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 .
Restriction/Election
Applicant’s election without traverse of the species SEQ ID NOs: 2 and 9, chaotropic agents and removing chaotropic agents to revert to active state is withdrawn because the prior art search covered the scope of the claimed species. As such, all claims are under examination and an Office action on the merits follows.
Claim Rejections 35 USC 112(B)
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.
Regarding claim 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections 35 USC 102(A)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-9 and 11-28 are rejected under 35 U.S.C. 102(A) as being anticipated by Wood et al. (US2020/0024370).
Wood teaches a method for selective protein purification using a stable, transformative intein system wherein the system comprises a split intein consisting of two separate peptides: an N-terminal intein segment and a C-terminal intein segment (i.e., cognate binding partner), wherein the N-terminal intein segment can be linked to a solid support, and wherein cleaving of the C-terminal intein segment is suppressed in the absence of the N-terminal intein segment, and wherein the assembled N-terminal and C-terminal intein segment complex is highly sensitive to extrinsic conditions when compared to a native intein complex [0008, 0010]. This reference teaches the steps of exposing the N-terminal intein segment and the C-terminal intein segment (cognate binding partner) to each other so that they associate on the solid support, washing the solid support to remove non-bound contaminating material, placing the associated the N-terminal intein segment and the C-terminal intein segment under conditions that allow for the intein to self-cleave (disrupt) and isolating the protein of interest [0010]. This reference further teaches that the solid support can be a solid chromatographic resin backbone, such as a crosslinked agarose and that “solid support matrix” or “solid matrix” refers to the solid backbone material of the resin which material contains reactive functionality permitting the covalent attachment of ligand (such as N-terminal intein segments) thereto and that the correct folding and the native protein structure was retained after intein purification [0109-0111, 0171]. .
Wood teaches that the N-terminal intein segment can be been modified from a native intein (including Npu DnaE), so that the N-terminal intein segment does not comprise any internal cysteine residues to eliminate side reactions associated with immobilization of the NpuN intein segment onto a solid support using the scheme shown in FIG. 7 [0103]. This reference also teaches an N-terminal intein segment in which one or more of the native cysteine residues have been mutated to serine [0103]. An example of NpuN in which the cysteine residues have been mutated can be found in SEQ ID NO: 2 (identical to instantly claimed SEQ ID NO: 2) [0103].
This meets the limitations of claim 1 by teaching an N-intein forming a complex with a cognate binding partner (C-intein) to form a complex on a solid support for purification. Although the reference does not explicitly state that the method is for stabilizing the N-intein, the same exact method steps are taught by the prior art. Claim 2 is met because Wood teaches that the N-intein and C-intein are cleaved (disrupted) and the N-intein is covalently immobilizing on the resin and retained native protein folding and structure, as discussed above. Claim 3 is met because C-intein is on the C-terminus. Claims 4 and 5 are met because Wood teaches that the Npu DnaE full protein or NpucHN tagged target protein is constructed in a cell from a plasmid for mammalian expression [0173-0185]. Claim 6 is met because Npu DnaE is split into two, or in trans. Claims 7-9 are met because Wood teaches covalent immobilization of the N-intein to a resin chromatographic backbone [0099; claim 9]. Claim 12 is met because this reference teaches that the N-terminal intein segment and the C-terminal intein segment become separate molecules that can non-covalently reassociate, or reconstitute, into an intein that is functional for splicing or cleaving reactions, which means it can revert back to accepting a new binding partner. Claims 14-16 are met because Wood teaches that the split intein is an Npu DnaE intein. Claim 17 is met because the N-intein comprises a purification tag on the N-segment [0103-0104]. Claim 18 is met because Wood teaches that the N-terminal intein segment is been modified so as not to comprise any internal cysteine residues, and that at least one of the internal cysteine residues has been mutated to serine [Claims 4-5]. Claim 20 is met because Wood teaches that the purification tag comprises histidine [claim 7]. Claims 21-23 are met because Wood teaches that the N-terminal intein segment comprises one or more amino acids at its C-terminus which allow for covalent immobilization of the N-terminal intein segment to a solid support, wherein cleaving of the C-terminal intein segment is more sensitive to extrinsic conditions when compared to a native intein, and wherein the amino acids may be cysteine [claims 1 and 8]. Claims 24-26 are met because this reference teaches that the N-terminal intein segment further comprises a sensitivity-enhancing motif, which renders it more sensitive to extrinsic conditions, wherein the sensitivity-enhancing motif is on the N-terminus of the N-terminal intein segment, and wherein the extrinsic condition is pH, temperature, or both [claims 10-12].
As to claims 11 and 13, the claim states that the chaotropic agent “can” be used to create conditions that disrupt association, and claim 13 includes the indefinite term “such as” before the listed guanidine hydrochloride, which does not require the option in the claim. As such, the use of a chaotropic agent to disrupt the association between the inteins is inherent and not a required step in the claimed method because the same exact N-intein and cognate binding partner are taught, with the same other parameters, so it would be expected to have the same disrupting reaction to a chaotropic agent. Furthermore, acidic or basic solutions with disport the N-intein and cognate binding partner because the reference teaches that disruption is pH dependent.
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.
Claim(s) 1-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wood in view of Ohman et al. (US2019/0263856).
The teachings of Wood have been described supra.
The difference between the prior art and the instant claims is that the prior art does not teach the ligand density is greater than 10mg N-intein ligand/ml resin volume.
Ohman teaches chromatography resin with immobilized, covalently attached N-terminal intein fragments, which provides higher ligand densities and enables multiple re -use even after harsh cleaning procedures [0007]. Specifically, this reference teaches the ligand density on said chromatography resin is 2-10 mg ligand / ml resin, , most preferably >5 mg ligand /ml resin [0012]. For Npu N-Inteins, SEQ ID NOs: 1-5 (at least 95%identical to NpuN) have been covalently attached to the resin in a ligand density of 2-10mg/ml for the same purpose of purifying target proteins [0017].
It would have been obvious to one of ordinary skill in the art at the effective filing date of the invention to have optimized the N-intein density at above 10mg/ml resin because Ohman teaches a similar range and preferences for the higher end. One would be motivated to use the method of Wood with the range of Ohman because Ohman teaches that this is an effective for the Npu N-intein density on resin. Furthermore, the MPEP states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
As such, there is a reasonable expectation of success that the N-inteins of Wood can be effectively optimized and used at above 10mg ligand/ml resin density on a solid support.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9 and 11-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,669,351.
The claims of ‘351 are as follows:
1. A split intein comprising two separate peptides: an N-terminal intein segment and a C-terminal intein segment, wherein the N-terminal intein segment comprises one or more amino acids at its C-terminus which allow for covalent immobilization of the N-terminal intein segment to a solid support, and wherein cleaving of the C-terminal intein segment is more sensitive to extrinsic conditions when compared to a native intein.
2. The split intein of claim 1, wherein the split intein has been derived from a native intein.
3. The split intein of claim 2, wherein the intein is derived from an Npu DnaE intein.
4. The split intein of claim 2, wherein the N-terminal intein segment has been modified so as not to comprise any internal cysteine residues.
5. The split intein of claim 4, wherein at least one of the internal cysteine residues have been mutated to serine residues.
6. The split intein of claim 1, wherein a purification tag is attached to the N-terminal intein segment at its C-terminus.
7. The split intein of claim 6, wherein the purification tag comprises one or more histidine residues.
8. The split intein of claim 1, wherein the one or more amino acids at the C-terminus are cysteine residues.
9. The split intein of claim 1, wherein the N-terminal intein segment is immobilized on a solid chromatographic resin backbone.
10. The split intein of claim 1, wherein the N-terminal intein segment further comprises a sensitivity-enhancing motif, which renders it more sensitive to extrinsic conditions.
11. The split intein of claim 10, wherein the sensitivity-enhancing motif is on the N-terminus of the N-terminal intein segment.
12. The split intein of claim 10, wherein the extrinsic condition is pH, temperature, or both.
13. The split intein of claim 1, wherein the N-terminal intein segment comprises SEQ ID NO: 2.
14. The split intein of claim 1, wherein the N-terminal intein segment comprises SEQ ID NO: 3.
15. The split intein of claim 1, wherein the N-terminal intein segment comprises SEQ ID NO: 4.
16. The split intein of claim 1, wherein the N-terminal intein segment comprises SEQ ID NO: 5.
17. The split intein of claim 1, wherein the N-terminal intein segment comprises SEQ ID NO: 6.
18. The split intein of claim 1, wherein the C-terminal intein segment comprises SEQ ID NO: 9.
19. The split intein of claim 10, wherein the sensitivity enhancing motif comprises one or more amino acids that render an intein cleaving reaction more sensitive to pH.
20. The split intein of claim 10, wherein the sensitivity enhancing motif allows for slower or faster cleaving of the C-terminal intein segment under specific conditions compared to a split intein with no sensitivity enhancing motif.
21. The split intein of claim 10, wherein the specific conditions are pH and/or temperature.
Because the above applied art US2020/0024370 was the same application as the ‘351 patent and the specifications have the same teachings, the claims of ‘351 drawn to the same split inteins and sequences in view of the specification render obvious instant claims 1-28 for the same reasons as stated above.
Claims 1-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,669,351 in view of Ohman et al. (US2019/0263856).
The teachings of ‘351 have been described supra.
The difference between the ‘351 and the instant claims is that the prior art does not teach the ligand density is greater than 10mg N-intein ligand/ml resin volume.
Ohman teaches chromatography resin with immobilized, covalently attached N-terminal intein fragments, which provides higher ligand densities and enables multiple re -use even after harsh cleaning procedures [0007]. Specifically, this reference teaches the ligand density on said chromatography resin is 2-10 mg ligand / ml resin, , most preferably >5 mg ligand /ml resin [0012]. For Npu N-Inteins, SEQ ID NOs: 1-5 (at least 95%identical to NpuN) have been covalently attached to the resin in a ligand density of 2-10mg/ml for the same purpose of purifying target proteins [0017].
It would have been obvious to one of ordinary skill in the art at the effective filing date of the invention to have optimized the N-intein density at above 10mg/ml resin because Ohman teaches a similar range and preferences for the higher end. One would be motivated to use the method of ‘351 with the range of Ohman because Ohman teaches that this is an effective for the Npu N-intein density on resin. Furthermore, the MPEP states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
As such, there is a reasonable expectation of success that the N-inteins of Wood can be effectively optimized for protein purification at above 10mg ligand/ml resin density on a solid support.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANETTE M LIEB whose telephone number is (571)270-3490. The examiner can normally be reached M-F 10-7.
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654
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