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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/27/2025 has been entered.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1,6, and 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen et al. (US 2004/0265964) as applied to claims above, and further in view of Hiller et al. (US 2019/0031997).
Regarding claims 1, 6, and 8 Allen et al. discloses a method of producing etanercept from recombinant CHO cells comprising running an N-1 bioreactor at a temperature of between 37° C to 38° C before running an N production bioreactor. (See Allen Abstract and [0063], [0072], [0082] wherein recombinant CHO cells are grown in an N-1 bioreactor at 37° C before running an N production bioreactor.)
Allen does not specifically disclose the N-1 bioreactor being a perfusion bioreactor.
Hiller discloses a device for cultivating cells including CHO cells comprising an N-1 perfusion bioreactor and an N production bioreactor. (See Hiller Abstract [0057]-[0058] and Fig. 1)
It would have been obvious to one of ordinary skill in the art at the time of filing to utilize a perfusion bioreactor as an N-1 bioreactor as described by Hiller in the method of Allen because such a perfusion bioreactor allows simple operation and increase in productivity over other N-1 production systems as would be desirable in the method of Allen.
modified Allen discloses all the claim limitations as set forth above as well as the method wherein said N-1 perfusion bioreactor is run at a temperature of 37.5° C. (See Allen [0063] wherein the N-1 bioreactor is run at temperatures between 35 and 38° C, i.e. which includes 37.5 degrees.)
Additionally It would have been obvious to one of ordinary skill in the art at the time of invention to have selected the overlapping portion of the temperature ranges disclosed by the reference because selection of overlapping portion of ranges has been held to be a prima facie case of obviousness. In re Malagari, 182 USPQ 549.
It is noted that modified Allen discloses all the claim limitations as set forth above and it is noted that the cited prior art teaches production methods which run an N-1 bioreactor at 37 and/or 37.5 0 C and this produces more protein and production titer than an identical method at lower temperatures, i.e. this is an inherent characteristic of the production method that flow naturally from utilizing such a temperature.
Response to Arguments
Applicant's arguments filed 2/5/2025 have been fully considered but they are not persuasive.
Applicant argues that “It is stated that “Allen et al. discloses a method of producing etanercept from recombinant CHO cells comprising running an N-1 bioreactor at a temperature between 37° C to 38° C .” But the cited passages from Allen do not recite this range. The prophetic description of paragraph [0063] says that the “growth phase” of a culture may be done under conditions that “maximize cell proliferation and viability” and provides a temperature range “from about 35° C to about 38° C.” This of course does not specifically identify 37.5° C as a particularly desirable or effective temperature. It doesn’t even suggest that the temperature should be maintained at a constant level within this range, and so allows for temperatures that vary within these limits. This all suggests that temperature is not a particularly critical variable for N-1 bioreactor runs.
The working examples described at cited paragraphs [0072] and [0082] each recites a growth phase temperature of 37° C, not 37.5° C as recited in the present claims. The present application at Table 1 provides data showing that N-1 production runs done at 37.5° C give on average superior results to those done at 37° C (with an even greater benefit over runs done at 36.5° degrees, see below), even as other parameters are varied. ”
It is noted that the examiner specifically pointed out where Allen contemplates running a N-1 stage reactor at temperatures between 35 and 38° C, which includes the temperature of 37.5 ° C. In regards to temperatures being maintained at a constant level it is noted that the claims do not require constant temperature but merely require “running” at 37.5 ° C without specifying any continuous maintenance or time frame of such “running”.
The examiner specifically noted that while Allen does not provide a specific example of temperature being 37.5 it would have been obvious to one of ordinary skill in the art at the time of invention to have selected the overlapping portion of the temperature ranges disclosed by the reference because selection of overlapping portion of ranges has been held to be a prima facie case of obviousness. In re Malagari, 182 USPQ 549.
Applicant has not specifically addressed this reasoned statement of obviousness and as such the rejection stands.
Also applicant merely alleges that Fig. 1 shows more consistent and less variability at 37.5. This is not a sufficient showing of unexpected results. Alleging improved results is not the same as demonstrating unexpected results, i.e. improved results may be wholly expected.
To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
The criticality of a N-1 bioreactor run at 37.5 degrees and any unexpected results cannot be ascertained due to applicant’s insufficient showing of evidence.
It is suggested that applicant provide additional evidence demonstrating unexpected results to differentiate from the cited prior art.
It is also admitted that "Allen does not specifically disclose the N-1 bioreactor being a perfusion bioreactor.” To fill this gap, Hiller and its use of a N-1 perfusion reactor are cited, and it is asserted that it would have been “obvious” to substitute the perfusion reactor of Hiller into the method of Allen. The rejection lists various purported benefits of this substitution, but none is supported by citation to a reference. Gaps cannot be so easily filled in a prima facie obviousness argument. This argument also ignores that the cited examples in Hiller use an N-1 incubation temperature of 36.5° C (see Table 5). Surely, even If the skilled person were to substitute the N- perfusion reactor of Hiller (and, again, the motivations and benefits of doing so have merely been impermissibly assumed by the present rejection), the operating parameters of Hiller itself would have been used, not the 37° C value from Allen’s fed batch examples, and certainly not 37.5° C, a value not explicitly disclosed in any cited portion of Allen, but merely encompassed within a prophetic range cited in Allen.”
It is noted that Allen is silent with respect to any details regarding reactor design used to carry out the methods described other than a brief overview of known existing technologies which includes perfusion (See Allen [0062]). Hiller was recited to show the obviousness of utilizing a reactor allowing perfusion in the method of Allen because it allows for simple operation and increased productivity over non-perfused reactor designs. Allen specifically discloses that the methods therein improve production using such known devices. Thus one would be well appraised that one should carry out the method of Allen, i.e. controlling a temperature between 35 to 38, using known devices, i.e. perfusion reactors described by Hiller, to obtainer the increased production methods described by Allen.
Furthermore while Hiller gives 1 non-limiting example of running a reactor at 36.5 degrees in an experimental setup, one of ordinary skill in the art would clearly understand that such a reactor would not only be limited to running at such a specific temperature depending upon cells cultured and processes to be carried out using such a device.
Applicant finally argues that “again, the present application shows in Table 1 that superior results are obtained according to the methods of the claimed invention using an N-1 perfusion bioreactor run of 37.5°C than when it is run at 36.5° C, even as other parameters are varied. Nothing in the cited references can fairly be described as suggesting such a result.”
The examiner does not agree that applicant has shown specific evidence of superior results in Table 1. See for example a comparison of experiment 2 and 19. Experiment 2 which is run at 36.5 degrees produces a higher titer than experiment 19 run at 37.5 degrees. The table is replete with examples where superior results are obtained using temperatures which differ from 37.5.
Furthermore even assuming arguendo that the applicant has shown a general trend that 37.5 degrees may produce more than other temperatures a showing of “superior results” is not sufficient to overcome the examiner’s reasoned statement of obviousness.
Applicant has been repeatedly asked to show or demonstrate “unexpected results” not “superior results”. Since applicant has failed to demonstrate, or even argue, that “unexpected results” are provided at 37.5 degrees the rejections stand.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 JONATHAN M HURST whose telephone number is (571)270-7065. The examiner can normally be reached on M-F 7AM-4PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Marcheschi can be reached on 571-272-1374. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JONATHAN M HURST/ Primary Examiner, Art Unit 1799