DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Claim Status
Applicant’s arguments and amendments dated 3/9/26 have been received and entered in the application
Claims 1, 4-8, 10-12, 16, 19 are currently pending.
Claim 19 is withdrawn as directed to a non-elected invention effectively without traverse in the response dated 7/7/20.
Claims 1, 4-8, 10-12, 16 are elected and examined on the merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections rejections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(b)/2nd paragraph
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.
Claims 1, 4-8, 10-12, 16, 19 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 pre-AIA the applicant regards as the invention.
Claim 1 contains the limitation “in order to increase an expression level of the aflibercept and reduce amount of aggregates”. It is unclear if this limitation is a requirement of the claim or merely optional.
Claim 1 contains the limitation “in order to increase an expression level of the aflibercept”. Claim 1 appears to be directed to a cell-based method of producing aflibercept, not a method increasing expression of a protein within the cells. For examination purposes, this limitation is interpreted as “whereby production is increased and an aflibercept aggregates is reduced as compared to…”
Claim Interpretation
The specification as originally filed indicates that “any type of cell may be used without limitation as long as the cell is a stable cell line capable of constantly expressing the fusion protein”. Therefore, the claims are interpreted as limiting the cells to stable cell lines which have been genetically engineered to constantly express a fusion protein comprising a soluble extracellular domain of a VEGF receptor and a human IgG Fc domain.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-8, 10, 12, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Daly et al., US Patent No. 7,396,664 (cited on IDS dated 7/20/22, hereinafter Daly) in view of Kuystermans, D. & Al-Rubeai, M., “Biopharmaceutical products from Animal Cell Culture.” In: Animal Cell Culture. (Switzerland, Springer Int., 2015), pp. 717-758 (hereinafter Kuystermans) and Fan et al., Effect of culture temperature on TNFR-Fc productivity in recombinant glutamine synthetase-Chinese hamster ovary cells. Biotechnology Letters, Vol. 32 (2010) pages 1239-1244 (cited on IDS dated 7/20/22, hereinafter Fan).
Regarding claims 1, 14 and 16 Daly discloses methods of producing fusion proteins with a vascular endothelial growth factor (VEGF) receptor component using Chinese hamster ovary (CHO) cells (col 1 ln 35-51, col 2 ln 39-63). Daly discloses first constructing nuclei acid sequences encoding the fusion proteins (col 1 ln 35-42, col 4 ln 23-37). The nucleic acid sequences are then inserted into a vector and inserted into an appropriate host cell, such as CHO cells (col 2 ln 39-63, col 4 ln 38-46). Preferably, the fusion protein contains the VEGF receptor component Ig domain 2 of FLt-1 and the Ig domain 3 of FLk-1, or their functional equivalents (col 1 ln 35-51, col 5 ln 15-49).
Regarding claims 15 and 18, Daly further discloses that the fusion protein may be useful for treating any disease or condition for which the fusion protein may have therapeutic value (col 8 ln 9-27).
Regarding claim 8, the CHO cells may be CHO K1 cells (col 17 ln 10-26). In some embodiments, the fusion component comprises an immunoglobulin (Ig)-derived domain such as human IgG or, more particularly, the Fc domain of IgG (col 7 ln 5-63).
Regarding claim 17, the fusion protein secreted by the CHO cells may subsequently be recovered from the culture media (col 17 ln 10-26).
Daly does not disclose that the fusion protein is aflibercept.
Kuyerstermans reviews biopharmaceutical products produced by animal cell cultures (Abstract). Kuyerstermans explains that CHO cells are the preferred cell line for the production of Fc fused recombinant proteins (23.4). Kuyerstermans discloses that Aflibercept comprises VEGFR1 and VEGFR2 fused with the Fc portion of IgG which has been successfully produced by CHO cells (23.4).
As both Daly and Kuystermans are directed to methods of producing fusion proteins using CHO cells it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that the aflibercept of Kuystermans could be used in the methods of Daly as a simple substitution of one VEGF Fc fusion protein for another, with a reasonable expectation that the CHO cells would successfully produce aflibercept.
The combination of Daly and Kuyerstermans does not disclose that the CHO cells are cultured at a first temperature followed by a second lower temperature.
Fan discloses methods of modulating culture temperature to improve the production of recombinant proteins secreted by CHO cells (Abstract). Fan explains that “many studies have suggested that specific antibody productivity can be increased by in vitro culturing of mammalian cells at sub-physiological temperatures” (Introduction, Discussion). Fan discloses utilizing CHO cells which have been transfected to produce a TNFR-Fc fusion protein (Cell line and maintenance). The cells are initially maintained at basal media at 37°C then cultured at a reduced temperature (Cell line and maintenance). Fan explains that cultivation and sub-physiological temperatures increased the final TNFR-Fc concentrations as compared to cells cultured at 37°C (Effects of culture temperature on TNFR-Fc production, Fig. 2).
Regarding claims 4-5, Fan discloses that after culture at 37°C the cells are then harvested and transferred to batch-fed bioreactors (Introduction, Batch cultivation).
Regarding claims 9-10, the cells are cultured at temperatures of 30°C, 33.5°C, and 37°C (Batch cultivation, Effects of culture temperature on TNFR-Fc production, Figs. 1-2).
Regarding claims 12-13 Fan discloses that the cells are cultured at the reduced temperature for between 4 and 10 days (Batch cultivation, Effects of culture temperature on TNFR-Fc production, Figs. 1-2).
As each of the references are directed to methods of producing fusion proteins using CHO cells it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to combine the references for improved production of the fusion protein of Daly and Kuystermans.
The combination is silent as to the amount of aggregates present in the fusion protein. However, as currently presented, this limitation recites the intended result of the method (reduction in aggregates and increased production of aflibercept) rather than requiring an additional, active method step be performed. MPEP § 2111.04 states “[c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, art reading on a method of culturing cells which produce aflibercept at a temperature of between 33 °C and 38 °C, then culturing the cells at a temperature of between 28 °C and 35 °C, necessarily results in reduction in aggregates and increased production of aflibercept in the absence of evidence to the contrary.
Further, the Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the fusion protein produced by the methods of the prior art differs, and if so to what extent, from the fusion protein produced by applicant’s methodology. The prior art discloses a method for producing a fusion protein which is similar to applicant’s method for these reasons: CHO cells which produce a fusion protein with a soluble extracellular domain of a VEGF receptor and an IgG Fc domain (e.g., aflibercept) are cultured at physiological temperatures followed by culture at a temperature of between 28°C and 35°C such that the CHO cells produce the fusion protein at a higher concentration than those maintained at physiological temperatures. Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §103 is appropriate. See MPEP §§ 2112-2112.02. The cited art taken as a whole demonstrates a reasonable probability that the fusion protein produced by the methods of the prior art is either identical or sufficiently similar to the fusion protein produced by the claimed methods that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence that the methods of the cited prior art does not possess a critical characteristic that is possessed by the claimed methods would advance prosecution and might permit allowance of claims to applicant’s methods.
Regarding claim 3, none of the references disclose that the culture is a large-scale culture. However, there are a finite number of scales for cell culture (e.g., small-, intermediate-, and large-scale). Therefore, it would be obvious to one of ordinary skill in the art to try the methods of the combination on a large-scale with a reasonable expectation that the fusion protein could be successfully produced.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Daly in view of Kuystermans and Fan as applied to claims 1-10, 12-18 above, and in further view of R. Ian Freshney, “Quatitiation.” In: Culture of Animal Cell: A Manual of Basic Technique and Specialized Applications. (Hoboken, NJ, John Wiley & Sons, Inc., 2010), pp. 335-364. QH585.2.F74 2010 (hereinafter Freshney).
Regarding claim 11, the combination does not disclose that the cells are cultured for 1 to 5 days before the temperature change.
Freshney explains that knowledge of the growth state of a culture and it status is critical for design of culture experiments (20.9.1). Freshney discloses methods for determining growth curves, including lag, log, and plateau phases, for cell lines (20.9-20.9.7). Freshney explains that cell culture are most consistent and uniform in the log phase, such that cell yields and reproducibility is significantly enhanced (20.9.1) In a prototypical growth curve, the log phase may occur between 1 and 7 days (20.9.2, Fig. 20.8). Therefore, there is a suggestion present in Freshney that the growth phase of a culture is a result-effective variable. A skilled artisan would understand that the date for experimental conditions to be initiated could be optimized through routine experimentation requiring no more than ordinary skill in the art.
Response to Arguments
Applicant's arguments dated 3/9/26 have been fully considered but are moot in part and not persuasive in part due to the new grounds of rejection necessitated by applicant’s amendments. To the extent that the arguments are pertinent to the current grounds of rejection they are responded to below.
Claims 1, 4-8, 10, 12, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Daly et al., US Patent No. 7,396,664 (cited on IDS dated 7/20/22, hereinafter Daly) in view of Fan
Applicant argues that the different proteins in Daly and Fan do not provide a reasonable expectation of success in combining methods therein; that the different structures of the proteins have differing production needs (Response p5-6).
Fan explicitly states that “many studies have suggested that specific antibody productivity can be increased by in vitro culturing of mammalian cells at sub-physiological temperatures” (Introduction). Therefore, there is a clear suggestion present in Fan that the disclosed methods may be successfully utilized for other antibodies beyond the TNFR-Fc explicitly disclosed.
Applicant argues that shifting temperatures in protein production effects different proteins differently (Response p6-7). Applicant points to Johari in support of the position that a change to a lower temperature does not necessarily lead to an increase in the expression of the protein (Response p6-7).
In response, both figures 4 and 5 of Johari demonstrate that shifting to 32°C at 3 hours post transfection results in an increase in cell-specific production rates (qP) of Sp35Fc. Johari explicitly states that the shift in temperature results in “a stimulation of qP with repression of [integral of viable cell density] IVCD”. This indicates that the shift in temperature significantly increases production; the converse of applicant’s position.
Applicant argues that lowering the temperature unexpectedly increases production, decreases aggregates, and decreases fragments of aflibercept (Response p7).
As noted above in the art rejection, this limitation recites the intended result of the method (reduction in aggregates and increased production of aflibercept) rather than requiring an additional, active method step be performed. MPEP § 2111.04 states “[c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, art reading on a method of culturing cells which produce aflibercept at a temperature of between 33 °C and 38 °C, then culturing the cells at a temperature of between 28 °C and 35 °C, necessarily results in reduction in aggregates and increased production of aflibercept in the absence of evidence to the contrary. As the combination is deemed to read on the actively recited method steps, the claims as presented are deemed to be obviated.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached on Monday-Friday 8:00-4:00 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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