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 .
Status of Application, Amendments and/or Claims
The amendment, filed 24 April 2024, has been entered in full. The amendment, filed 11 November 2024, has been entered in full. Claims 3-12 and 14 are amended.
Claims 1-14 are under examination.
Foreign Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy (EP 16179755.0) has been filed in parent Application No. 17/145,653 (now US Patent 11993630), filed on 7/15/2016.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-6, 8-10, 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Falkenstein et al. (US 2012/0197007; published 8/2/12) in view of Haddad et al. (US 2012/0276576; published 11/1/12).
Falkenstein et al. teach a method for the purification of a protein comprising erythropoietin (EPO) and a single polyethylene glycol (PEG) residue by a cation exchange chromatography method (abstract). Falkenstein et al. teach that in one embodiment the erythropoietin is human erythropoietin. In one embodiment the human erythropoietin has the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 (para 0015)(applies to claims 12 and 13). Falkenstein et al. teach that in one embodiment the single PEG residue has a molecular weight of from 20 kDa to 40 kDa (para 0016)(applies to claim 14).
Falkenstein et al. teach that depending on the nature of the charged group (substituent) the "ion exchange resin" is referred to as, for example, in the case of cation exchange resins, sulfonic acid resin (S), or sulfopropyl resin (SP), or carboxymethyl resin (CM)(para 0031). Falkenstein et al. teach that in one embodiment the SP Sephacryl S500 HR chromatography material is in a chromatography column. Falkenstein et al. teach that the method is especially useful for the purification of PEGylated recombinant erythropoietin, which is glycosylated, i.e. which has been produced by a mammalian cell (i.e. CHO cell, or a HEK293 cell, or a BHK cell, or a Per.C6.RTM. cell, or a Hela cell) and is afterwards chemically PEGylated (para 0042). Falkenstein et al. teach that the term "SP Sephacryl S500 HR chromatography material” denotes a cation exchange chromatography material and also denotes MacroCap SP (both available from GE Healthcare). Falkenstein et al. teach the SP Sephacryl S500 HR chromatography material is in one embodiment a cross-linked copolymer of allyl dextran and N,N-methylene bisacrylamide with sulfonic acid as chromatographical functional group and is, thus a strong cation exchange chromatography material (paras 0042 and 0076) (applies to claim 1a).
Falkenstein et al. teach a method for purifying erythropoietin and a single poly(ethylene glycol) residue, comprising a) applying a solution with a conductivity of about 21 mS/cm to a chromatography column comprising SP Sephacryl.TM. S 500 HR chromatography material, b) applying a solution comprising a mixture of free erythropoietin as well as fusion proteins of erythropoietin and poly(ethylene glycol) with one or more poly(ethylene glycol) residues per erythropoietin molecule to the column of a), c) applying a solution with a conductivity of about 21 mS/cm to the column and thereby recovering fusion proteins comprising two or more poly (ethylene glycol) residues, d) applying a solution with continuously and linearly increasing conductivity up to a final value of at least 60 mS/cm to the column and thereby recovering separately the fusion protein comprising erythropoietin and a single poly(ethylene glycol) residue and free erythropoietin, whereby the fusion protein comprising erythropoietin and a single poly(ethylene glycol) residue is obtained first (paras 0007-0011 and claims)(applies to claim 1a and 1c and 8).
Falkenstein et al. teach that in one embodiment the solution with a conductivity of about 21 mS/cm is a solution with a pH value of from pH 2.5 to pH 3.5. In one embodiment the solution with a conductivity of about 21 mS/cm is a phosphate buffered solution with a pH value of from pH 2.5 to pH 3.5 (para 0012)(applies to claim 1a).
Falkenstein et al. do not explicitly teach that the second solution has an increased pH value. However, Falkenstein et al. teach in one embodiment the solution with a conductivity of about 21 mS/cm is a solution with a pH value of from pH 2.5 to pH 3.5 (para 0012). Falkenstein et al. teach in the method that the first solution and the second solution both have a conductivity of about 21 mS/cm. Therefore, the first solution and the second solution have a pH value from pH 2.5 to pH 3.5. The pH range of from 2.5 to pH 3.5, encompasses applying a second solution with an increased pH value with respect to the first solution. Indeed, Falkenstein et al. teach in "continuous elution" one or more conditions, for example the pH, the tonic strength, concentration of a salt and/or the flow of a chromatography, may be changed linearly or exponentially or asymptotically (para 0030)(applies to claims 1b, 3-6).
Falkenstein et al. teach that in one embodiment the solution applied in step d) has a pH value of from pH 2.5 to pH 3.5. In one embodiment, applying a solution with continuously and linearly increasing conductivity is up to a final conductivity value of about 70.0 mS/cm (para 0013)(applies to claim 1c). Falkenstein et al. teach in one embodiment the solution with the continuously and linearly increasing conductivity is a solution with continuously and linearly increasing sodium chloride concentration (paras 0013-0014)(applies to claims 1c, 9 and 10).
Falkenstein et al. teach after poly-PEGylated erythropoietins have been recovered from the chromatography material, “a continuous’ elution with a linear conductivity gradient is started. The conductivity of the mobile phase passing the chromatography material is continuously and linearly increased to at least a conductivity of about 62.5 mS/cm. In the linear gradient at first mono-PEGylated erythropoietin is recovered from the column and afterwards substantially homogeneous non-PEGylated erythropoietin is recovered. Falkenstein et al. teach that the increase in the conductivity is in one embodiment by applying a solution with an increasing sodium chloride concentration. Falkenstein et al. teach in one embodiment the solution applied to increase the conductivity has a pH value of from pH 2.5 to pH 3.5. In one embodiment the increase of the conductivity from a value of about 21 mS/cm to the final value of at least 62.5 mS/cm. In one embodiment the solution with a conductivity of about 21 mS/cm is a sodium buffered solution of about 100 mM with a pH value of about pH 3.0 with (i.e. containing) about 120 mM sodium chloride. In one embodiment the linear gradient is a sodium chloride concentration gradient from about 120 mM to about 1000 mM sodium chloride in a sodium or potassium phosphate buffered solution of about 100 mM with a pH value of about pH 3.0 (paras 0071-0074)(applies to claim 1c).
Falkenstein et al. teach that the term "bind-and-elute mode" denotes an operation mode of a chromatography step, in which a solution containing a substance of interest to be purified is applied to a chromatography material, whereby the substance of interest binds to the chromatography material. The substance of interest is retained on the chromatography material, whereas substances not of interest are removed with the flow- through or the supernatant. The substance of interest is afterwards recovered from the chromatography material in a second step with an elution solution. Falkenstein et al. teach that the "flow-through" denotes the solution obtained after the passage of the device, which may either be the applied solution or a buffered solution, which is used to wash the column (paras 0027-0028). Based on this teachings it would be obvious to wash the column before the elution step (applies to claim 2).
Falkenstein et al. teach the SP Sephacryl S500 HR chromatography material is in one embodiment a cross-linked copolymer of allyl dextran and N,N-methylene bisacrylamide with sulfonic acid as a chromatographical functional group (sulfopropyl) and thus is a strong cation exchange chromatography material.
Falkenstein et al. do not explicitly teach the chromatography column comprises methacrylate.
Haddad et al teach ion exchange chromatography columns comprising cation-exchanging group. Haddad et al. teach that the experimental work behind the present application has been carried out with sulfopropyl methacrylate (paras 0015, 0032 and 0034). Haddad et al. teach the grafting of poly(sulfopropyl methacrylate), which converted a hydrophobic poly(S-co-DVB) monolith into a strong cation exchanger (para 0056).
It would have been obvious for one of ordinary skill in the art before the effective filing date to modify a method of purifying a protein comprising EPO and a single PEG residue by a cation exchange chromatography column comprising sulfopropyl, as taught by Falkenstein et al., by using a cation exchange chromatography column comprising sulfopropyl and methacrylate, as taught by Haddad et al. One of ordinary skill in the art before the effective filing date, would have been motivated to modify the method and expect success for the following reasons. Falkenstein et al. teach a method of purifying a mono-pegylated human EPO using different cation materials/resins. Falkenstein et al. teach the SP Sephacryl S500 HR chromatography as a strong cation exchange chromatography material to isolate/purify mono-pegylated human EPO. Haddad et al. teach the grafting of poly(sulfopropyl methacrylate), which converted a hydrophobic poly(S-co-DVB) monolith into a strong cation exchanger (para 0056). Using a chromatography column comprising sulfopropyl methacrylate is another example of a strong cation.
Based on the teachings one of ordinary skill in the art of making and purifying mono-pegylated EPO compositions would have been motivated to discern the most favorable conditions such as adjusting the chromatography column materials because these modifications are deemed a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). See M.P.E.P. § 2144.05, section Il.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Falkenstein et al. in view of Haddad et al., as applied to claims 1 and 10 above, and further in view of Makino et al. (US 5,817,238; published 10/6/98).
The teachings of Falkenstein and Haddad are described above. The teachings do not teach the diameter size of the cation exchange chromatography column.
Makino et al. teach a process for purifying L-ascorbic acid (vitamin C), using a strong cation exchange chromatography column (abstract and column 1, lines 40-column 2, line 50). Makino et al. teach a strong cation exchange chromatography column being 30 cm in diameter (column 6, lines 25-37)(applies to claim 11).
It would have been obvious for one of ordinary skill in the art before the effective filing date to modify a method of purifying a protein comprising EPO and a single PEG residue by a strong cation exchange chromatography comprising sulfopropyl and methacrylate, as taught by Falkenstein and Haddad, by using a column with a 30 cm diameter, as taught by Makino et al. One of ordinary skill in the art before the effective filing date, would have been motivated to modify the method and expect success because Makino et al. teach that strong cation exchange chromatography columns with a diameter of 30 cm are suitable for large-scale separation. Based on the instant teachings, it would be obvious to use a column with a particular diameter, if a large yield/amount of proteins are being purified.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,993,630.
The instant claims are drawn to a method for purifying a protein, which comprises erythropoietin and a single poly (ethylene glycol) residue, comprising the following steps:
a) applying a solution comprising a mixture of erythropoietin and conjugates of erythropoietin and poly (ethylene glycol) with one or more poly (ethylene glycol) residues per erythropoietin molecule to a column, comprising a chromatography material that has a matrix of methacrylate with a sulfopropyl as functional group, to which a first solution with a pH of about 2.4 to about 2.7 has been applied, b) applying a second solution with an increased pH value with respect to the first solution, c) applying a solution with increased or increasing conductivity to the column and thereby recovering the protein, which comprises erythropoietin and a single poly (ethylene glycol) residue.
The instant claims are further drawn to wherein the second solution with an increased pH value has a pH of about 2.7 to about 3.0 and has a conductivity value of about 17 mS/cm to about 19 mS/cm. The instant claims are further drawn to wherein the solution with increasing conductivity is a solution with increasing sodium chloride concentration. The instant claims are further drawn to wherein the solution with increasing conductivity has a conductivity that increases linearly or step-wise. The instant claims are further drawn to wherein the chromatography column has a diameter of at least 30 cm. The instant claims are further drawn to wherein the erythropoietin is human and has the amino acid of SEQ ID NO:1 or SEQ ID NO:2. The claims further drawn to wherein the single polyethylene glycol residue has a molecule weight of from 20 kDa to 40 kDa.
The claims of U.S. Patent No. 11,993,630 teach a method for purifying a protein, which comprises erythropoietin and a single poly (ethylene glycol) residue, comprising the following steps: a) applying a solution comprising a mixture of erythropoietin and conjugates of erythropoietin and poly (ethylene glycol) with one or more poly (ethylene glycol) residues per erythropoietin molecule to a column, comprising a chromatography material that has a matrix of methacrylate with a sulfopropyl as functional group, to which a first solution with a pH of about 2.4 to about 2.7 has been applied, b) applying a second solution with an increased pH value with respect to the first solution, c) applying a solution with increased or increasing conductivity to the column and thereby recovering the protein, which comprises erythropoietin and a single poly (ethylene glycol) residue, wherein the second solution with an increased pH value has a pH of about 2.7 to about 3.0 and has a conductivity value of about 17 mS/cm to about 19 mS/cm.
The claims of U.S. Patent No. 11,993,630 further teach wherein the solution with increasing conductivity is a solution with increasing sodium chloride concentration. The claims of U.S. Patent No. 11,993,630 further teach wherein the solution with increasing conductivity has a conductivity that increases linearly or step-wise. The claims of U.S. Patent No. 11,993,630 further teach wherein the chromatography column has a diameter of at least 30 cm. The claims of U.S. Patent No. 11,993,630 further teach wherein the erythropoietin is human and has the amino acid of SEQ ID NO:1 or SEQ ID NO:2. The claims of U.S. Patent No. 11,993,630 further teach wherein the single polyethylene glycol residue has a molecule weight of from 20 kDa to 40 kDa.
Although the claims at issue are not identical, they are not patentably distinct from each other because the species of the second solution taught in the claims of U.S. Patent No. 11,993,630 (i.e. second solution having increased pH value with respect to the first solution, has a pH of about 2.7 to about 3.0 and has a conductivity value of about 17 mS/cm to about 19 mS/cm) renders obvious the genus of the second solution taught in the instant claims (i.e. increased pH value with respect to the first solution). In addition, the instant dependent method steps and the dependent method steps taught in the claims of U.S. Patent No. 11,993,630 are either the same or obvious variant of each other.
Claims 1-5, 9,10, 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-9 of U.S. Patent No. 10,273,277 in view of Burg et al. (HOFFMAN-LA ROCHE WO 2009/010270; published Jan 22, 2009).
The instant claims are described above.
The claims of U.S. Patent No. 10,273,277 teach a chromatography method for obtaining a protein, which comprises erythropoietin and a single poly (ethylene glycol) residue, comprising: a) applying a solution comprising a mixture of erythropoietin and conjugates of erythropoietin and poly (ethylene glycol) with one or more poly (ethylene glycol) residues per erythropoietin molecule to a column comprising SP Sephacryl S500 HR chromatography material, to which a solution with a conductivity of 21 mS/cm has been applied, b) applying a solution with a conductivity of 21 mS/cm to the column and thereby recovering free poly (ethylene glycol), and proteins comprising two or more poly (ethylene glycol) residues, and c) applying a solution with linearly increasing conductivity up to a final value of 62.5 mS/cm to the column and thereby recovering separately the protein, which comprises erythropoietin and a single poly (ethylene glycol) residue, and erythropoietin, whereby the protein comprising erythropoietin and a single poly (ethylene glycol) residue is recovered first, wherein the protein comprising erythropoietin and a single poly (ethylene glycol) is purified after one single chromatography step.
The claims of U.S. Patent No. 10, 273,277 further teach wherein the solution with a conductivity of 21 mS/cm is a solution with a pH value of from pH 2.5 to pH 3.5. The claims of U.S. Patent No. 10,273,277 further teach wherein the solution with linearly increasing conductivity is a solution with linearly increasing sodium chloride concentration. The claims of U.S. Patent No. 10,273,277 further teach wherein the erythropoietin is human and has the amino acid of SEQ ID NO:1 or SEQ ID NO:2. The claims of U.S. Patent No. 10,273,277 further teach wherein the single polyethylene glycol residue has a molecule weight of from 20 kDa to 40 kDa.
The claims of U.S. Patent No. 10,273,277 do not teach wherein the chromatography column comprises methacrylate. The claims of U.S. Patent No. 10,273,277 do not teach wherein the method further comprises re-applying the first solution after step b) and before step c).
Burg et al. teach a method for the purification of mono-PEGylated erythropoietin using chromatography. In one embodiment of the method, the cation exchange material is a strong cation exchange material. Burg et al. teach strong cation exchange materials includes SP Sepharose and Toyopearl SP 650M wherein both material have sulfopropyl (SP)(abstract pages 3-5). Toyopearl SP-650 chromatography material has a matrix of methacrylate with a sulfopropyl as functional group.
Burg et al. teach a purification method in which a solution containing a substance of interest to be purified is brought in contact with a stationary phase. The solution containing the substance of interest to be purified passes through the stationary phase allowing for an interaction between the stationary phase and the substances in solution. Burg et al. teach that depending on the conditions, such as e.g. pH, conductivity, salt concentration, temperature, and/or flow rate, some substances of the solution are bound to the stationary phase and thus are removed from the solution and other substances remain in solution. Burg et al. teach that the substances remaining in solution can be found in the flow- through. The "flow-through" denotes the solution obtained after the passage of the chromatographic device, which may either be the applied solution containing the substance of interest or the buffer, which is used to flush the column or to cause elution of one or more substances bound to the stationary phase (page 6, line 27-page 7, line 7).
Although the claims at issue are not identical, they are not patentably distinct from each other. It would be obvious to modify a method for obtaining a protein, which comprises EPO and a single PEG residue, as taught in the claims of U.S. Patent No. 10,273,277 to include reapplying the first solution wherein the cation exchange material is a sulfopropyl cation exchange material, such as toyopearl SP 650M as taught by Burg et al. to make the instant invention.
One having ordinary skill in the art would have been motivated to make such modifications because the skilled artisan is merely substituting one strong cation exchange chromatography column for another strong exchange chromatography column. One of ordinary skill in the art of making and purifying mono-pegylated EPO compositions would have been motivated to discern the most favorable conditions such as adjusting the chromatography column materials because these modifications are deemed a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). See M.P.E.P. § 2144.05, section Il. In addition, the species of the conductivity solutions taught in the claims of U.S. Patent No. 10,273,277 renders obvious the genus of the conductivity solutions recited in the instant claims. The pH of the solutions taught in the claims of U.S. Patent No. 10,273,277 overlap with the pH of the solution recited in the instant claims. Burg et al. teach that the flow-through may either be the applied solution containing the substance of interest or the buffer, which is used to flush the column or to cause elution of one or more substances bound to the stationary phase. Based on the teachings it would be obvious to wash the column before the elution step.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 10/24/2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647