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 10/27/2025 has been entered. Claims 1-11 and 13-18 are pending in this US patent application. Applicant’s election without traverse of species: claim 2 for type A; claim 5 for type B; claim 7 for type C and claim 15 for type D in the reply filed on 7/25/2022 is acknowledged. Claims 3-4, 6, 8 and 16-18 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-2, 5, 7, 9-11, and 13-15 are currently under examination and were examined on their merits.
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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 negatived by the manner in which the invention was made.
Claims 1-2, 7, 9-11, and 13-15 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Buntru et al., Biotechnol. Bioeng. 112: 867-878 (2015; cited on the IDS filed 03/17/2020), in view of Yao et al., J. Ferment. Bioeng. 84(1): 7-13 (1997).
Buntru teaches a method for synthesis of a protein (see entire document, including page 867, title and abstract). For claims 1-2 and 7: the reference teaches a method comprising introducing into an aqueous tobacco plant cellular lysate comprising evacuolated mitochondria/protoplasts: an aqueous mitochondria from tobacco plant lysate (page 868, left column, 4th full paragraph++, claim 2); an exogenous nucleic acid template encoding a polypeptide: plasmid eYFP DNA template (page 869, left column, 1st full paragraph++, claim 7) and nucleotide triphosphates: ATP, GTP (page 869, left column, 1st full paragraph, line 5++), 15 mM creatine phosphate (page 871, Table I, 4th row) and 50 µg/ml creatine kinase (page 870, right column, 2nd paragraph, line 7++) and synthesizing the polypeptide in a batch reaction for 18 h (page 869, left column, 1st full paragraph, line 2++). For claim 11: the reference teaches isolating the polypeptide from the synthesis reaction volume by gel analysis (page 872, Fig. 3C). For claim 15: the reference teaches synthesizing more than 250 µg/mL of encoded polypeptide/eYFP (page 872, Fig. 3B).
Buntru teaches 15 mM creatine phosphate (page 871, Table I, row 4) and 50 µg/ml creatine kinase (page 870, right column, 2nd paragraph, line 7++; cf. claims 1 and 9-10) in the translation mix and the reaction carried out for 18 hours (page 869, left column, 1st full paragraph, line 2++; cf. claims 12-14).
Buntru does not explicitly teach less than 15 mM creatine phosphate and less than 50 µg/ml creatine kinase and synthesizing for more than 20 hours as recited in claim 1, less than 10 mM or no creatine phosphate to the reaction as recited in claims 9-10, or synthesizing polypeptide for more than 20/40 hours as recited in claims 12-14.
Yao teaches cell free protein synthesis with reaction mixtures containing, among other ingredients, 40 µg/mL creatine kinase and 8 mM creatine phosphate (see entire document, including page 6, left column, paragraph 6; cf. claim 1). The synthesis time could be extended by replenishing the energy charge in the reaction mixture (page 11, right column, paragraph 1, to page 12, left column, paragraph 1).
While Buntru does not teach the concentrations of creatine phosphate and creatine kinase recited in instant claims 1 and 9-10, it would have been obvious to one of ordinary skill in the art to lower the concentrations recited in Buntru because Yao teaches that cell free protein synthesis can be achieved with reaction mixtures containing 40 µg/mL creatine kinase and 8 mM creatine phosphate. One of ordinary skill in the art would have a reasonable expectation that using the amounts of reagents taught by Yao in Buntru’s method of cell-free protein synthesis using tobacco cell lysates would successfully result in cell-free protein synthesis.
While Buntru and Yao do not teach the lengths of synthesis time recited in instant claims 1 and 13-14, the recited reaction times 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 times to perform the protein synthesis reaction because the length of time that a synthesis reaction is run is an art-recognized, result-effective variable known to affect the amount of protein produced by the reaction, which would have been optimized in the art to provide the desired yield. The Examiner notes that, as discussed above, Yao teaches a method for extending the synthesis time for cell-free systems by replenishing the energy charge.
Therefore, claims 1-2, 7, 9-11, and 13-15 are rendered obvious by Buntru in view of Yao and are rejected under 35 U.S.C. 103.
Claims 1-2, 5, 7, 9-11, and 13-15 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Buntru et al., Biotechnol. Bioeng. 112: 867-878 (2015; cited on the IDS filed 03/17/2020), in view of Yao et al., J. Ferment. Bioeng. 84(1): 7-13 (1997), and Poyton et al., Proc. Nat’l. Acad. Sci. USA 72(1): 172-176 (1975).
As discussed above, claims 1-2, 7, 9-11, and 13-15 are rendered obvious by Buntru in view of Yao. However, these references do not teach that the synthesis reaction volume further comprises chloramphenicol as recited in claim 5.
Poyton teaches polypeptide synthesis using mitochondria in the presence of chloramphenicol (see entire document, including page 173, Table 1, and the coordination of biosynthesis of mitochondrial protein and cytoplasmic protein, page 175, right column, 2nd full paragraph, line 3++; cf. claim 5) to inhibit mitochondrial protein synthesis, wherein no creatine phosphate is added to the reaction mix (page 173, left column, 5th full paragraph++, for claim 10).
While Buntru and Yao do not teach adding chloramphenicol to the reaction mixture containing a tobacco cell lysate with mitochondria for cell-free protein synthesis rendered obvious by their teachings, it would have been obvious to one of ordinary skill in the art to do so because Poyton teaches that chloramphenicol reduces the synthesis of mitochondrial proteins. One of ordinary skill in the art would have had a reasonable expectation that including the chloramphenicol of Poyton in the reaction mixture rendered obvious by Buntru and Yao would successfully result in higher yields of the desired protein because of reduced mitochondrial protein synthesis.
Therefore, claims 1-2, 5, 7, 9-11, and 13-15 are rendered obvious by Buntru in view of Yao and Poyton 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 above rejection of the claims under 35 U.S.C. 103 as being unpatentable over Buntru in view of Yao. Applicant states that Buntru teaches synthesis for only 18 hours, in contrast to the range of “more than 20 hours” recited in instant claim 1, and Yao teaches synthesis for 30-60 minutes, which Applicant asserts teaches away from the claimed invention (remarks, pages 5-7). This argument has been fully considered but has not been found persuasive.
As discussed above and in the previous Office action, 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 times to perform the protein synthesis reaction because the length of time that a synthesis reaction is run is an art-recognized, result-effective variable known to affect the amount of protein produced by the reaction, which would have been optimized in the art to provide the desired yield. The Examiner notes that, as discussed above and in the previous Office action, Yao teaches a method for extending the synthesis time for cell-free systems by replenishing the energy charge. As such, Yao’s teaching of a shorter synthesis time cannot in any way be interpreted as a teaching away from the claimed invention.
Applicant states that Buntru teaches an optimization method that does not suggest less than 15 mM creatine phosphate and less than 50 µg/mL creatine kinase as instantly recited (remarks, page 7). This argument has been fully considered but has not been found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the above-presented rejection is predicated not on Buntru alone but, rather, on the combination of Buntru with Yao, which teaches 40 µg/mL creatine kinase and 8 mM creatine phosphate, concentrations that fall within the instantly recited ranges.
Applicant states that, using Yao’s method, at least 20 separate reaction volumes would allegedly be required to achieve more than 20 hours of synthesis, which Applicant asserts would prevent a person of ordinary skill in the art from having a reasonable expectation of success in achieving more than 20 hours of synthesis (remarks, page 8). This argument has been fully considered but has not been found persuasive because Applicant provides no explanation or evidence as to why this process, which falls within the scope of the instant claims as it is not a “continuous flow reaction system,” would be inoperative.
Applicant states that the magnitude of improvement provided by the claimed method is surprising and unexpected. Applicant states that Example 2 of the specification discloses a direct comparison of polypeptide synthesis using either 30 mM creatine phosphate or 0 mM creatine phosphate. Applicant states that the polypeptide synthesis time doubled to 40 hours with no CP and that yield amounts improved by as much as 60%, which Applicant states would be a surprising improvement that contradicts the allegation of prima facie obviousness (remarks, pages 8-9). This argument has been fully considered but has not been found persuasive.
The Examiner first notes that the experiment in question only tests 30 mM CP/100 µg/mL CK and 0 mM CP/0 µg/mL CK. Applicant does not demonstrate any results from other concentrations of CP or CK that fall within the CP and CK concentration ranges recited in the instant claims. As such, the results in question are not commensurate in scope with any of the instant claims and, accordingly, cannot be used to overcome a finding of prima facie obviousness. See MPEP § 716.02(d). The Examiner further notes that it would not be surprising to one of ordinary skill in the art that the yield is increased when the polypeptide synthesis reaction is performed for a longer time. As such, the Examiner does not agree with Applicant’s assertion that the results in Example 2 of the instant specification represent surprising and unexpected results that overcome the Examiner’s finding of prima facie obviousness. Finally, the Examiner notes that, as shown by the teachings of Yao cited above, the ability to extend the synthesis time by replenishing the energy charge in a batchwise manner would be within the level of ordinary skill in the art. As such, it would not be unexpected to one of ordinary skill in the art that synthesizing the protein for a longer period of time with energy replenishment would result in improved yields and longer reaction times.
Therefore, the Examiner has maintained the rejections presented above.
Conclusion
No claims are 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 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 02/19/2026