DETAILED ACTION
Status of claim rejections
The rejections of record under 35 USC 103 are maintained in view of Applicant’s arguments in the response filed 01/15/2026.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
First rejection
Claims 1-3 and 5-12 are rejected under 35 U.S.C. 103 as obvious over Soane et al (WO2018152165A1; cited in Applicant’s 04/01/2022 IDS; hereinafter Soane; prior art of record) in view of Bian et al (US 20160122385A1; hereinafter Bian; prior art of record) and Kempf et al. (Pathogen inactivation and removal procedures used in the production of intravenous immunoglobulins. Biologicals. 2007 Mar;35(1):35-42. doi: 10.1016/j.biologicals.2006.01.002. Epub 2006 Apr 3; hereinafter “Kempf”).
Soane teaches a purification process for producing therapeutic and non-therapeutic proteins such as monoclonal antibodies from cell culture medium (see paragraph 16-18; FIG.2) using 1) an affinity chromatography step, 2) virus inactivation, 3) polishing chromatography, 4) virus filtration, and 5) final purification (see Fig. 2). Soane teaches various examples of purification of monoclonal antibodies by loading the sample onto Protein A chromatography columns, elution using various elution buffers at pH of 2.6, using excipients such as sucrose (i.e., disaccharides), trehalose and PEG, and collecting the elution fractions (see Example 28; see also Tables 21-23, and Example 30). Soane also teaches the viral inactivation process is conducted at a pH level of about 2.5 to about 5.0 (see paragraph 17).
Soane does not explicitly teach combining fractions obtained to form an elution pool.
However, Bian teaches a method of reducing the level of protein aggregates in an elution pool of Fc-protein and reduce the number of downstream steps in order to remove protein aggregates using Protein A chromatography (see claim 1, paragraph 0008). Specifically, Bian teaches that step elution can be used to elute the Protein A bound Fc-containing protein, where small changes in pH are used for elution of the protein in multiple steps over time (paragraph 0071). Furthermore, Bian teaches that protein elution fractions can be combined to form an elution pool to help recover the target protein (paragraph 0052, 0071).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of purifying proteins as taught by Soane and include creation of an elution pool as taught by Bian to arrive at the claimed invention. As Bian teaches that elution fractions can be combined to create an elution pool and help recover target protein, one of ordinary skill would have been motivated to create elution pools during protein purification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Bian explicitly teaches that protein elution fractions can be combined to form an elution pool to help recover the target protein.
Neither reference explicitly teaches that the elution product pool comprising the excipient wherein the excipient increases stability of the target protein during low pH viral inactivation.
However, Kempf teaches pathogen inactivation and removal procedures used in production of IV immunoglobulins (i.e., antibodies) (see title, abstract). Kempf teaches various known procedures to remove viruses during immunoglobulin purification, including virus filtration, heat treatment, low pH incubation, and use of sugar stabilizers (see pg. 37, Fig. 1). Specifically, Kempf teaches treatment of IV immunoglobulins in the presence of sugar stabilizers such as 33% (w/w) sorbitol at pH 5.5 (i.e., during low pH), where all enveloped and nonenveloped viruses studied were completely inactivated within detection limits of the assays used (see pg. 38, col 1, paragraph 2). Kempf also teaches that sucrose and potassium acetate are also good stabilizers during viral inactivation of nonenveloped viruses (see pg. 38, col 1, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of purifying proteins as taught by Soane and Bian and include stabilizing sugar excipients as taught by Kempf to arrive at the claimed invention. As Kempf teaches that sugars (such as sorbitol and sucrose) can be used as stabilizing agents during viral inactivation at low pHs, one of ordinary skill would have been motivated to use the sugars with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Kempf explicitly teaches treatment of IV immunoglobulins in the presence of sugar stabilizers (such as 33% (w/w) sorbitol at pH 5.5) advantageously inactivates all enveloped and nonenveloped viruses and that sucrose and potassium acetate are also good stabilizers during viral inactivation.
Regarding claim 2, Soane and Bian teach using Protein A chromatography (see above).
Regarding claim 3, Soane teaches purification of monoclonal antibodies (see Example 28).
Regarding claim 5, Soane teaches using sucrose and trehalose as excipients (see Table 21 and 24) and Kempf teaches sorbitol and sucrose excipients (see above).
Regarding claim 6-7, Soane teaches using sucrose (i.e., disaccharide) at concentration of 101 mM, which lies inside of the claimed range of 1mM to 1.5 M (claim 6) and 5 mM to 500 mM (claim 7). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (MPEP 2144.05(I)).
Regarding claim 8, Soane teaches using citrate buffer (see Example 28 and 30).
Regarding claim 9, Soane teaches the pH of each elution buffer was adjusted to about 2.6, which lies inside of the claimed range of 2.5-5.5 (Example 28, paragraph 0147). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (MPEP 2144.05(I)).
Regarding claim 10, Bian teaches using step elution using pH gradients (see paragraphs 0067-69 and 0077), where the high point of the pH gradient ranges from pH 5.1 to 6.0 and the low point of the pH gradient ranges from pH 3.0 to 3.7 (paragraph 0077). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (MPEP 2144.05(I)).
Regarding claim 11, Soane teaches that the viral inactivation step occurs at pH of 2.5-5 (see above) which typically involve holding the protein solution at a low pH, e.g., pH lower than 4, for an extended period of time (see paragraph 0097). It would have been prima facie obvious to one of ordinary skill to adjust the pH of the elution pool to a pH of 2-5 in order to advantageously create a low pH environment to remove viral impurities from the protein product with a reasonable expectation of success.
Regarding claim 12, Soane teaches that the viral inactivation step (i.e., incubation step) occurs at pH of 2.5-5, which the claimed range of 2.5-4.5 lies inside. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Soane, Bian, and Kempf as applied to claims 1-3, and 5-12 above, and further in view of Jungbauer et al (US20160272675 A1; hereinafter “Jungbauer”; prior art of record).
As discussed above, claims 1-3, and 5-12 were rendered prima facie obvious by the combined teachings of Soane, Bian, and Kempf.
The difference between the references and the instant claim is that none of the references explicitly teaches the poly(ethylene glycol) polymer has an average molecular weight from 1000 g/mol to 10,000 g/mol.
However, Jungbauer teaches a method for isolating a protein of interest from nucleic acids and other host cell proteins present in cell culture supernatant comprising said protein using polyethylene glycol (see claim 1). Jungbauer teaches that use of PEG (such as PEG 2000, PEG4000, and PEG6000; see claim 2) is known in the art for precipitation and purification of proteins (see claim 1, paragraph 0008, 0045-0048; Example 1).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of purifying protein using Protein A chromatograph as taught by Soane, Bian, and Kempf by using PEG polymers as taught by Jungbauer to arrive at the claimed invention. As Jungbauer teaches that PEG2000, PEG4000, and PEG6000 can be used to for isolating a protein of interest from nucleic acids and other host cell proteins present in cell culture supernatant, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Jungbauer explicitly teaches PEG moieties that can be successfully used to purify proteins during chromatography.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Third rejection
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Soane, Bian, and Kempf as applied to claims 1-3 and 5-12 above, and further in view of Jin et al (Protein aggregation and mitigation strategy in low pH viral inactivation for monoclonal antibody purification. MAbs. 2 September 2019; 11(8):1479-1491; hereinafter “Jin”; prior art of record).
As discussed above, claims 1-3, and 5-12 were rendered prima facie obvious by the combined teachings of Soane, Bian, and Kempf.
The difference between the references and the instant claim is that none of the references explicitly teaches that the incubation step is performed at room temperature.
However, Jin teaches low pH viral inactivation for purification of monoclonal antibodies (title, abstract). Jin teaches that typical viral inactivation includes an acidification step where Protein A eluate is adjusted to low pH and held for several hours to achieve sufficient inactivation (pg. 1479, col 1). Jin also teaches that environmental conditions, such as pH, ionic strength, temperature, protein concentration, and excipients species/concentration play important roles in mAb aggregation (see pg. 1479, col 2). Jin further teaches viral inactivation of IgG4-N1 where the pH of the sample was lowered to 3.6 during the inactivation step before the pool was held for various durations (from 10 min to 24h) at room temperature before viral neutralization to pH 5.5 (see pg. 1481, col 1-2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of purifying protein using Protein A chromatograph as taught by Soane, Bian, and Kempf by performing the viral inactivation step at room temperature as taught by Jin to arrive at the claimed invention. As Jin teaches the inactivation and neutralization of viruses during purification of monoclonal antibodies, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Jin explicitly teaches that successful viral inactivation can be performed at room temperature during monoclonal antibody purification.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 01/15/2026 have been fully considered but they are not persuasive.
On pg. 2-5, Applicant argues Soane explicitly teaches using viscosity reducing excipients like hindered amines, anionic aromatics, etc. to improve stability of proteins during low pH viral inactivation (and not PEG, disaccharides, or polyols) such that a PHOSITA would have no reason to look beyond the teachings of the Soane reference. Applicant argues in example 28 of Soane, there is no teaching/motivation to add sucrose or trehalose in another purification step and is only used to recover target protein. Applicant argues that Kempf teaches using sucrose or sorbitol as stabilizers during heat virus inactivation and not during low pH, and argues against the examiner’s use of in re Keller regarding “attacking references individually”. Applicant further argues that Soane does teach using various protein stabilizing excipients (citing to paragraph 14) and in the context of low pH viral inactivation, Soane teaches viscosity lowering excipients for improving process parameters or net yield (citing to para 0097), such that a PHOSITA would have been led to try hindered amines, anionic aromatics, functionalized amino acids, oligopeptides, etc. and not the path taken by Applicant.
In response, the examiner disagrees. First, it should be noted that the claimed invention is drawn to purification of a target protein from cell culture sample using 1) and affinity chromatography step (generally), 2) a virus inactivation step (generally), and optionally other downstream purification steps. The claimed affinity chromatography requires, inter alia, loading sample, eluting target protein with elution buffer and an excipient, collecting fractions, and combining the fractions, where the inactivation step comprises incubation of the product pool at a specific pH range. Put simply, the method requires these general steps, which is taught by Soane. The claims require addition of the claimed excipient to the viral inactivation step for the purpose of stabilizing the target protein. While Soane provides various examples of excipients, the reference does not provide teachings regarding an excipient such as sucrose for that purpose. However, the disclosure of Soane as to the types of excipients used are preferred embodiments. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
Indeed, Soane does not disclose that the excipients recited are the only excipients that are capable of providing protein stabilization, and further, does not disavow the use of any other excipients not cited in the reference, as, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). As such, one of ordinary skill in the art would have necessarily looked beyond the disclosure of Soane for teachings regarding sugars as stabilizing excipients for use during viral inactivation because a PHOSITA has access to any and all references relevant to the claimed invention and is not limited to just the Soane reference (which is the essence of a rejection under 35 USC 103). This is where the Kempf reference is relevant. Soane provides a teaching, suggestion, and motivation to perform the method steps recited above, including low pH viral inactivation. The newly cited Kempf reference is cited for its explicit teaching that sugars can be used as a stabilizing excipient during protein purification and viral inactivation (see Kempf above), which is enough of a teaching, suggestion, or motivation to use sugars like sucrose as a stabilizing excipient during viral inactivation.
Second, regarding Applicant’s argument regarding “inappropriate” reliance on Keller (see pg. 4 of the arguments), the examiner points Applicant to the arguments made in the remarks filed 08/19/2025, in which Applicant only argued against the teachings of the primary reference (Soane) and not the combination of the teachings of Soane and Bian, which the rejections previously made and maintained were based on. This is why In re Keller was cited.
On pg. 5-10, Applicant argues that Kempf uses sucrose as a sugar stabilizer during heat virus inactivation and not low pH and cites to section 4.2 on pg. 38, arguing that there is no teaching, suggestion, or motivation of using a stabilizer such that a PHOSITA would not consider adding a sugar during low pH virus inactivation step. Applicant also further argues example 28 of Soane which uses the sucrose and trehalose on purified antibodies and not on a cell culture sample, citing to paras 95-97 regarding using viscosity reducing excipients before and or during chromatography and not during another stage of the purification process. Applicant urges that Soane fails to provide any reason to add sucrose or trehalose during viral inactivation and the modification of Soane with Kempf would render the operation of the claims unsatisfactory for its intended purpose or change the principle of operation.
In response, the examiner disagrees for the same reasons as set forth above. Applicant’s argument regarding Example 28 runs contrary to the disclosure of the prior art. Example 28 does not just teach adding trehalose and sucrose to Protein A chromatography generally. In fact, the example explicitly teaches using the excipients in Table 20 (i.e., trehalose and sucrose) as excipients to improve Protein-A chromatography elution (see Example 28 and paragraph 146-148). When claimed so generally, there is no need for disclosure of using disaccharides, polyols, or PEG polymers “as viscosity-reducing excipients in the virus inactivation step” as argued because Soane provides one of ordinary skill the teaching, suggestion, and motivation to add those to the purification steps throughout the reference as pointed out by Applicant. Furthermore, Kempf provides the explicit teachings that sugar stabilizers (such as 33% (w/w) sorbitol at pH 5.5) advantageously inactivates all enveloped and nonenveloped viruses and that sucrose and potassium acetate are also good stabilizers during viral inactivation (i.e., the same purpose as Applicant).
Conclusion
NO CLAIMS ALLOWED.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGIANA C REGLAS whose telephone number is (571)270-0995. The examiner can normally be reached M-Th: 8:00am-2:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
Prosecution Insights