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 .
Claim Status
Claims 22-30, 32-36, and 38-40 are pending.
Claim 22, 27-28, 32, 34, and 36 are currently amended.
Claims 1-21, 31, and 37 are cancelled.
Claims 22-30, 32-36, and 38-40 are examined.
Priority
This application is a 371 of PCT/EP2018/097125 filed on 12/28/2018 and claims foreign priority of EP 17211122.1 filed on 12/29/2017.
Modified Objection
Claims 22, 27-28, 32, 34, and 36 are objected to because of the following informalities:
The amendments to the cited claims are not in permanent black ink.
Claim 22 is further object to more than 1 periods.
Each claim should have only a single period at the end of the claim. An extra period can be found at steps “A.”, “B.”, “C.”, and “D.”. The examiner suggests to revise them as “(A)”, “(B)”, “(C)”, and “(D)” to overcome this objection.
Appropriate correction is required.
Withdrawn Rejection
The rejection of claims 22-30 and 32-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn because the amendments to the claims overcome the rejection.
The rejection of claims 22-30 and 32-40 are rejected under 35 U.S.C. 103 as being unpatentable over Defrees et al. in view of Tegner, Staby et al., Muller et al. evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S and further in view of Lai et al. is withdrawn because pH and salt concentration for PEGylated EPO protein purification by AEC and HIC is result effective variables known in the art taught by the previously cited references of record. Lai et al. is not needed for the limitation of the base claim 22.
New Ground of Rejection
Claim Rejections - 35 USC § 103
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.
Claims 22-30, 32-36 and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Defrees et al. (US 2008/0253992 A1, previously cited 12/30/2022) in view of Tegner (Ph.D. thesis, previously cited 9/11/2025), JenKem Technology USA (https://jenkemusa.com/ application-instructions-for-y-nhs-40k-for-amine-pegylation, 2015), Staby et al. (Journal of Chromatography A, 1164 (2007) 82–94, previously cited 9/11/2025), and Muller et al. (J. Chromatogr. A 1217 (2010) 4696–4703, cited in IDS 1/26/2021), and as evidenced by (i) Toyopearl SuperQ-650C (https://separations.us. tosohbioscience.com/Process_Media/id-8115/TOYOPEARL_ SuperQ-650C., previously cited 11/20/2024) and (ii) Toyopearl Phenyl-650S (https://separations.us.tosohbioscience.com /process_media/id-8140/toyopearl_phenyl-650s., previously cited 11/20/2024).
Claim 22 is drawn to a process for producing a mono-Pegylated protein (intended for 90% purity by weight) comprising the steps:
Performing a PEGylation reaction by reacting non-PEGylated protein with a PEGylation agent to provide a first mixture comprising non-PEGylated protein, mono-PEGylated, and oligo-PEGylated protein. The first mixture comprising less than 25% oligo-PEGylated protein by weight;
(a) Applying the first mixture to an ion exchange chromatography (IEC) step to provide an IEC flow-through solution and the IEC material under conditions suitable for binding non-PEGylated protein; and
(b) Collecting the IEC flow-through solution to provide a second mixture comprising at least about 80-95% of a mixture of mono- and oligo-PEGylated protein by weight;
C. Eluting non-PEGylated protein from the IEC material with < 50 mM salt to recycle the non-PEGylated protein in the IEC eluate and adding the non-PEGylated protein directly to a second PEGylation reaction of step A, and performing a second cycle of steps (a) and (b);
D. Applying the second mixture of PEGylated proteins to a hydrophobic interaction chromatography (HIC) step in either bind-and-elute or flow through mode to provide a mono-PEGylated protein composition comprises at least about 90% mono-PEGylated protein by weight; and
E. wherein, each of Steps A, B. C and D is performed at substantially the same pH within the range of about.7.0 to 9.0 ± 0.5 pH units.
DeFrees et al. show a method for purifying PEGylated erythropoietin (EPO) from a provided solution mixture comprising EPO and PEGylated EPO by anion exchange chromatography (AEC) followed by hydrophobic interaction chromatography (HIC) shown in figure 1 as follows. DeFrees et al. teach the anion exchange conditions are selected to
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preferentially bind impurities at a salt concentration below the elution salt concentration (reading on non-PEGylated bound on AEC resin), while the purified PEGylated EPO (mono-PEGylated and residual oligo-PEGylated EPO) is found in the flow-through [0211,0295]. DeFrees et al. show that the PEGylated EPO in AEC flow through is further applied to HIC in figure 1 above. DeFrees et al. teach the PEGylation of EPO protein is via chemical PEGylation reaction or an enzymatically catalyzed PEGylation reaction [0006]. DeFrees et al. suggest the “unwanted” PEG conjugated EGO, e.g., oligo PEG conjugated protein, is less than about 1% to less than 30% in the mixture [0104].
Tegner teaches optimization of a PEGylation process (Title). Tegner teaches after the batch reactor of PEGylation process, the products and remaining reactants (e.g., unreacted protein) are separated with an ion exchange chromatography (IEC) column. Tegner teaches the benefits with using IEC are that it is easy to clean, have a higher capacity and they are smaller than a SEC and thereby making it possible to achieve higher flow rates without high pressure drops (p9, 2.5.1 Batch reactor process), consistent with DeFrees et al. described above. To be able to reach a higher yield without producing a large amount of byproducts, a recirculation of unreacted protein is sent back to the batch reactor. The unreacted protein is then recycled back to
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the batch reactor where it can PEGylate again resulting in a higher monoPEGylated protein yield (p9, 2.5.2 Combined recirculation process) shown as follows (p20, Fig 4.5). Tegner shows the molar ratio of PEG to a protein is a result effective variable can be optimized and the molar ratio of PEG to protein at 1:1 ratio for PEGylation has the highest monoPEG to multiPEG ratio in a PEGylated reaction (p20, Fig 4.6). JenKem Technology USA is cited to show a commercial service of protein PEGylation using Phosphate buffer (compatible with AEC and HIC) at pH 7.0-7.5 known in the art (p1, Material, last para).
Staby et al. is cited to show linear gradient elution retention of ion-exchange chromatography as a function of pH (p87, col 1, last para) and the use of this physical property for development of step gradient programs for elution by decreased pH to avoid salt elution and for planning of flow-through mode operation (p88, col 2, para 1).
Similarly, Muller et al. teach ion-exchange chromatography (IEX) and hydrophobic-interaction chromatography (HIC) are commonly used chromatography for purifying PEGylated proteins (p4696, col 2, para 2; p4698, Table 1) consistent with DeFrees et al. Muller et al. show the use of HIC alone in a suitable condition sufficient to completely separate the mono-
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PEGylated protein from Di- PEGylated protein into different fraction/peak shown as follows (p4702, Fig 5). Thus, it would be obvious for DeFrees’s PEGylated EPO protein in a composition comprising at least about 90% mono-PEGylated EPO after a combination purification using AEC followed by HIC.
With respect to Step A, DeFrees et al. teach the PEGylation of EPO protein is via chemical PEGylation reaction or an enzymatically catalyzed PEGylation reaction [0006]. DeFrees et al. suggest the “unwanted” PEG conjugated EGO, e.g., oligo PEG conjugated protein, is less than about 1% to less than 30% in the mixture [0104] overlapping with less than 25% oligo-PEGylated protein as claimed. Tegner shows the molar ration of PEG to a protein in PEGylation reaction is a result effective variable can be routinely optimized and the molar ratio of PEG to protein at 1:1 ratio for PEGylation has the highest monoPEG to multiPEG ratio in a PEGylated reaction (p20, Fig 4.6).
With respect to Step B(a), DeFrees et al. show application of a provided solution mixture comprising EPO and PEGylated EPO to anion exchange chromatography (AEC) in figure 1. Consistently, Tegner teaches PEGylated protein products and remaining reactants (unreacted protein) are separated with an ion exchange chromatography (IEC) column after the batch reactor of PEGylation process because the benefits with using IEC are that it is easy to clean, have a higher capacity and they are smaller than a SEC and thereby making it possible to achieve higher flow rates without high pressure drops (p9, 2.5.1 Batch reactor process).
With respect to Step B(b), DeFrees et al. teach the anion exchange conditions are selected to preferentially bind impurities (non-PEGylated polypeptide), while the purified peptide (e.g., PEGylated EPO comprises mono-PEGylated and oligo-PEGylated EPO) is found in the flow-through [0211,0329]. Because (i) DeFrees’s AEC and PEGylated polypeptide in the flow through fraction meet the claim limitations and (ii) non-PEGylated proteins and/or oligo-PEGylated EPO are bound by AEC matrix, DeFrees’s PEGylated polypeptide in the flow through would be able to achieve purity at least 80-95% in a mixture of PEGylated protein comprising mono- and oligo-PEGylated protein. MPEP 2112.01 (I) states “Product and apparatus claims - When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent”. In the present case, DeFrees’s anion exchange chromatography in a flow-through mode is necessary to produce at least 80-95% PEGylated protein as claimed. Furthermore, DeFrees et al. teach loading buffer comprising a salt concentration below the concentration at which the peptide would elute from the column. The pH of the buffer is selected so that the purified peptide is retained on the anion exchange medium. Changing the pH of the buffer alters the charge of the peptide, and lowering the pH value shortens the retention time with anion exchangers [0209, 0211]. Thus, a salt concentration and pH are result effective variables that can be optimized by routine experimentation under prior art conditions as anion exchange media are commercial products known to one of ordinary skill in the art [0214-0215] further evidenced by Toyopearl SuperQ-650C and Toyopearl Phenyl-650S. See MPEP 2144.04 (II)A. The salt concentration and pH are also result effective variables applied to HIC as taught by DeFrees et al. [0260-0262]. DeFrees et al. teach the anion exchange conditions are selected to preferentially bind impurities at a salt concentration below the elution salt concentration (reading on non-PEGylated bound on AEC resin), while the purified PEGylated EPO (mono-PEGylated and residual oligo-PEGylated EPO) is found in the flow-through [0211,0295].
With respect to Step C, DeFrees et al. teach the use of a buffer comprising a salt concentration below the concentration at which the peptide to elute bound protein (e.g., unreacted EPO) from AEC column [0211], reading on elution of the unreacted EPO protein bound to AEC at a lower salt concentration. Tegner teaches unreacted protein is then recycled back to the batch reactor where it can PEGylate again resulting in a higher monoPEGylated protein yield (p9, 2.5.2 Combined recirculation process) shown in Fig 4.5 (p20), reading on adding the eluted unreacted EPO protein (in a buffer compatible with PEGylation) directly recycled back to the batch reactor where it can PEGylate again resulting in a higher monoPEGylated protein yield as suggested by Tegner (p9, 2.5.2 Combined recirculation process). Staby et al. is further cited to show linear gradient elution retention of ion-exchange chromatography as a function of pH (p87, col 1, last para) and the use of physical property for development of step gradient programs for elution by decreased pH to avoid salt elution and for planning of flow-through mode operation, demonstrating one of ordinary skill in the art would beneficially lower ionic strength at a suitable pH to elute the bound unreacted EPO at a low salt buffer compatible with PEGylation reaction from AEC as suggested by DeFrees et al. in view of Tegner.
With respect to Step D, DeFrees et al. show that the PEGylated EPO in AEC flow through is further applied to HIC [Fig 1; 0267]. DeFrees et al. teach the desired peptide conjugate (e.g., oligo-PEGylated EPO) can adhere selectively to the separation medium and the retained components are then eluted differentially by varying the composition of the solvent or buffer system, reading on PEGylated EPO purified by HIC via a bind-and-elute mode. DeFrees et al. further teach the desired components are found in the flow through while impurities are retained on the column and thus removed from the mixture [0207], reading on PEGylated EPO purified by HIC via a flow through mode. Muller et al. teach ion-exchange chromatography (IEX) and hydrophobic-interaction chromatography (HIC) are commonly used chromatography for purifying PEGylated proteins (p4696, col 2, para 2; p4698, Table 1) consistent with DeFrees et al. Muller et al. show the use of HIC in a suitable condition to completely separate the mono-PEGylated protein from other PEGylated protein comprising different number of conjugated PEG (e.g., Di- PEGylated protein) into different fraction/peak (p4702, Fig 5), suggesting DeFrees’s purified mono-PEGylated protein composition (e.g., mono-PEGylated EPO) after a combination of AEC and HIC would be with a purity at least about 90% mono-PEGylated protein in the purified composition.
With respect to pH in the wherein clause of limitation (E), JenKem Technology USA is cited to show a commercial service of protein PEGylation using Phosphate buffer (compatible with AEC and HIC) at pH 7.0-7.5 known in the art (p1, Material, last para). DeFrees et al. teach the pH of a buffer is selected so that the purified peptide is retained on the anion exchange medium. Changing the pH of the buffer alters the charge of the peptide, and lowering the pH value shortens the retention time with anion exchangers [0209, 0211]. DeFrees et al. teach the anion exchange flow through is conditioned to generate a HIC loading sample that includes a sufficient salt concentration for binding to the HIC medium and further suggest a pH is about 7.5 [0268]. Thus, a salt concentration and pH are result effective variables that can be optimized by routine experimentation under prior art conditions as anion exchange media are commercial products known to one of ordinary skill in the art [0214-0215]. The salt concentration and pH are also result effective variables applied to HIC as taught by DeFrees et al. [0260-0262]. See MPEP 2144.04 (II)A.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Defrees et al. (ii) Tegner, and (iii) Staby et al. because (a) Defrees et al. teach a process of PEGylation reaction and purification of mono-PEGylated protein via both ion exchange chromatography (IEC) and hydrophobic interaction chromatography (HIC) in a bind-and-elute or flow-through mode, (b) Tegner teaches beneficial use of an ion exchange chromatography (IEC) column after batch reactor of PEGylation process to separate PEGylated protein from unreacted protein (p9, 2.5.1 Batch reactor process) and further teach unreacted protein is then beneficially recycled back to the batch reactor where it can PEGylate again resulting in a higher monoPEGylated protein yield (p9, 2.5.2 Combined recirculation process), and (c) Staby et al. is cited to show linear gradient elution retention of ion-exchange chromatography as a function of pH (p87, col 1, last para) and the use of this physical property for development of step gradient programs for elution by decreased pH to avoid salt elution and for planning of flow-through mode operation (p88, col 2, para 1). The combination would have reasonable expectation of success because all references teach ion exchange chromatography and linear gradient elution retention of ion-exchange chromatography as a function of pH (decreasing pH can reduce salt concentration used for elution a bound protein from the anion exchange matrix).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Defrees et al. in view of Tegner, JenKem Technology USA, and Staby et al. with (ii) Muller et al. because (a) Defrees et al. in view of Tegner, JenKem Technology USA, and Staby et al. teach a process of purifying mono-PEGylated protein by AEC and HIC and (b) Muller et al. teach ion-exchange chromatography (IEX) and hydrophobic-interaction chromatography (HIC) are commonly used chromatography for purifying PEGylated proteins (p4696, col 2, para 2; p4698, Table 1) consistent with DeFrees et al. Muller et al. show the use of HIC in a suitable condition to completely separate the mono-PEGylated protein from Di- PEGylated protein into different fraction/peak (p4702, Fig 5). The combination would have reasonable expectation of success because both DeFrees et al. and Muller et al. teach the use of ion exchange chromatography and HIC to purify mono-PEGylated protein.
With respect to claims 23-24, DeFrees et al. show the purified protein is erythropoietin (Fig 1).
With respect to claim 25, DeFrees et al. show the ICE step is an anion exchange chromatography (AEC) step (Fig 1).
With respect to claim 26, DeFrees et al. suggest the anion exchanger is a commercial strong anion exchanger resin of Toyopearl Super Q 650 [0217]. The instant specification disclosed a commercial strong anion exchanger resin of Toyopearl Super Q 650 having low binding capacity for PEGylated EPO less than 0.5 g/L (p20, para 1). Thus, DeFrees’s Toyopearl Super Q 650 anion exchanger resign reads on the claim limitation.
With respect to claim 27, Muller et al. suggest the use of HIC to completely separate the mono-PEGylated protein from Di- and/or oligo- PEGylated proteins bound on HIC media about 100% mono-PEGylated protein, (p4702, Fig 5).
With respect to claim 28, Tegner shows the molar ration of PEG to a protein is a result effective variable can be optimized and in particular, the molar ratio of PEG to protein at 1:1 for PEGylation has the highest monoPEG to multiPEG ratio in a PEGylated reaction (p20, Fig 4.6). Since multi-PEGylated EPO proteins are undesired, one of ordinary skill in the art would use a molar ratio of PEG to protein at 1:1 for PEGylation reaction.
With respect to claim 29, DeFrees et al. suggest the salt concentration up to about 50 mM [0210], overlapping with less than or equal to about 45 mM salt. DeFrees et al. teach the pH of PEGylation is 7.0 under low salt concentration comprising 20 mM NaCl [0037], further reading on less than about 45 mM salt.
With respect to claims 30 and 32, Tegner teaches the unreacted protein is then recycled back to the batch reactor where it can PEGylate again resulting in a higher monoPEGylated protein yield (p9, 2.5.2 Combined recirculation process). Tegner show recycle efficiency of protein PEGylation dropping significantly after 5-6 cycles (p20, Fig 4.5) Thus, it would be obvious to perform (i) AEC purification of PEGylaed protein in a flow-through mode and (ii) elute the unreacted protein from AEC at a low salt concentration compatible with PEGylation reaction with 3-5 times/cycles. Furthermore, it would be further obvious to add more non-PEGylated protein to the batch reactor comprising the recycled non-PEGylated protein to maintain constant PEGylation reaction for each repeating cycle.
With respect to claim 33, it would be obvious to collect each flow-through fraction of AEC and polled the collected fractions together until sufficient volume for downstream HIC purification.
With respect to claim 34, DeFrees et al. teach the most common ion exchange chemistries comprising quaternary ammonium residues (Q) for strong anion exchange [0208]. DeFrees et al. suggest anion exchange resin as super Q 650 [0217]. Toyopearl SuperQ-650C is cited as evidence to show super Q 650 resin is composed of a base material of hydroxylated methacrylic polymer beads that have been functionalized with quaternary amine (Q) strong anion exchange groups (p1, para 1).
With respect to claim 35, DeFrees et al. teach the desired peptide conjugate (e.g., oligo-PEGylated EPO) can adhere selectively to the separation medium and the retained components are then eluted differentially by varying the composition of the solvent or buffer system, reading on PEGylated EPO purified by HIC via a bind-and-elute mode [0207].
With respect to claim 36, DeFrees et al. teach the HIC medium is Phenyl 650S [0267]. Toyopearl Phenyl-650S is cited as evidence to show the resin is composed of a base material of hydroxylated methacrylic polymer beads that have been functionalized with a Phenyl ligand group (p1, para 1).
With respect to claim 38, DeFrees et al. teach the molecular weight of PEG conjugated to the EPO protein more preferably from about 10 kDa to about 40 kDa [0134].
With respect to claim 39, DeFrees et al. teach a pharmaceutical formulation including a composition (PEGylated EPO) made by a method of the invention and a pharmaceutically acceptable carrier [0218].
With respect to claim 40, DeFrees et al. further teach the desired components are found in the flow through while impurities are retained on the column and thus removed from the mixture [0207], reading on PEGylated EPO purified by HIC via a flow through mode.
Applicant’s Arguments
The amendment to claim 22 overcomes the rejection of record (Remarks, p6, 2nd last para)
(i) Toyopearl SuperQ-650C - is a strong anion exchange column with a quaternary ammonium group (Q), but Staby et al. is directed to a study on "weak anion exchangers" which, as set out on page 19 of the PCT publication "display pH-dependent function" (Remarks, p7, para 2).
While Tegner discloses re-cycling of non-PEGylated protein to increase yield of PEGylated protein, PEGylation and separation are performed in the same column with the aim of preventing mono-PEGylated protein from PEGylating further different from the claimed process (Remarks, p7, para 3).
Lai’s HIC step produces mixture of mono-PEGylated EPO and unreacted PEG
Lai et al do not teach that the pH of each of the PEGylation, HIC and IEC steps is the same. Furthermore, the claimed process is an automatic process by directly adding unreacted EPO directly from ICE elute to the next cycle of PEGylation (Remarks, p7, last para to p10 whole page).
Response to Arguments
Applicant's arguments filed 2/18/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s argument (A) is not persuasive because DeFrees et al. teach a salt concentration and pH are result effective variables that can be optimized by routine experimentation under prior art conditions as anion exchange media are commercial products known to one of ordinary skill in the art [0214-0215] further evidenced by Toyopearl SuperQ-650C and Toyopearl Phenyl-650S. See MPEP 2144.04 (II)A. The salt concentration and pH are also result effective variables applied to HIC using a commercial product as taught by DeFrees et al. [0260-0262]. See the rejection above in details. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144(I). In particular, (a) Toyopearl SuperQ-650C and Toyopearl are commercial product and (b) DeFrees et al. teach a salt concentration and pH are result effective variables that can be optimized by routine experimentation.
Applicant’s Argument B(i) is not persuasive because either strong or weak anion exchange has to follow the physical rule by binding to a negatively charged protein. DeFrees et al. teach the pH of the buffer is selected so that the purified peptide is retained on the anion exchange medium. Changing the pH of the buffer alters the charge of the peptide, and lowering the pH value shortens the retention time with anion exchangers [0209, 0211]. DeFrees et al. teach anion exchange media are known in the art [0214]; thus, one of ordinary skill in the art would have known how to optimize pH for protein binding to either strong or weak anion exchange media.
Applicant’s Argument B(ii) is not persuasive because (a) It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). See MPEP 2144(IV), (b) The expectation of some advantage is the strongest rationale for combining references. See MPEP 2144(II) and (c) The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144(I). Thus, Tegner is a relevant reference providing benefit of recycling the unreacted protein for the next cycle of PEGylation reaction.
Applicant’s Argument B(iii) is not persuasive because Lai is not cited for this rejection. Furthermore, the word “comprising” is an open-ended word” in the base claim 22, which does not exclude any additional step added to the claimed process. Finally, applicant failed to provide any data to show optimization of pH or salt concentration under conditions taught by the combined prior art references CANNOT achieve the claimed invention. See MPEP 2145 “Argument does not replace evidence where evidence is necessary”.
Modified Rejection
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.
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Claims 22-30, 32-36 and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of U.S. Patent No. 11,518,781 B2 (the ‘781 patent) in view of Defrees et al. in view of Tegner, JenKem Technology USA, Staby et al., Muller et al. evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S.
Claim 1 of the ‘781 patent disclosed a method of producing a composition comprising at least about 90% mono-PEGylated protein using HIC as follows.
Claim 1 of the ‘781 patent does not teach purification of a mono-PEGylated protein further comprising ion exchange chromatography (IEC) for PEGylated protein purification.
Claim 3 of the ‘781 patent disclosed purified protein is PEGylated erythropoietin.
Claims 1 and 3 of the ‘781 patent do not teach a combination of ion exchange chromatography and HIC for purification of the mono-PEGylated protein.
The relevancy of Defrees et al. in view of Tegner, Staby et al., Muller et al. evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S. as applied to claims 22-30, 32-36 and 38-40 described above not repeated here.
Because Defrees et al. in view of Tegner, Staby et al., Muller et al. evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S. teach beneficial combination of AEC and HIC for purification of monoPEGylated erythropoietin, one of ordinary skill in the art would have found it obvious to combine claims 1 and 3 of the ‘781 patent in view of Defrees et al., Tegner, Staby et al., Muller et al. and evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S.
Thus, claims 1 and 3 of the ‘781 patent in view of Defrees et al., Tegner, Staby et al., Muller et al. and evidenced by (i) Toyopearl SuperQ-650C and (ii) Toyopearl Phenyl-650S are obvious to the instant claims 22-30, 32-36 and 38-40.
Response to Arguments
Applicant's arguments filed 2/18/2026 have been fully considered but they are not persuasive. See response to arguments above.
Claims 22-30, 32-36 and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8-12, 14, 17-18, 23, and 26-27 of U.S. Patent No. 12,208,142 B2 (the ‘142 patent).
Claim 1 of the ‘142 patent disclosed a process for producing a PEGylated erythropoietin comprising the steps,
Performing PEGylation reaction at a pH of about 7.0 to 9.0, and the PEG/protein molar ratio is about 0.6-1.0 (See claims 10-12 of the ‘142 patent) to produce the first mixture comprising less than 25% oligo PEGylated protein (See claims 1 and 8(i) of the ‘142 patent);
subjecting the first mixture to an ion exchange chromatography (IEC) step to provide the IEC flow-through solution comprises at least 90% PEGylated protein (See claims 1, 8 (ii), and 9 of the ‘142 patent);
eluting non-PEGylated protein from the IEC material uses an elution buffer comprising less than or equal to about 45 mM salt (See claims 1, 8 (ii) and 14 of the ‘142 patent);
subjecting the second mixture to a hydrophobic interaction chromatography (HIC) step to provide a mono-PEGylated protein comprises at least about 90% mono-PEGylated protein (See claims 1, 5, 8(iii) and 9).
Furthermore, claim 11 of the ‘142 patent disclosed PEGylation at pH 7.0 to 9.0. Claim 23 of the ‘142 patent disclosed AEC step is performed at pH of about 7.0 to 9.0. Claim 27 of the ‘142 patent disclosed HIC step is performed at pH of about 7.0 to 9.0.
Thus, claims 1, 8-12, 14, 23, and 27 of the ‘142 patent are obvious to the instant claims 22, 25, 27-30, 32-33, 35, and 40.
Claims 2-3 of the ‘142 patent disclosed the PEGylated protein is erythropoietin, satisfying the instant claims 23-24 respectively.
Claim 6 of the ‘142 patent disclosed the IEC material has a binding capacity for the PEGylated protein of less than about 1.5 g/L, satisfying the instant claim 26.
Claim 23 (iii) of the ‘142 patent disclosed the AEC step is performed at a conductivity of about 1.0 to 3.0 mS/cm, satisfying the instant claim 34.
Claim 26 (iii) of the ‘142 patent disclosed the HIC step is performed at a conductivity of about 30-40 mS/cm, satisfying the instant claim 36.
Claim 17 of the ‘142 patent disclosed the mono-PEGylated protein comprises a PEG residue having a molecular weight of at least about 20 kDa, satisfying the instant claim 38.
Claim 18 of the ‘142 patent disclosed formulating the protein composition with a pharmaceutically acceptable carrier to provide a pharmaceutical composition, satisfying the instant claim 39.
Response to Arguments
Applicant's arguments filed 2/18/2026 have been fully considered but they are not persuasive because this is a single reference for ODP rejection.
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Claims 22-30, 32-35, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/006,696 (the ‘696 application, 5/19/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims merely combine and/or reorganize order the limitations from the dependent claims of the copending ‘696 application described as follows.
Claim 1 of the ‘696 application disclosed A process for producing a PEGylated protein comprising the steps as follows, satisfying step A.
Claim 12 of the ‘696 application disclosed the PEGylated protein mixture comprising less than 25% oligo PEGylated protein before IEC purification satisfying step B(a). Claim 12 of the ‘696 application further disclosed the IEC flow-through solution comprising at least 90% PEGylated protein satisfying step B(b).
Claim 9 of the ‘696 application disclosed IEC eluate is added directly to the subsequent PEGylation reaction. Claims 5-6 of the ‘696 application disclosed IEC eluate of non-PEGylated protein is reused for 3-5 cycles of PEGylation, satisfying step C.
Claims 15-16 and 18 of the ‘696 application disclosed PEGylated protein obtained from step C further purified by a hydrophobic interaction chromatography (HIC) step in a flow through mode to provide a composition comprising at least 95% mono-PEGylated protein, satisfying step D.
Furthermore, claim 14 of the ‘696 application disclosed PEGylation at pH 7.0 to 9.0. Claim 13 of the ‘696 application disclosed AEC step is performed at pH of about 7.0 to 9.0. Claim 19 of the ‘696 application disclosed ICE and HIC steps performed at the same pH.
Thus, claims 1, 5-6, 9, 12-16, and 18-19 of the ‘696 application are obvious to the instant claims 22, 27, 30, and 40.
Claims 2-4 of the ‘696 application disclosed the limitations satisfying the instant claims 23-25 respectively.
Claim 10 of the ‘696 application disclosed non-PEGylated protein is recovered and used in a subsequent PEGylation reaction, and wherein fresh non-PEGylated protein is also added to the subsequent PEGylation reaction in order to maintain substantially constant PEGylation reaction conditions, satisfying the instant claim 32.
Claim 11 of the ‘696 application disclosed IEC material has a binding capacity for the PEGylated protein of less than about 1. 5 g/L, satisfying the instant claim 26.
Claim 14 of the ‘696 application disclosed PEGylation reaction is performed at a pH of about 7.0 to 9.0, and wherein the PEG/protein molar ratio is about 0.6 - 1.0, satisfying the instant claim 28.
Claim 8 of the ‘696 application disclosed IEC material uses an elution buffer comprising
less than or equal to about 45 mM salt, satisfying the instant claim 29.
Claim 7 of the ‘696 application disclosed pooling the flow-through solution collected from each IEC step to provide a pooled PEGylated protein mixture, satisfying the instant claim 33.
Claim 13 of the ‘696 application disclosed the AEC step is performed at a conductivity of about 1.0 to 3.0 mS/cm, satisfying the instant claim 34.
Claim 17 of the ‘696 application disclosed PEGylated protein mixture applied to a hydrophobic interaction chromatography (HIC) step in bind and elute mode to provide a HIC eluate in which the fraction of mono-PEGylated protein, satisfying the instant claim 35.
Claim 20 of the ‘696 application disclosed mono-PEGylated protein comprising a PEG residue having a molecular weight of at least about 20kDa, satisfying the instant claim 38.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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.
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/J.L/Examiner, Art Unit 1658
15-May-2026
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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