DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06 April 2026 has been entered.
Status of Application, Amendments and/or Claims
The amendment of 06 April 2026 has been entered in full. Claims 1 and 19 are amended. Claims 5 and 6 are cancelled.
Claims 1-4 and 7-21 are under consideration in the instant application.
New Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claims 1-4 and 7-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
1a. Claims 1-4 and 7-18 are rejected as being indefinite because claim 1 recites the limitation "the anion chromatography resin" in step (b)(v). There is insufficient antecedent basis for this limitation in the claim. Claim 1, step (b) only recites “a second chromatography step wherein the first eluate is subjected to anion exchange chromatography”. There is no recitation of an anion chromatography resin.
1b. Claims 19-21 are rejected as being indefinite because claim 19 recites the limitation "the anion chromatography resin" in step (c)(v). There is insufficient antecedent basis for this limitation in the claim. Claim 19, step (c) only recites “a second chromatography step wherein the purified first eluate is subjected to anion exchange chromatography”. There is no recitation of an anion chromatography resin.
New Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
2. Claims 1-4 and 7-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 1 recites a process for the purification of an antibody fragment from a periplasmic cell extract, wherein anion exchange chromatography step (b)(v) recites, “loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8—about 1.1 mS/cm onto the anion chromatography resin”.
Claim 19 recites a process for the purification of an antibody fragment from a periplasmic cell extract, wherein anion exchange chromatography step (c)(v) recites, “loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8—about 1.1 mS/cm onto the anion chromatography resin”.
The specification as originally filed does not provide adequate written description for an anion exchange chromatography step of loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8—about 1.1 mS/cm (emphasis added by the Examiner). The “conductivity of about 0.8—about 1.1 mS/cm” range limitation as recited in claims 1 and 19 is not expressly asserted, nor does it flow naturally from the specification.
At the top of the Remarks section of the Response of 06 April 2026, Applicant states that support for the amended claims may be found throughout the specification, e.g. on page 12, lines 22-24, and page 25, line 25 to page 27, line 3, and in the claims as originally filed. However, upon the Examiner’s independent review of the specification, Figures, and originally filed claims, the specification only teaches the following regarding second chromatography step (anion exchange chromatography) conductivity:
(i) “In further embodiments of the invention the elution of the antibody fragment from the anion exchange chromatography column in the second chromatography step occurs during the loading and wash steps. The bound process-related impurities can be eluted by using a buffer either at a lower pH, higher conductivity or a combination of both. Ideally, the higher conductivity should be at least 70 mS/cm”;
(ii) “Subsequently diafiltration was performed until the CDP870 Fab' pool in 20 mM Tris had reached pH 8.0 and a conductivity of 1.1 mS/cm” (page 24, lines 12-13);
(iii) “Subsequently diafiltration was performed until the CDP870 Fab' pool in 20 mM Tris had reached pH 8.3 and a conductivity of 1.0 mS/cm”; and
(ii) “The CDP870 Fab’ was concentrated to 51 mg/mL before diafiltration with 5.8 volumes of 20 mM Tris pH 8.5 until the pH of the Fab’ solution was pH 8.5 and the conductivity was 0.8 mS/cm” (page 27, lines 1-3);
Therefore, the Examiner is unable to locate where the specification provides adequate written description of an anion exchange chromatography step of loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity range of about 0.8—about 1.1 mS/cm.
Maintained 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).
3. 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 4-9 of the previous Office Action of 06 November 2025 and at pages 9-13 of the Office Action of 06 May 2025 and is reiterated herein below for convenience.
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 (in a pH 8.0 buffer) 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)) from a periplasmic extract, said method 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; Arunakumari et al., pages 1-3). 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.
Applicant’s arguments
(i) At the bottom of page 6 of the Response of 06 April 2026, Applicant states that claim 1 has been amended to recite that the second chromatography step comprises: loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8 to about 1.1 mS/cm onto the anion chromatography resin; and producing a flow through containing the antibody fragment. Applicant argues that the combined references fail to disclose the claimed method.
Applicant’s arguments have been fully considered but are not found to be persuasive. First, it is noted that Humphreys et al. teach that a mixture containing Fab fragments is subjected to cation exchange chromatography on a SP sepharose column (from Pharmacia) and the resultant eluate (in a pH 8.0 buffer) is subsequently subjected to anion exchange chromatography on a Poros HQ column (page 21, last paragraph through page 23). Thus, Humphreys et al. disclose a first eluate in a buffer having a pH of 8.0, meeting the requirements of instant claims 1 and 19.
Second, regarding the entirety of the new limitation in instant claims 1 and 19 (“loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8—about 1.1 mS/cm onto the anion chromatography resin”), the Arunakumari et al. reference utilized in the instant pre-AIA 35 U.S.C. 103(a) rejections, teaches that in the anion exchange chromatography (AEC) step, the pH of the buffers can be from about 4 to 10, more preferably from about pH 6.0 to 9.0; and conductivity can be from about 0.1 to 10.0 mS/cm, more preferably from about 0.5 to 5 mS/cm (page 20, 1st full paragraph; page 21, 1st full paragraph; page 23, 4th full paragraph). Therefore, contrary to Applicant’s arguments, the teachings of Arunakumari et al. meet the new limitations of instant claims 1 and 19.
(ii) At the bottom of page 6 of the Response, Applicant asserts that only Humphreys et al. is directed towards Fab fragments and its anion exchange conditions are not specifically disclosed. Applicant states that the other references mention antibody fragments generically but do not provide any processes involving such fragments (Arunakumari, Wan) or do not mention antibody fragments at all (Davies, Soares). Applicant submits that none of Arunakumari, Soares, Davies, and Wan provide any teaching or suggestion on how to apply their disclosed method steps (exemplified only on whole antibodies) to antibody fragment purification. Applicant contends that one skilled in the art at the time of the invention was aware that whole antibodies (having an Fc portion) and Fab fragments differ significantly in their size and charge characteristics such that methods depending on pH and conductivity of buffers used with whole antibodies were recognized as unpredictable as to the ability of such buffers to permit purification of antibody fragments.
Applicant’s arguments have been fully considered but are not found to be persuasive.
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 (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. state that their invention is not limited to just antibodies (page 4, last 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 (page 12, lines 1-5; bottom of page 25 through the top of page 26).
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 with respect to the purification methods, the antibody may be an antigen-binding portion, such as a Fab fragment, a F(ab’) fragment, a Fc fragment, scFv, etc. (page 6, [0080-0082]; page 10, [0146-0147]; page 12, [0167]).
The Examiner acknowledges that 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). However, Davies et al. also teach that these methods may be applied to the purification of other biomolecules produced in microbial cell culture (page 7, lines 4-6).
Although Humphreys et al. is the only cited reference that discloses a specific example in their Examples section of purifying an antibody fragment, Arunakumari et al., Davies et al., and Wan et al. are all directed to the purification of antibodies. Arunakumari et al. and Wan specifically discuss that their inventions can be extended to the purification of antibody fragments. The disclosures of Arunakumari et al., Davies et al., and Wan et al. of more than one alternative (i.e., antibody v. antibody fragment) does not constitute a teaching away from any of the disclosed alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed (see MPEP 2123(II); In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Additionally, “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments” (see MPEP 2123(II); In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)).
(iii) It is noted that at pages 7-8 of the Response, Applicant cites pertinent case law reviewing the legal standard of obviousness. The Examiner takes no issue with Applicant's general comments regarding the legal standard for obviousness.
(iv) At the bottom of page 7 of the Response, Applicant argues that one skilled in the art would not have been motivated to combine Soares, Arunakumari, Davies, and Wan with Humphreys to achieve the claimed method. Applicant indicates that Soares, Arunakumari, Davies, and Wan do not provide methods to purify antibody fragments, and the methods provided in these references either do not use anion exchange at all (Soares); use membranes instead of resins (teaching that membranes provide higher clearance and flow rates (Arunakumari); use anion exchange buffers of unknown conductivity following a displacer cation exchange step (Davies); or use anion exchange chromatography buffers of higher conductivities (Wan). Applicant asserts that because of the differences in starting materials and assay conditions, one skilled in the art would not have an apparent reason to combine known elements of Soares, Arunakumari, Davies, and Wan with Humphrey to achieve the claimed method nor would one skilled in the art have arrived at the claimed invention. Applicant also submits that Soares, Arunakumari, Davies, and Wan teach mammalian cell extracts used in their antibody purification methods.
Applicant’s arguments have been fully considered but are not found to be persuasive. First, it is noted that Soares et al. was only cited by the Examiner to evidence that the SP sepharose column (from Pharmacia) of Humphreys et al. is a sulphopropyl (SP) chromatography column (for the limitations recited in claim 10).
Furthermore, as discussed in section (ii) above, Arunakumari et al., Davies et al., and Wan et al. are all directed to the purification of antibodies. Arunakumari et al. and Wan specifically discuss that their inventions can be extended to the purification of antibody fragments.
Arunakumari et al. teach that the anion exchange chromatography step in their methods may be performed using a resin or a membrane (page 16, 2nd and 3rd full paragraphs through the middle of page 17; page 37, #15). Arunakumari et al.’s disclosure of more than one alternative does not constitute a teaching away from any of the disclosed alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed (see MPEP 2123(II); In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Additionally, “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments” (see MPEP 2123(II); In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)).
Davies et al. and Wan et al. were cited by the Examiner for the teachings of large-scale purification requirements of the instant claims (i.e., a mixture containing an antibody fragment at a concentration of at least 1.5 g/L is subjected to cation chromatography and 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).
Lastly, contrary to Applicant’s arguments that Arunakumari, Davies, and Wan teach mammalian cell extracts are used in their antibody purification methods, Arunakumari et al. disclose that the protein of interest can be produced and purified from living host cells, including bacterial cells, fungal, or animal cells grown in culture (page 25, last paragraph through page 26). Arunakumari et al. state that when using recombinant techniques, the protein of interest can be produced intracellularly, in the periplasmic space, or secreted into the medium (page 26, last paragraph). Wan et al. also teach that host cells in their purification method include prokaryotes, such as E. coli (page 13, [0172]). Wan et al. indicate that when using recombinant techniques, the antibody may be produced intracellularly, in the periplasmic space, or secreted into the medium (pages 14-15, [0181]).
Therefore, in response to applicant' s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, 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)) from a periplasmic extract, said method 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; Arunakumari et al., pages 1-3). 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.
(v) At the top of page 8 of the Response, Applicant contends that in view of the unpredictability of protein and protein fragment purification in generation and the specific known differences in size and charge characteristics between whole antibodies and antibody fragments, one skilled in the art would not have looked to Soares, Arunakumari, Davies, and Wan to modify Humphreys’ method. Applicant argues that even if they did, the skilled artisan would not have had a reasonable expectation of arriving at the claimed invention because the combined cited references fail to teach a process for the purification of an antibody fragment from a periplasmic cell extract comprising the recited steps of cation exchange chromatography followed by anion exchange chromatography using a buffer having the recited pH and conductivity. Applicant submits that even where the references provide generic teachings of general purification conditions, the inquiry of motivation and reasonable expectation of success must focus on arriving at the claimed invention. Applicant asserts that the skilled artisan would not have been motivated to combine the teachings of the references and would not have had a reasonable expectation of success of arriving at the claimed invention.
Applicant’s arguments have been fully considered but are not found to be persuasive.
As discussed in-depth in the previous Office Actions and above, 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 cation exchange and anion exchange chromatography columns), (page 6, lines 19-22; page 21, lines 18-32 through page 23). Specifically, Humphreys et al. teach that a mixture containing Fab fragments is subjected to cation exchange chromatography on a SP sepharose column (from Pharmacia) and the resultant eluate (in a pH 8.0 buffer) is subsequently subjected to anion exchange chromatography on a Poros HQ column (page 21, last paragraph through page 23).
Similar to Humphreys et al., Arunakumari et al. teach that a protein of interest can be produced in the periplasmic space before purification (page 12, lines 1-5; bottom of page 25 through page 26). 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 (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. teach that in the anion exchange chromatography (AEC) step, the pH of the buffers can be from about 4 to 10, more preferably from about pH 6.0 to 9.0; and conductivity can be from about 0.1 to 10.0 mS/cm, more preferably from about 0.5 to 5 mS/cm, meeting the new limitations of claims 1 and 19 (page 20, 1st full paragraph; page 21, 1st full paragraph; page 23, 4th full paragraph).
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)) from a periplasmic extract, said method 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; Arunakumari et al., pages 1-3). 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).
4. 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 page 9 of the previous Office Action of 06 November 2025 and at pages 15-17 of the Office Action of 06 May 2025.
Applicant’s arguments
(i) At the bottom of page 8 of the Response, Applicant argues that the deficiencies associated with Humphreys, Soares, Arunakumari, Davies, and Wan have been discussed and that O’Donnell does not mention anion exchange chromatography. Applicant submits that thus, O’Donnell does not cure the deficiencies of Humphreys, Soares, Arunakumari, Davies, and Wan.
Applicant’s arguments have been fully considered but are not found to be persuasive. Humphreys et al., Arunakumari et al., Davies et al., and Wan et al. do not teach that the cation exchange chromatography is performed at a flow rate of at least 300 cm/hr or that the resin has a mean particle size of at least 50 μm. The combination of references also do not teach that the cation exchange chromatography column has a dynamic binding capacity (DBC) for the antibody fragment of between 50-75 g/L resin.
O’Donnell et al. was cited by the Examiner because O’Donnell et al. teach that it was known that cation exchange resins were commercially available to process biotherapeutic proteins, such as antibodies, at levels up to 10 mg/ml in the cell culture fluid and that such also had extremely fast flow rates of 1060 cm/hr with a dynamic binding capacity (such as 145 mg/ml-gel, which is equivalent to 145 g/L) (pages 3, 6, and 9). O’Donnell et al. disclose that the DBC at 10% breakthrough of such a resin (referred to as the “Toyopearl GigaCap S-650M) using polyclonal IgG sample at 1 mg/ml at high flow rates of 1060 cm/hr, result in a 75 mg/ml resin binding capacity (which is equivalent to 75 g/L), meeting the limitations of instant claims 8 and 11 (page 6; Figure 1). O’Donnell et al. also indicate that this resin has a nominal particle size of 75 μm, meeting the limitations of instant claim 12 (page 5, Table 1).
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)) from a periplasmic extract, said method comprising a cation exchange chromatography step and an anion chromatography step as taught by Humphreys et al., Arunakumari et al., Davies et al., and Wan et al. by utilizing the Toyopearl GigaCap S-650M cation exchange resin as taught by O’Donnell et al., in the cation exchange chromatography step. The person of ordinary skill in the art would have been motivated to make that modification to the cation exchange resin because (i) one of the bottlenecks in the downstream processes of purifying higher levels of protein is the binding capacity of chromatography resin (O’Donnell et al., page 3); (ii) the Toyopearl GigaCap S-650M cation exchange resin of O’Donnell et al. utilizes a small column, has very high capacity and quantitative protein recovery, and consumes less buffer (see O’Donnell et al., pages 3 and 13); and (iii) Arunakumari et al. teach that while the flow rate is not essential to achieving purity levels, rates are provided for purposes of guidance and one having ordinary skill in the art can modify the flow rate as needed (page 30, 2nd full paragraph). The person of ordinary skill in the art would have expected success because the Toyopearl GigaCap S-650M cation exchange resin of O’Donnell et al. is a commercially available cation exchange resin meeting the DBC, flow rates, and particle size requirements of instant claims 8, 11, and 12. Furthermore, the substitution of one known element for another yields predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). A person of ordinary skill has good reason to pursue the known options within his or her grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
5. 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 page 9 of the previous Office Action of 06 November 2025 and at pages 17-29 of the Office Action of 06 May 2025.
Applicant’s arguments
(i) At the top of page 9 of the Response, Applicant argues that the deficiencies associated with Humphreys, Soares, Arunakumari, Davies, and Wan have been discussed and that Fahrner does not cure these defects.
Applicant’s arguments have been fully considered but are not found to be persuasive. Humphreys et al., Arunakumari et al., Davies et al., and Wan et al. do not teach that the method of purifying a recombinant antibody comprises two additional ultrafiltration steps (one after the cation exchange chromatography and one after the anion exchange chromatography). The combination of references also do not teach that the purified antibody fragment binds glycoprotein IIb/IIIa receptor or that the antibody is “abciximab”.
Fahrner et al. was cited by the Examiner because Fahrner et al. teach that ultrafiltration is frequently used throughout the downstream processing for protein concentration, buffer exchange and desalting, protein purification, virus clearance, and clarification (page 4, lines 9-12; page 27, lines 30-32). Fahrner et al. further exemplify purification of the anti-CD40 recombinant human monoclonal antibody in host cell culture fluid using cation exchange chromatography followed by anion exchange chromatography followed by HPTFF ultrafiltration (page 60, lines 20-23). Fahrner et al. indicate that preferred proteins to be purified according to the invention are antibodies, such as anti-GpIIb/IIIa antibody, abciximab (page 29, lines 9-10; page 30, line 29).
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)) from a periplasmic extract, said method comprising a cation exchange chromatography step and an anion chromatography step as taught by Humphreys et al., Arunakumari et al., Davies et al., and Wan et al. by purifying the anti-GpIIb/IIIa antibody, abciximab, and including two additional ultrafiltration steps as taught by Fahrner et al. The person of ordinary skill in the art would have been motivated to make those modifications for large scale production of purified abciximab 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; Fahrner et al., page 4) and to remove additional impurities, clear viruses, and/or eliminate protein oligomers or degradation products during purification (see Fahrner et al., (page 4, lines 9-12; page 27, lines 30-32)). The person of ordinary skill in the art would have expected success because additional ultrafiltration steps were already successfully included with antibody purification and concentration strategies at the time the instant application was filed. 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)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Maintained 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.
6. Claims 1-4 and 7-21 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 in detail at pages 12-14 of the previous Office Action of 06 November 2025 and at pages 20-21 of the Office Action of 06 May 2025.
7. Claims 1-4 and 7-21 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 in detail at pages 12-14 of the previous Office Action of 06 November 2025 and at pages 20-21 of the Office Action of 06 May 2025.
8. Claims 1-4 and 7-21 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 in detail at pages 12-14 of the previous Office Action of 06 November 2025 and at pages 20-21 of the Office Action of 06 May 2025.
(i) At the middle to bottom of page 9 of the Response of 06 April 2026, Applicant acknowledges that terminal disclaimers can be filed to overcome these rejections. However, Applicant asserts that the claims are not obvious over the cited patents. Applicant requests that these issues be held in abeyance until such time as allowable subject matter is identified.
Applicant’s statements have been fully considered but are not found to be persuasive. The rejections of instant claims 1-4 and 7-21 on the grounds of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 9,309,280, U.S. Patent No. 10,189,897, and U.S. Patent No. 11,339,214 as set forth in detail in the previous Office Action of 06 November 2025 are maintained. First, it is noted that regarding the new limitation in instant claims 1 and 19 (“loading the first eluate in a buffer having a pH between 8.0 and 9.0 and a conductivity of about 0.8—about 1.1 mS/cm onto the anion chromatography resin”), the Arunakumari et al. reference utilized in all three rejections, teaches that in the anion exchange chromatography (AEC) step, the pH of the buffers can be from about 4 to 10, more preferably from about pH 6.0 to 9.0; and conductivity can be from about 0.1 to 10.0 mS/cm, more preferably from about 0.5 to 5 mS/cm (page 20, 1st full paragraph; page 21, 1st full paragraph; page 23, 4th full paragraph).
Second, Applicant traverses the rejections, but does not present any arguments pointing out the specific distinctions that render the instant claims patentable over the ‘280, ‘897, and ‘214 double patenting rejections. Applicant is reminded that only objections or requirements as to form not necessary to further consideration of the claims may be held in abeyance until allowable subject matter is indicated (see 37 CFR 1.11(b)). Applicant is encouraged to submit terminal disclaimers at Applicant’s earliest convenience.
Conclusion
No claims are allowable.
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BEB
Art Unit 1647
19 June 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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