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 .
Claim Status
The amendment of 07/08/2026 has been entered. Claims 1-10, 12-18, and 21-44 are currently pending in this US patent application and were examined on their merits.
Withdrawn Rejections
All rejections of claim 11 set forth in the previous Office action are withdrawn in light of the amendment of 07/08/2026, which canceled claim 11.
The rejections of the claims under 35 U.S.C. 103 as being unpatentable over Reitmeir in view of Sun as set forth in the previous Office action are withdrawn in light of the amendment of 07/08/2026, which added multiple limitations to the instant claims. Applicant’s arguments that the previous rejection did not address the newly-added limitations have been found persuasive.
Information Disclosure Statement
The information disclosure statement filed in this application on 07/08/2026 has been received and considered.
Claim Interpretation
Multiple claims in the instant application recite optional limitations. Limitations that are not required in the instant claims will not be included in the broadest reasonable interpretation of the claims. See MPEP § 2111.04 (II).
Claim Rejections - 35 USC § 112
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 1-10, 12-18, and 21-44 are newly rejected as necessitated by amendment 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.
Independent claims 1 and 21 have been amended to recite a step of supplying an inducer as “a bolus induction/single-dose induction.” The phrasing of this limitation is unclear. Does the slash indicate the word “or,” or does the slash indicate that a bolus induction and a single-dose induction are equivalent? As such, one of ordinary skill in the art would be unable to determine the metes and bounds of claims 1 and 21, rendering them indefinite.
Because claims 2-10 and 12-18 depend from claim 1 and claims 22-44 depend from claim 21, and because these dependent claims do not further clarify the indefinite language in the claims from which they depend, these claims are also indefinite. Therefore, claims 1-10, 12-18, and 21-44 are rejected under 35 U.S.C. 112(b).
In the interest of compact prosecution, the Examiner has interpreted the limitation “a bolus induction/single-dose induction” to indicate that the induction occurs either as a bolus or as a single dose.
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.
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 1-7, 10, 13-18, 21-32, and 38-44 are newly rejected as necessitated by amendment under 35 U.S.C. 103 as being unpatentable over US patent application publication 2014/0170702 filed by Reitmeir et al., published 06/19/2014, in view of US patent application publication 2008/0026425 filed by Sun et al., published 01/31/2008, and US patent application publication 2009/0269306 filed by Wu et al., published 10/29/2009.
Reitmeir teaches the production of recombinant proteins in E. coli in inclusion bodies (see entire document, including page 1, paragraphs 0002-0003). The recombinant protein may be interferon α2B (page 4, paragraph 0036; cf. claims 1, 21, and 40-44). In particular embodiments, the cells were grown in a shake flask to produce an inoculum, and then 30 mL of the inoculum was seeded into a 3-L volume in a bioreactor in fed-batch mode at pH 6.8 (maintained by ammonia), 37°C, and a dissolved oxygen level stabilized above 20% by stirrer speed (page 12, paragraphs 0118-0119; cf. claims 1, 21 [“…carrying out seeding (time S0) of a culture of prokaryote host cell engineered to inducibly express a recombinant protein and transferring the culture into one or more fermenters each containing a culture medium; measuring a dissolved oxygen (DO) level, an agitation rate, and a pH in the one or more fermenters”], and 10). The fed-batch process with a substrate feed was used to provide a constant growth rate for 8.5 hours, after which the recombinant protein expression was induced (page 12, paragraphs 0119-0120). Following culture, the cells and the expressed inclusion bodies containing the recombinant protein were isolated (pages 12-13, paragraphs 0122-0130; cf. claims 13-15).
However, Reitmeir does not teach the specific feed conditions of claims 1-4 and 21-26 or the inclusion of a nitrogen source in the feed medium. Reitmeir also does not teach that the interferon α2B is Pro-IFN-α2B as recited in instant claims 1 and 21.
Sun teaches fed-batch fermentation methods that provide improved protein expression in bacterial systems (see entire document, including page 1, paragraph 0002). The bacterial system may be E. coli (page 4, paragraph 0051). An inducer is continuously fed to the culture once the culture achieves a threshold parameter, and the carbon source, which may be glucose and may include additional carbon sources, may be fed along with the inducer (page 3, paragraphs 0041 and 0046; cf. claim 5; cf. claims 1 and 21 [“supplying an inducer at…time at initiation of induction…as a…single-dose induction…a total of two or more carbon source feeding solution”]; the Examiner notes that the continuous addition of the inducer can be interpreted as one single dose added slowly; the Examiner further notes that the claims do not preclude additional doses of inducer being provided to the culture at any point). The carbon source may be fed to the culture at a rate of 24 g/L/hr (page 7, paragraph 0082; cf. claim 6 and 27-32). The threshold parameter that instigates the addition of the carbon source may be dissolved oxygen or pH (page 7, paragraph 0078). Whenever the dissolved oxygen rises above 30% in the culture, the feed controller for the carbon source/inducer may be turned on, and the dissolved oxygen level may be controlled by adjusting the agitation rate (page 8, paragraph 0091; cf. claims 1-2 and 21-26). Whenever the pH rises above 7.0, the carbon source/inducer feed controller may be turned on (page 8, paragraph 0092; cf. claims 1, 3, and 21-26). The feed medium may also contain nitrogen and potassium supplements (page 8, paragraph 0087; cf. claims 1, 4-5, 7, and 21-26). The culture may be harvested at any suitable time, such as 2-10 hours from induction (page 8, paragraph 0093; cf. claims 1, 4, 15, and 21; the Examiner notes that a 10-hour continuous feed of inducer/carbon source medium containing nitrogen supplements, as is within the scope contemplated by Sun, would intrinsically include feeding at the particular time points referenced in claims 1, 4, 15, and 22-26). The yield of the recombinant protein produced by the fermentation process is determined and is at least about 1.5 g/L based on the total volume of the culture (page 9, paragraph 0098; cf. claims 16-18; the Examiner notes that the “other fermentation method” as recited in claims 16-17 is not defined in any way and so is sufficiently broad to encompass any fermentation method). In particular embodiments, the agitation rate can range from 150-1000 rpm (page 10, paragraph 0108; cf. claims 1-3).
The terms “feed”, “fed”, “feeding” or “continuously adding”, as used interchangeably by Sun, refer to adding a substance continuously over a period of time rather than all at once. The terms contemplate a single initiation and/or termination or multiple start and/or stop points for continuously adding the substance during a fermentation process (paragraph 0039, emphasis added; cf. claims 1 and 21 [“…wherein the method to increase recombinant protein production in a prokaryote host cell is carried out in a fed-batch method”]). According to various embodiments, once a threshold parameter has been achieved, the feed on the carbon source may be continued, stopped or temporarily interrupted. The feed of the carbon source may be interrupted in which case the feed will re-start at the constant rate once a threshold for starting the feed has been achieved. Thus, according to an embodiment, a start threshold and a stop threshold may be used to regulate the feed of the carbon source into the culture (paragraph 0083). Sun does not teach removing culture medium during the fermentation process, and so one of ordinary skill in the art would understand Sun’s teachings to intrinsically incorporate the increase of the working volume in the fermenter based on the multiple additions of medium that Sun teaches (cf. claims 1 and 21).
Wu teaches that including a proline residue on the N-terminus of interferon α2B (Pro-IFN-α2B) decreases the formation of non-natural disulfide bonds in the protein (see entire document, including paragraphs 0015-0017; cf. claims 1 and 21). Pro-IFN-α2B was produced in a pET-24a vector transfected into E. coli (paragraph 0024; cf. claims 1 and 21; the Examiner notes that the pET-24a vector intrinsically contains a T7 promoter).
While Reitmeir does not teach the fed-batch protocol of Sun in the method of expressing recombinant interferon α2B in E. coli through fed-batch fermentation, it would have been obvious to one of ordinary skill in the art to use the fed-batch method of Sun because Sun teaches that their fed-batch methods improve the expression of recombinant proteins in bacterial systems, including E. coli. While Reitmeir and Sun do not teach that the recombinant interferon α2B produced in E. coli rendered obvious by their teachings is Pro-IFN-α2B, it would have been obvious to one of ordinary skill in the art to have the interferon α2B of Reitmeir be a Pro-IFN-α2B produced in a pET-24a vector because Wu teaches that including a proline at the N-terminus of interferon α2B reduces the formation of non-natural disulfide bonds and that such a protein may be produced in E. coli by inclusion in a pET-24a vector. One of ordinary skill in the art would have a reasonable expectation that using the fed-batch methods of Sun as the fed-batch protocol for producing recombinant interferon in E. coli of Reitmeir with the proline residue of Wu would successfully result in the production of inclusion bodies containing recombinant interferons that have fewer non-natural disulfide bonds.
Reitmeir, Sun, and Wu do not teach the specific amounts of glucose or inoculum recited in instant claims 6, 10, 27-32, and 38-39. However, the instantly recited values would be within the realm of routine experimentation. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 part II A. It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal concentrations of glucose and bacterial cells to add to the fermenter because the amount of carbon source and cells used to inoculate are art-recognized, result-effective variables known to affect the yield of the recombinant protein produced by the cells, which would have been optimized in the art to provide the desired protein yield.
Therefore, claims 1-7, 10, 13-18, 21-32, and 38-44 are rendered obvious by Reitmeir in view of Sun and are rejected under 35 U.S.C. 103.
Claims 1-10, 13-18, and 21-44 are newly rejected as necessitated by amendment under 35 U.S.C. 103 as being unpatentable over US patent application publication 2014/0170702 filed by Reitmeir et al., published 06/19/2014, in view of US patent application publication 2008/0026425 filed by Sun et al., published 01/31/2008, US patent application publication 2009/0269306 filed by Wu et al., published 10/29/2009, and Zhong et al., Catalysts 11: 269 (2021).
As discussed above, claims 1-7, 10, 13-18, 21-32, and 38-44 are rendered obvious by Reitmeir in view of Sun and Wu. However, these references do not teach that the nitrogen source included within the feed medium is yeast extract.
Zhong teaches that yeast extract is an appropriate nitrogen source for the expression of recombinant proteins in E. coli using fed-batch fermentation (see entire document, including page 3, paragraph 2, through page 4, paragraph 1; cf. claims 8-9 and 33-37).
While Reitmeir, Sun, and Wu do not teach that the nitrogen source in the feed medium in the method of producing inclusion bodies containing recombinant Pro-IFN-α2B through fed-batch fermentation of E. coli rendered obvious by their teachings is yeast extract, it would have been obvious to one of ordinary skill in the art to use yeast extract as the nitrogen source in the fermentation because Reitmeir and Sun teach that a nitrogen source can be included in the feed medium and because Zhong teaches that yeast extract is a suitable nitrogen source for use in fed-batch fermentations of E. coli for the production of recombinant proteins. One of ordinary skill in the art would have a reasonable expectation that using the yeast extract of Zhong as the nitrogen source in the method rendered obvious by Reitmeir, Sun, and Wu would successfully result in the production of recombinant Pro-IFN-α2B by E. coli.
Reitmeir, Sun, Wu, and Zhong do not teach the addition of the particular amount of yeast extract solution recited in instant claims 9 and 33-37. However, the instantly recited amount would be within the realm of routine experimentation. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 part II A. It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal concentrations of yeast extract to add to the fermenter because the amount of nitrogen source, such as yeast extract, is an art-recognized, result-effective variable known to affect the yield of the recombinant protein produced by the cells, which would have been optimized in the art to provide the desired protein yield.
Therefore, claims 1-10, 13-18, and 21-44 are rendered obvious by Reitmeir in view of Sun and Zhong and are rejected under 35 U.S.C. 103.
Claims 1-7, 10, 12-18, 21-32, and 38-44 are newly rejected as necessitated by amendment under 35 U.S.C. 103 as being unpatentable over US patent application publication 2014/0170702 filed by Reitmeir et al., published 06/19/2014, in view of US patent application publication 2008/0026425 filed by Sun et al., published 01/31/2008, US patent application publication 2009/0269306 filed by Wu et al., published 10/29/2009, and Goffin et al., Genome Announc. 5: e00441-17 (2017).
As discussed above, claims 1-7, 10, 13-18, 21-32, and 38-44 are rendered obvious by Reitmeir in view of Sun and Wu. In addition, Reitmeir teaches that the E. coli strain used for recombinant protein production can be BL21 (DE3) (see, for example, page 12, paragraph 0109). However, Reitmeir and Sun do not teach the use of the particular E. coli strain recited in instant claim 12.
Goffin teaches that E. coli BLR(DE3) is a derivative of BL21(DE3) that helps stabilize plasmids containing repetitive sequences (see entire document, including page 1, paragraph 2; cf. claim 12).
While Reitmeir, Sun, and Wu do not teach the use of the particular E. coli strain recited in instant claim 12, it would have been obvious to one of ordinary skill in the art to use BLR(DE3) as the E. coli strain in the method of producing recombinant interferon through fed-batch fermentation rendered obvious by Reitmeir, Sun, and Wu because Goffin teaches that this strain is a derivative of the strain used in Reitmeir that helps to stabilize plasmids containing repetitive sequences. One of ordinary skill in the art would have a reasonable expectation that using the strain of Goffin to perform the expression rendered obvious by Reitmeir, Sun, and Wu would successfully result in the production of inclusion bodies containing recombinant Pro-IFN-α2B.
Therefore, claims 1-7, 10, 12-18, 21-32, and 38-44 are rendered obvious by Reitmeir in view of Sun, Wu, and Goffin and are rejected under 35 U.S.C. 103.
The Supreme Court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation…103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions……the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant has traversed the previous rejection of the claims under 35 U.S.C. 103 as being unpatentable over Reitmeir in view of Sun. Applicant states that Reitmeir and Sun teach a constant feeding of inducer, whereas Applicant states that the instant claims are drawn to a single addition of inducer. Applicant states that the fed-batch process recited instantly results in a greater yield that is both surprising and unexpected. Applicant states that the additional references cited by the Examiner do not cure the alleged deficiencies of Reitmeir and Sun (remarks, pages 10-24). These arguments have been fully considered but have not been found persuasive.
The Examiner notes that the portions of Sun that Applicant states “disparage” the fed-batch invention of the instant claims despite Sun’s consistent use of the term “fed-batch” to describe their fermentation process appear to rely on a misinterpretation of Sun’s use of the term “continuous” process. As noted above, Sun defines the term as follows: “The terms “feed”, “fed”, “feeding” or “continuously adding”…refer to adding a substance continuously over a period of time rather than all at once. The terms contemplate a single initiation and/or termination or multiple start and/or stop points for continuously adding the substance during a fermentation process” (paragraph 0039, emphasis added). Regarding the specific addition of the inducer, as discussed above, any addition of an inducer can be interpreted as a “single dose” of the inducer, and Applicant’s claims in no way preclude additional steps of providing doses of inducer to the culture. If Sun’s teachings incorporate multiple start and/or stop points for the addition of substances, which Sun explicitly states is incorporated within their use of the term “continuously adding,” then Sun’s use of the term “continuous” falls within the scope of what Applicant’s remarks refer to as “fed-batch” fermentation. Sun cannot be interpreted to disparage an invention that Sun clearly teaches. The Examiner notes that patents are prior art for all they contain, including alternative or nonpreferred embodiments. See MPEP § 2123. Additionally, Sun teaches that their fed-batch process results in unexpectedly high yields of protein as compared with batch fermentation processes (see, for example, paragraph 0041 of Sun), and so the Examiner does not agree with Applicant’s assertion that it would be unexpected to one of ordinary skill in the art that fed-batch fermentation would result in higher yields of protein.
Therefore, the Examiner has maintained the rejections presented above.
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 Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 08/26/2026
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