol, amongst other types of alcohols, to the hydroxyapatite column for elution of proteins (see, e.g., Schmalz, [0093]). Therefore, based on the teachings of Schmalz, Gagnon, and Brierley, the addition of an alcohol aqueous solution containing ethanol to the column would result in elution of a protein from the column, wherein the elution time depends directly on the size of the column and the size of the protein.; One would have expected success because Schmalz, Gagnon, and Brierley all teach elution of proteins from chromatography columns using alcohol. .
Regarding claims 13, 22, and 24’s limitation of how long the aqueous alcohol solution is in contact with the hydroxyapatite filler, those working in the biological and/or pharmaceutical arts would understand that the adjustments of conventional working conditions is deemed a matter of routine optimization, which is in the purview of the skilled artisan. For example, Brierley teaches elution of IGF-1, wherein “These IGF-I forms include authentic IGF-I (approximately 18% of the total IGF-I) eluting at 7.3 minutes; misfolded monomeric IGF-I (approximately 15%) eluting at 5.08 minutes; degraded or amino-terminal clipped (des-2) monomer form (approximately 1% of total) eluting at 6.0 minutes; oxidized and glycosylated monomer forms (approximately 7% of total) eluting at 6.7 minutes; a variety of degraded or nicked monomer forms (approximately 7% of total) eluting between 8 and 11 minutes; and numerous multimeric forms (approximately 50% of total) eluting between 11 and 22 minutes” (see, e.g., Brierley, col. 10, lines 52-63). Furthermore, Brierley teaches “elution time will vary as a function of column dimensions, matrix material, and the like. Flow of eluent through the column is preferably about 10 to 300 cm/h” (see, e.g., Brierley, col 8, lines 10-12). Therefore, one of ordinary skill in the art would readily understand that the amount of time it takes to elute the protein from the column would depend on the size of the chromatography column and the size of the protein. see, e.g., This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning this time, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation is a result effective variable which can be met as a matter of routine optimization.
Examiner’s Response to Arguments
Applicant's arguments filed 11/24/2025 have been fully considered but they are not persuasive.
Regarding Applicant’s argument pertaining to the hydroxyapatite filler being in contact with an alcohol aqueous solution for 48 hours or more and that this is a unique technical feature (remarks, page 7), this is not persuasive for multiple reasons. First, the broadest reasonable interpretation (BRI) of independent claim 13 is a method of bringing a hydroxyapatite filler in contact with a liquid containing a phosphate, followed by a liquid containing an alkali, following by a solution containing an alcohol that is free of phosphate and alkali for 48 hours or more. Based on the BRI of independent claim 13, Schmalz teaches a liquid containing a concentration of 5 mM phosphate ions is brought into contact with the hydroxyapatite (see, e.g., Schmalz, [0015]). Schmalz teaches a stock solution with sodium hydroxide, which is a liquid containing alkali (see, e.g., Schmalz, [0112]). Additionally, Schmalz teaches bringing a low molecular weight alcohol solution into contact with the hydroxyapatite (see, e.g., Schmalz, [0093]). Schmalz teaches an aqueous alcohol solution that contains “20 mM TRIS-HCl, 5 mM CaCl2, 0.25 M NaCl, 9% (v/v) 2-propanol with a pH of 6.9±0.2 (see, e.g., Schmalz, [0082]); therefore, this solution is free of phosphate and alkali. Furthermore, Schmalz teaches that the alcohol solution is added to the hydroxyapatite for elution (see, e.g., Schmalz, [0093]); therefore, one of ordinary skill in the art would understand that elution of the protein by addition of the alcohol would come after treatment with the phosphate and alkali solutions. Furthermore, Brierley teaches that ethanol can be added to the column for protein elution (see, e.g., Brierley, col. 8, lines 26-35). see, e.g., Furthermore, as discussed above, the amount of time that the hydroxyapatite filler can be left in the buffer containing ethanol is deemed a matter of routine optimization. Brierley teaches elution of IGF-1, wherein “These IGF-I forms include authentic IGF-I (approximately 18% of the total IGF-I) eluting at 7.3 minutes; misfolded monomeric IGF-I (approximately 15%) eluting at 5.08 minutes; degraded or amino-terminal clipped (des-2) monomer form (approximately 1% of total) eluting at 6.0 minutes; oxidized and glycosylated monomer forms (approximately 7% of total) eluting at 6.7 minutes; a variety of degraded or nicked monomer forms (approximately 7% of total) eluting between 8 and 11 minutes; and numerous multimeric forms (approximately 50% of total) eluting between 11 and 22 minutes” (see, e.g., Brierley, col. 10, lines 52-63). Furthermore, Brierley teaches “elution time will vary as a function of column dimensions, matrix material, and the like. Flow of eluent through the column is preferably about 10 to 300 cm/h” (see, e.g., Brierley, col 8, lines 10-12). Therefore, one of ordinary skill in the art would readily understand that the amount of time it takes to elute the protein from the column would depend on the size of the chromatography column and the size of the protein. Therefore, one of ordinary skill in the art can optimize the time that the protein is in contact with ethanol by manipulating the column size and the protein size.
In response to applicant's argument that the references fail to show certain features of the invention (remarks, page 8), it is noted that the features upon which applicant relies (i.e., ethanol not undergoing an ion exchange reaction, washing the hydroxyapatite filler with 1.0 M NaOH, storage in 20 wt% ethanol, and repetition numbers) 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). Furthermore, even if there is unexpectedness in the results, the results are not commensurate in scope with the claimed invention. Applicant is relying on a specific temperature (25oC), a specific flow ate (0.5 mL/min), and a specific flow volume (10 CV) (see, e.g., instant specification, Example 1, [0167]). Moreover, the instant specification relies on a specific number of repetition steps in order to show that EtOH preservation increases the number of times the hydroxyapatite filler can be used (see, e.g., instant specification, Table 1, [0184]). Therefore, assuming arguendo that there is some unexpectedness, the results are not commensurate in scope with the claimed invention because Applicant is relying on specific temperatures, volumes, and rates.
Conclusion
Claims 13-22 and 24 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653