DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Application, Amendments and/or Claims
The amendment of 06 August 2025 has been entered in full. Claims 1, 3, 7-14, and 19 are amended. Claims 5 and 6 are cancelled. Claims 20 and 21 are added.
Claims 1-4 and 7-21 are under consideration in the instant application.
Drawings
The replacement drawings were received on 06 August 2025. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objection to the drawings as set forth at pages 2-3 of the previous Office Action of 06 May 2025 is withdrawn in view of the replacement drawings submitted on 06 August 2025.
2. The Sequence Listing Requirement deficiency set forth at pages 3-5 of the previous Office Action of 06 May 2025 is withdrawn in view of Applicant’s amendment to the instant specification (06 August 2025).
3. The objections to claims 1, 5, 6, 11, and 13 as set forth at pages 5-6 of the previous Office Action of 06 May 2025 are withdrawn in view of the amended and cancelled claims (06 August 202%)5
4. The rejections of claims 5-7, 12, 13, 18, and 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 6-8 of the previous Office Action of 06 May 2025 are withdrawn in view of the amended and cancelled claims (06 August 2025).
5. The rejection of claims 1-7, 9, 10, 13-16, and 18 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Humphreys et al. (WO 2004/035792), Soares et al. (Biotechnol Appl Biochem 32: 127-135, 2000), Arunakumari et al. (WO 2007/108955), Davies et al. (WO 2009/135656), Wan et al. (US 2007/0292442), and Kelley et al. (US 2007/00607841) as set forth at pages 13-15 of the previous Office Action of 06 May 2025 is withdrawn in view of the cancellation of claims 5 and 6 (06 August 2025)..
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
6. Claims 1-4, 7, 9, 10, 13-16, and 18 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Humphreys et al. (WO 2004/035792; cited on the IDS of 23 May 2022), Soares et al. (Biotechnol Appl Biochem 32: 127-135, 2000), Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022), Davies et al. (WO 2009/135656; cited on the IDS of 23 May 2022), and Wan et al. (US 2007/0292442). The basis for this rejection is set forth at pages 9-13 of the previous Office Action of 06 May 2025.
Humphreys et al. teach purification of a recombinant antibody, including fragments such as Fab, produced in E. coli host cells from the periplasmic extract using two chromatography steps (and performed on chromatography columns), as required by instant claims 1-3 and 15 (page 6, lines 19-22; page 21, lines 18-32 through page 22, lines 1-11). Specifically, Humphreys et al. disclose that a mixture containing Fab fragments is subjected to cation exchange chromatography on a SP sepharose column (from Pharmacia) and the resultant eluate subsequently subjected to anion exchange chromatography on a Poros HQ column, as required by instant claims 1-4 and 10 (page 21, last paragraph through page 23). It is noted that the SP Sepharose column of Humphreys et al. is a sulphopropyl (SP) chromatography column, as evidenced by Soares et al. (see page 30, column 1, 3rd full paragraph)).
Humphreys et al. teach that after centrifugation to remove cell debris, the supernatant is adjusted to a pH of typically pH 4.5, 5.0, or 6.0 (prior to the first chromatography step, the pH is of between 4.0 and 5.0), meeting the limitations of instant claim 7 (page 21, lines 19-25).
Humphreys et al. indicate that the conductivity of the periplasmic extract, at a conductivity of <3.5 mScm-1, is loaded on the cation exchange chromatography, meeting the limitations of instant claim 9 (page 21, lines 23-25).
Similar to Humphreys et al., Arunakumari et al. teach that it is desirable to develop a purification scheme applicable to various types of proteins, scaleable, controllable, and that employs cheaper, reusable resin (page 3, 3rd full paragraph). Arunakumari et al. indicate that the protein of interest can be produced in the periplasmic space before purification (page 26, last paragraph). Arunakumari et al. disclose that according to their invention, proteins (such as antibody fragments (Fab, Fab’, scFv)) are highly purified using cation exchange chromatography and anion exchange chromatography, meeting the limitations of instant claims 1, 2, and 15 (page 4, 2nd full paragraph; page 5, 3rd and 4th full paragraphs; page 25, 4th full paragraph; page 6, 1st full paragraph). Arunakumari et al. indicate that the inventive process can purify the protein of interest (from cells such as E. coli) to achieve a composition which contains less than 100 ppm host cell protein, meeting the limitations of instant claim 18 (page 12, lines 1-5; bottom of page 25 through the top of page 26). Arunakumari et al. state that commercially available cation resins include those with a sulphopropyl based group or carboxymethyl based group, meeting the limitations of instant claim 10 (page 15, 2nd full paragraph). Additionally, commercially available anion exchange resins include those comprising quaternary ammonium (Q), DEAE, and TMAE, meeting the limitations of instant claim 14 (page 16, 2nd and 3rd full paragraphs through the top of page 17).
Arunakumari et al. indicate that the chromatography may be carried out on columns, meeting the limitations of instant claim 3 (page 28, last paragraph). Arunakumari et al. disclose that prior to purification, columns are typically sanitized and then charged using a lyotropic salt, e.g., 1 M NaCl, and equilibrated using an equilibration buffer, meeting the limitations of instant claim 1(a)(i) (page 29, lines 3-6; page 33, Table 1). Arunakumari et al. state that the charge step neutralizes the resin by displacing the sanitizing solution and NaCl maintains the resin ligand in contact with positively charged ions (page 29, lines 9-11). Arunakumari et al. continue to teach that after the column is charged, an equilibrium buffer is used to equilibrate the column in order to prepare the pH and conductivity of the resin to bind the protein of interest, meeting the limitations of instant claim 1(a)(i) (page 29, lines 11-13). Arunakumari et al. disclose that a load mixture is prepared (that contains the protein of interest) and loaded onto the column, meeting the limitations of instant claim 1(a)(ii) (page 29, 1st full paragraph). Arunakumari et al. indicate that once the mixture has been loaded onto the column and the protein of interest is bound to the resin, wash steps using a wash buffer are performed, meeting the limitations of instant claim 1(a)(iii) (page 29, last paragraph). Arunakumari et al. disclose that an appropriate elution buffer is used to elute the protein of interest, meeting the limitations of instant claim 1(a)(iv) (page 30, 1st full paragraph). Arunakumari et al. teach that the wash, equilibration, and loading buffers can be the same, meeting the limitations of instant claim 1(a)(iii) (page 22, lines 1-15). Arunakumari et al. disclose that the conductivity and pH can be reduced, maintained, or increased in wash buffers and subsequent wash steps (page 22, lines 1-15). In particular, Arunakumari et al. teach an example wherein the pH of the wash buffer (6.2) is identical to the pH of a mixture containing an antibody prior to the first chromatography step, meeting the limitations of instant claim 1(a)(iii) (page 33, Table 1). Arunakumari et al. also teach an exemplary binding capacity of 40 mg/ml resin for cation exchange chromatography antibody capture (page 33, Table 1).
However, Humphreys et al. and Arunakumari et al. do not teach that a mixture containing an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation chromatography. Humphreys et al. and Arunakumari et al. do not teach that between 5 and 100 g antibody fragment per liter resin is loaded on the first cation exchange chromatography step or that the antibody fragment binds TNFα.
Davies et al. teach purification of monoclonal antibodies according to a process suitable for large scale manufacture by loading a chimeric monoclonal antibody at a titer of 2.95 g/L (concentration of at least 1.5 g/L) using cation exchange chromatography conducted displacement mode followed by anion exchange chromatography (abstract; page 16, lines 9-10; Example 2). It is noted that Davies et al. teach loading a cell culture supernatant (CCS) that expresses an antibody onto a CaptoS resin (cation exchange) (page 16, lines 3-25). Davies et al. disclose washing the column with equilibration buffer to remove unbound molecules from the resin and then eluting bound product from the column (page 16, lines 3-4, 24-25). The washing buffer is the same equilibration buffer, thus the pH remains unchanged.
Wan et al. teach a method for producing a host cell protein (HCP)-reduced antibody preparation from a mixture comprising an antibody and at least one HCP (page 20, [0220]). Wan et al. disclose that the mixture may be loaded onto an ion exchange column, such as a cation exchange column, at a load of about < 35 g antibody/L per cycle at pH 7 or at a load of about < 70 g antibody/L per cycle at pH 5 (page 21, [0229, 0238]). Wan et al. state that the column is washed and the antibody eluted (page 21, [0229]). The first eluate is virally inactivated and then loaded onto an anion exchange chromatography column (e.g., Q Sepharose) (page 21, [0230-0231, 0238]). Wan et al. teach that 35-70 g antibody per L of resin can be used (page 22, [0241]; Example 2). Wan et al. also disclose that an antibody produced by the inventive process is, for example, TNFα antibody, adalimumab, or its antigen-binding fragment (such as Fab or scFv), meeting the limitations of instant claim 16 ((page 6, [0080, 0087], page 16, [0192]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of purifying a recombinant antibody (such as antibody fragments (Fab, Fab’, scFv)) comprising a cation exchange chromatography step and an anion chromatography step as taught by Humphreys et al. and Arunakumari et al. by utilizing a mixture containing an antibody fragment (such as a TNFα antibody fragment) at a concentration of at least 1.5 g/L in the cation exchange chromatography step or between 5 and 100 g antibody fragment per liter resin in the first cation exchange chromatography step, as taught by Davies et al. and Wan et al. The person of ordinary skill in the art would have been motivated to make those modifications for large scale production of purified antibody preparations that comprise reduced amounts of host cell proteins (see Wan et al., page 1, [0002-0004]; Humphreys et al., page 1 through the top of page 2). A skilled artisan has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. v. Teleflex Inc. 550 U.S. 398, 82 USPQ2d 1385 (2007)). The person of ordinary skill in the art also reasonably would have expected success because optimization of loading/starting concentrations in chromatography is routine in the art. See In re Aller 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), “[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”. See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). See also In re Williams, 36 F.2d 436, 438 (CCPA 1929). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
7. Claims 8, 11, and 12 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Humphreys et al. (WO 2004/035792; cited on the IDS of 23 May 2022), Soares et al. (Biotechnol Appl Biochem 32: 127-135, 2000), Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022), Davies et al. (WO 2009/135656; cited on the IDS of 23 May 2022), and Wan et al. (US 2007/0292442) as applied to claims 1-4, 7, 9, 10, 13-16, and 18 above, and further in view of O’Donnell et al. (PREP 2007, Baltimore, Maryland, pages 1-13; cited on the IDS of 23 May 2022). The basis for this rejection is set forth at pages 15-17 of the previous Office Action of 06 May 2025.
8. Claims 17 and 19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Humphreys et al. (WO 2004/035792; cited on the IDS of 23 May 2022), Soares et al. (Biotechnol Appl Biochem 32: 127-135, 2000), Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022), Davies et al. (WO 2009/135656; cited on the IDS of 23 May 2022), and Wan et al. (US 2007/0292442) as applied to claims 1-4, 7, 9, 10, 13-16, and 18 above, and further in view of Fahrner et al. (WO 03/102132; cited on the IDS of 23 May 2022). The basis for this rejection is set forth at pages 17-29 of the previous Office Action of 06 May 2025.
(i) At page 9 of the Response of 06 August 2025, Applicant argues that the cited combination of references fails to establish a prima facie case of obviousness for the claimed invention. Applicant submits that none of the cited references teach or suggest the claimed steps of: i) equilibration of a cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer; ii) loading a mixture comprising an antibody fragment onto the cationic chromatography resin; and iii) washing the cationic chromatography resin with a wash buffer and wherein the pH of the wash buffer is identical to the pH of the mixture containing an antibody fragment prior to the first chromatography step.
Applicant’s arguments have been fully considered but are not found to be persuasive. Specifically, as discussed above, the Arunakumari et al. reference, which was utilized in combination with Humphreys et al., Soares et al., Davies et al., and Wan et al. (and further view of O’Donnell et al. and Fahrner et al.) in the rejections under pre-AIA 35 U.S.C. 103(a) made of record in the previous Office Action of 06 May 2025, teaches the claimed steps pointed out by Applicant.
Specifically, Arunakumari et al. disclose that prior to purification, columns are typically sanitized and then charged using a lyotropic salt, e.g., 1 M NaCl, and equilibrated using an equilibration buffer, meeting the limitations of instant claim 1(a)(i) (page 29, lines 3-6; page 33, Table 1). Arunakumari et al. state that the charge step neutralizes the resin by displacing the sanitizing solution and NaCl maintains the resin ligand in contact with positively charged ions (page 29, lines 9-11). Arunakumari et al. continue to teach that after the column is charged, an equilibrium buffer is used to equilibrate the column in order to prepare the pH and conductivity of the resin to bind the protein of interest, meeting the limitations of instant claim 1(a)(i) (page 29, lines 11-13). Arunakumari et al. disclose that a load mixture is prepared (that contains the protein of interest) and loaded onto the column, meeting the limitations of instant claim 1(a)(ii) (page 29, 1st full paragraph). Arunakumari et al. indicate that once the mixture has been loaded onto the column and the protein of interest is bound to the resin, wash steps using a wash buffer are performed, meeting the limitations of instant claim 1(a)(iii) (page 29, last paragraph). Arunakumari et al. disclose that an appropriate elution buffer is used to elute the protein of interest, meeting the limitations of instant claim 1(a)(iv) (page 30, 1st full paragraph). Arunakumari et al. teach that the wash, equilibration, and loading buffers can be the same, meeting the limitations of instant claim 1(a)(iii) (page 22, lines 1-15). Arunakumari et al. disclose that the conductivity and pH can be reduced, maintained, or increased in wash buffers and subsequent wash steps (page 22, lines 1-15). In particular, Arunakumari et al. teach an example wherein the pH of the wash buffer (6.2) is identical to the pH of a mixture containing an antibody prior to the first chromatography step, meeting the limitations of instant claim 1(a)(iii) (page 33, Table 1).
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.
9. Claims 1-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,309,280 (cited on the IDS of 23 May 2022) in view of Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022). The basis for this rejection is set forth at pages 20-21 of the previous Office Action of 06 May 2025 and has been reformulated in view of amended claim 1.
Both sets of claims recite a process for the purification of an antibody fragment from a periplasmic cell extract comprising a first chromatography step wherein a mixture comprising an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation exchange chromatography to produce a first eluate; and a second chromatography step wherein the first eluate is subjected to anion exchange chromatography.
The limitations of claims 2-21 of the instant application are encompassed by claims 2-7 and 9-19 of the ‘280 patent.
Instant independent claim 19 is similar to claim 1, except that it adds a first ultrafiltration step to the first eluate and a second ultrafiltration after the second chromatography step. Meanwhile, claim 20 of the ‘280 patent recites the method of claim 1, said process further comprising ultrafiltration of the first eluate and ultrafiltration of the second chromatography flow through containing the antibody fragment.
The claims of the ‘280 patent do not recite an equilibration step prior to loading a mixture comprising the antibody, wherein the equilibration step comprises equilibration of a cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer.
Arunakumari et al. disclose that prior to purification, columns are typically sanitized and then charged using a lyotropic salt, e.g., 1 M NaCl, and equilibrated using an equilibration buffer (page 29, lines 3-6; page 33, Table 1). Arunakumari et al. continue to teach that after the column is charged, an equilibrium buffer is used to equilibrate the column in order to prepare the pH and conductivity of the resin to bind the protein of interest (page 29, lines 11-13). Arunakumari et al. disclose that a load mixture is prepared (that contains the protein of interest) and loaded onto the column (page 29, 1st full paragraph). Arunakumari et al. indicate that once the mixture has been loaded onto the column and the protein of interest is bound to the resin, wash steps using a wash buffer are performed (page 29, last paragraph). Arunakumari et al. disclose that an appropriate elution buffer is used to elute the protein of interest (page 30, 1st full paragraph). Arunakumari et al. teach that the wash, equilibration, and loading buffers can be the same (page 22, lines 1-15).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the process for the purification of an antibody fragment from a periplasmic cell extract of the ‘280 patent claims by equilibrating the cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer prior to loading the mixture comprising the antibody fragment, as taught by Arunakumari et al. The person of ordinary skill in the art would have been motivated to make those modifications to (i) neutralize the cationic chromatography resin and maintain the resin ligand in contact with positively charged ions; and (ii) equilibrate the column in order to prepare the pH and conductivity of the resin to bind the antibody fragment (Arunakumari et al., page 29, lines 9-13). The person of ordinary skill in the art reasonably would have expected success because similar methods were already being performed at the time the invention was made. The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (KSR International Co. v. Teleflex Inc. 550 U.S. 398, 82 USPQ2d 1385 (2007)).
10. Claims 1-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,189,897 (cited on the IDS of 23 May 2022) in view of Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022). The basis for this rejection is set forth at pages 21-22 of the previous Office Action of 06 May 2025 and has been reformulated in view of amended claim 1.
Both sets of claims recite a process for the purification of an antibody fragment from a periplasmic cell extract comprising a first chromatography step wherein a mixture comprising an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation exchange chromatography to produce a first eluate; and a second chromatography step wherein the first eluate is subjected to anion exchange chromatography.
The limitations of claims 2-18, 20, and 21 of the instant application are encompassed by claims 2-7 and 9-19 of the ‘897 patent.
Claim 19 of the instant application and claim 20 of the ‘897 patent recite a process for the purification of an antibody fragment from a periplasmic cell extract consisting essentially of (a) a first chromatography step wherein a mixture comprising an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation exchange chromatography to produce a first eluate; (b) a first ultrafiltration applied to the first eluate; (c) a second chromatography step wherein the purified first eluate is subjected to anion exchange chromatography; and (d) a second ultrafiltration applied to the flow through.
The claims of the ‘897 patent do not recite an equilibration step prior to loading a mixture comprising the antibody, wherein the equilibration step comprises equilibration of a cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer.
Arunakumari et al. disclose that prior to purification, columns are typically sanitized and then charged using a lyotropic salt, e.g., 1 M NaCl, and equilibrated using an equilibration buffer (page 29, lines 3-6; page 33, Table 1). Arunakumari et al. continue to teach that after the column is charged, an equilibrium buffer is used to equilibrate the column in order to prepare the pH and conductivity of the resin to bind the protein of interest (page 29, lines 11-13). Arunakumari et al. disclose that a load mixture is prepared (that contains the protein of interest) and loaded onto the column (page 29, 1st full paragraph). Arunakumari et al. indicate that once the mixture has been loaded onto the column and the protein of interest is bound to the resin, wash steps using a wash buffer are performed (page 29, last paragraph). Arunakumari et al. disclose that an appropriate elution buffer is used to elute the protein of interest (page 30, 1st full paragraph). Arunakumari et al. teach that the wash, equilibration, and loading buffers can be the same (page 22, lines 1-15).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the process for the purification of an antibody fragment from a periplasmic cell extract of the ‘897 patent claims by equilibrating the cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer prior to loading the mixture comprising the antibody fragment, as taught by Arunakumari et al. The person of ordinary skill in the art would have been motivated to make those modifications to (i) neutralize the cationic chromatography resin and maintain the resin ligand in contact with positively charged ions; and (ii) equilibrate the column in order to prepare the pH and conductivity of the resin to bind the antibody fragment (Arunakumari et al., page 29, lines 9-13). The person of ordinary skill in the art reasonably would have expected success because similar methods were already being performed at the time the invention was made. The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (KSR International Co. v. Teleflex Inc. 550 U.S. 398, 82 USPQ2d 1385 (2007)).
11. Claims 1-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,339,214 (cited on the IDS of 23 May 2022) in view of Wan et al. (US 2007/0292442) and Arunakumari et al. (WO 2007/108955; cited on the IDS of 23 May 2022). The basis for this rejection is set forth at pages 22-24 of the previous Office Action of 06 May 2025 and has been reformulated in view of amended claim 1.
Both sets of claims recite a process for the purification of an antibody fragment from a periplasmic cell extract comprising a first chromatography step wherein a mixture comprising an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation exchange chromatography to produce a first eluate; and a second chromatography step wherein the first eluate is subjected to anion exchange chromatography.
The limitations of claims 2-12, 14-18, 20, and 21 of the instant application are encompassed by claims 2-17 of the ‘214 patent.
Claim 19 of the instant application and claim 17 of the ‘214 patent recite a process for the purification of an antibody fragment from a periplasmic cell extract consisting essentially of (a) a first chromatography step wherein a mixture comprising an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation exchange chromatography to produce a first eluate; (b) a first ultrafiltration applied to the first eluate; (c) a second chromatography step wherein the purified first eluate is subjected to anion exchange chromatography; and (d) a second ultrafiltration applied to the flow through.
However, the claims of the ‘214 patent do not recite that between 5 and 100 g antibody fragment per liter resin is loaded in the cation exchange chromatography of the first chromatography step.
Wan et al. teach a method for producing a host cell protein (HCP)-reduced antibody preparation from a mixture comprising an antibody and at least one HCP (page 20, [0220]). Wan et al. disclose that the mixture may be loaded onto an ion exchange column, such as a cation exchange column, at a load of about < 35 g antibody/L per cycle at pH 7 or at a load of about < 70 g antibody/L per cycle at pH 5 (page 21, [0229, 0238]). Wan et al. state that the column is washed and the antibody eluted (page 21, [0229]). The first eluate is virally inactivated and then loaded onto an anion exchange chromatography column (e.g., Q Sepharose) (page 21, [0230-0231, 0238]). Wan et al. teach that 35-70 g antibody per L of resin can be used (page 22, [0241]; Example 2). Wan et al. also disclose that an antibody produced by the inventive process is, for example, TNFα antibody, adalimumab, or its antigen-binding fragment (such as Fab or scFv), meeting the limitations of instant claim 16 ((page 6, [0080, 0087], page 16, [0192]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of purifying a recombinant antibody fragment comprising a cation exchange chromatography step and an anion chromatography step wherein the antibody fragment at a concentration of at least 1.5 g/L is loaded onto a cation exchange chromatography resin, as recited by the ‘214 claims by utilizing an antibody fragment concentration of between 5 and 100 g antibody fragment per liter resin in the first cation exchange chromatography step, as taught by Wan et al. The person of ordinary skill in the art would have been motivated to make that modification for large scale production of purified antibody fragment preparations that comprise reduced amounts of host cell proteins (see Wan et al., page 1, [0002-0004]). A skilled artisan has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. v. Teleflex Inc. 550 U.S. 398, 82 USPQ2d 1385 (2007)). The person of ordinary skill in the art also reasonably would have expected success because optimization of loading/starting concentrations in chromatography is routine in the art. See In re Aller 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), “[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”. See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). See also In re Williams, 36 F.2d 436, 438 (CCPA 1929).
The claims of the ‘214 patent also do not recite an equilibration step prior to loading a mixture comprising the antibody, wherein the equilibration step comprises equilibration of a cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer.
Arunakumari et al. disclose that prior to purification, columns are typically sanitized and then charged using a lyotropic salt, e.g., 1 M NaCl, and equilibrated using an equilibration buffer (page 29, lines 3-6; page 33, Table 1). Arunakumari et al. continue to teach that after the column is charged, an equilibrium buffer is used to equilibrate the column in order to prepare the pH and conductivity of the resin to bind the protein of interest (page 29, lines 11-13). Arunakumari et al. disclose that a load mixture is prepared (that contains the protein of interest) and loaded onto the column (page 29, 1st full paragraph). Arunakumari et al. indicate that once the mixture has been loaded onto the column and the protein of interest is bound to the resin, wash steps using a wash buffer are performed (page 29, last paragraph). Arunakumari et al. disclose that an appropriate elution buffer is used to elute the protein of interest (page 30, 1st full paragraph). Arunakumari et al. teach that the wash, equilibration, and loading buffers can be the same (page 22, lines 1-15).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the process for the purification of an antibody fragment from a periplasmic cell extract of the ‘214 patent claims by equilibrating the cationic chromatography resin with a first anionic equilibration buffer comprising 1 M NaCl followed by equilibration of said cationic chromatography resin with a second equilibration buffer prior to loading the mixture comprising the antibody fragment, as taught by Arunakumari et al. The person of ordinary skill in the art would have been motivated to make those modifications to (i) neutralize the cationic chromatography resin and maintain the resin ligand in contact with positively charged ions; and (ii) equilibrate the column in order to prepare the pH and conductivity of the resin to bind the antibody fragment (Arunakumari et al., page 29, lines 9-13). The person of ordinary skill in the art reasonably would have expected success because similar methods were already being performed at the time the invention was made. The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (KSR International Co. v. Teleflex Inc. 550 U.S. 398, 82 USPQ2d 1385 (2007)).
(i) At page 10 of the Response of 06 August 2025, Applicant asserts that the claims as amended are not obvious over the claims of the cited patents.
Applicant’s claim amendments and arguments have been fully considered. However, claims 1-21 are still rejected on the grounds of nonstatutory double patenting as being unpatentable over claims of the ‘280, ‘897, and ‘214 patents for reasons set forth in detail above.
Conclusion
No claims are allowable.
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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BEB
Art Unit 1647
03 November 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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