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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/6/25 has been entered.
Claims 13, 16-20, 23, and 35-47 are pending and under examination.
Maintained Rejection
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim(s) 13, 16-20, 23, and 35-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO 2017106795 A1, published June 22, 2017) in view of Laux et al. (WO 2015/166427 A2, published November 5, 2015).
The instant claims are drawn to an isolated interleukin 15 (IL-15)/interleukin 15 receptor alpha (IL-15Rα) heterodimer produced in a recombinant Chinese hamster ovary (CHO) cell, wherein the IL-15/IL-15Rα heterodimer comprises α(2,6) O-linked sialylation; wherein the IL-15 comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 1 or 5; wherein the IL-15Ra comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 6, 7, 10, 12, 14, or 21; and wherein CHO cell is altered to impair the function of matriptase.
Campbell et al. teach an isolated human IL-15/IL-15RA-P2A heterodimeric protein (See paragraph 0031, 0052, and 0055). Campbell et al. teach an expression plasmid encoding the human IL-15/IL-15RA-P2A heterodimeric protein comprising the amino acid sequence set forth in SEQ ID NO: 9. It should be noted that the amino acid sequence set forth in SEQ ID NO: 9 comprises an amino acid sequence having at least 100% sequence identity to SEQ ID NO: 1 and an amino acid sequence having at least 100% sequence identity to SEQ ID NO: 10, as recited in the instant claims. Campbell et al. teach expression plasmids comprising P2A operatively linked to the IL-15/IL-15RA heterodimer gene sequences to be expressed (See paragraph 0052 and 0055). Campbell et al. teach that clones of OMI2A-IL-15/IL-15R were transfected into HEK293 cells and supernatants comprising the expressed protein were collected from conditioned media and quantified (See paragraph 0097). Campbell et al. teach a method of treating a tumor in a subject, wherein the subject is human and the tumor is selected from the group of melanoma, and breast cancer comprising delivering the expression plasmids (See paragraph 0018). Campbell et al. teach that the plasmid was diluted in saline, which is interpreted as a pharmaceutically acceptable carrier (See paragraph 00120).
Campbell et al. do no teach wherein the IL-15/IL-15Ra heterodimer is produced in a Chinese hamster ovary (CHO) cell, wherein the heterodimer comprises α(2,6) O-linked sialylation, and wherein the CHO cell is altered to impair the function of matriptase.
However, Laux et al. teach a method for recombinantly producing a polypeptide of interest comprising transfecting CHO cells, in which the endogenous protease matriptase is impaired, with a polynucleotide encoding a polypeptide of interest (See claims 17-19 and paragraphs 7-8 and 41). Laux et al. teach that impairing the effect of matriptase in the vertebrate cell reduces clipping of the secreted recombinant polypeptide of interest compared to a corresponding vertebrate cell in which the effect of matriptase is not impaired (See paragraphs 8, 41, and 60). Laux et al. teach that altering the CHO cells to impair the effect of matriptase allows for significant improvement in the recombinant production of the polypeptide of interest, thereby increasing the yield of the intact polypeptide of interest (See paragraph 7). Laux et al. teach that using the CHO cell with impaired matriptase avoids the need to reengineer the polypeptide of interest to be expressed in order to eliminate proteolytic sites or to laboriously adapt production to reduce or prevent clipping or to design specific purification processes to remoted clipped protein (See paragraph 7). Laux et al. teach that the altered CHO cell can be used as a universal host cell for expressing different polypeptides of interest (See paragraph 7). Laux et al. teach that the polypeptide of interest is a cytokine (See paragraph 69). Laux et al. teach that the isolated and purified polypeptide of interest may be further processed and formulated into a composition, e.g., a pharmaceutical composition (See paragraph 0091).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing data of the claimed invention to produce the IL-15/IL15Ra heterodimer of Campbell et al. using the method of Laux et al. because KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a known technique has been used to improve a known product, and a person of ordinary skill would recognize that it would be used in similar products in the same way, using the technique is obvious unless its application is beyond that person’s skill. In the instant case, Campbell et al. contain a base product of an expression vector encoding an IL-15/IL-15Ra heterodimer; and Laux et al. teach a similar product of an expression vector encoding a polypeptide of interest, wherein the technique of using a CHO cell with impaired matriptase for recombinantly producing the polypeptide of interest is taught as advantageous. Specifically, Laux et al. teach that the method advantageously reduces clipping of the secreted recombinant polypeptide of interest and increases yield of the polypeptide of interest. One of ordinary skill in the art would have recognized that applying the known technique of Laux et al. to prepare the isolated IL-15/IL-15Ra heterodimer of Campbell et al. would have yielded the predictable result of a recombinantly produced IL-15/IL-15Ra heterodimer and a CHO cell comprising an expression plasmid encoding a human IL-15/IL-15Ra heterodimer, and provided the advantage reduced clipping of the heterodimer, and thus, increased the yield of the heterodimer. One of ordinary skill in the art would have a reasonable expectation of success because Laux et al. teach that the altered CHO cell can be used as a universal host cell for expressing different polypeptides of interest.
Regarding the limitation wherein the IL-15/IL-15Rα heterodimer comprises α(2,6) O-linked sialylation, the presence of α(2,6) O-linked sialylation is a result of producing the IL-15/IL-15Rα in CHO cells in which matriptase is impaired. Given that the combined teachings of Campbell et al. and Laux et al. teach producing the IL-15/IL-15Rα in CHO cells in which matriptase is impaired, the prior art IL-15/IL-15Rα heterodimer would necessarily comprise α(2,6) O-linked sialylation.
Regarding the limitations wherein the isolated IL-15/IL-15Ra heterodimer comprises the presence of O-linked glycans, and wherein at least 80% of the glycans are core-10-linked glycans; wherein the isolated IL-15/IL-15Ra heterodimer comprises O-linked glycans, and wherein at least 80% of the glycans are core-10-linked glycans; wherein about 15% of the O-glycans have a(2,6) O-linked sialylation; wherein the isolated IL-15/IL-15Ra heterodimer comprises O-linked glycans, and wherein at least 85% of the glycans are core-10-linked glycans; wherein the isolated IL-15/IL-15Ra heterodimer comprises O-linked glycans, and wherein at least 90% of the glycans are core-10-linked glycans; wherein the isolated IL-15/IL-15Ra heterodimer comprises O-linked glycans, and wherein at least 90% of the glycans are core-10-linked glycans; wherein the isolated IL-15/IL-15Ra heterodimer comprises O-linked glycans, and wherein at least 95% of the glycans are core-10-linked glycans; wherein the heterodimer comprises O-linked glycans, and wherein at least 80% of the glycans are core-10-linked glycans; wherein about 15% of the O-glycans have a(2,6) O-linked sialylation; wherein the heterodimer comprises O-linked glycans, and wherein at least 85% of the glycans are core-10-linked glycans; wherein the heterodimer comprises O-linked glycans, and wherein at least 90% of the glycans are core-10-linked glycans, the presence of α(2,6) O-linked sialylation, O-linked glycans, and the percent of glycans that are core-1 O-linked glycans is a result of producing the IL-15/IL-15Rα in CHO cells in which matriptase is impaired. Given that the combined teachings of Campbell et al. and Laux et al. teach producing the IL-15/IL-15Rα in CHO cells in which matriptase is impaired, the prior art IL-15/IL-15Rα heterodimer would necessarily comprise α(2,6) O-linked sialylation, the O-linked glycans, and the percent of glycans that are core-1 O-linked glycans recited in the instant claims.
uery Match 99.1%; Score 1719.4; Length 455;
Best Local Similarity 85.6%;
Matches 332; Conservative 0; Mismatches 0; Indels 56; Gaps 1;
Qy 1 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI 60
Qy 61 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 120
Qy 121 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS------------------ 162
||||||||||||||||||||||||||||||||||||||||||
Db 121 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSAAAGSGATNFSLLKQAGD 180
Qy 163 --------------------------------------ITCPPPMSVEHADIWVKSYSLY 184
||||||||||||||||||||||
Db 181 VEENPGPGSAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLY 240
Qy 185 SRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTT 244
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTT 300
Qy 245 AGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSH 304
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSH 360
Qy 305 GTPSQTTAKNWELTASASHQPPGVYPQG 332
||||||||||||||||||||||||||||
Db 361 GTPSQTTAKNWELTASASHQPPGVYPQG 388
Applicant’s Arguments
Applicant argues that a skilled artisan would not have been motivated to combine the cited references. Applicant argue disagrees with the examiners motivation for combining the rejection. Applicant argues that the presently claimed subject matter relates, in part, to hetIL-15 heterodimers produced in CHO cells and comprising o(2,6) O-linked sialylation. Laux, in contrast, describes impairment of matriptase specifically for the purpose of decreasing proteolytic degradation (clipping) of secreted polypeptides, which Laux utilizes to improve yield of the intact polypeptide. Meanwhile, Campbell relates to isolated human IL-15/IL-15RA-P2A heterodimeric proteins and successful production thereof in HEK293 cells. Nowhere does Campbell provide any teaching or suggestion that the HEK293 cell-based production methods disclosed therein were insufficient to produce the IL-15/IL-15RA-P2A heterodimeric proteins or required improvement in yield. Nor does Campbell teach or suggest that any undesirable clipping of the IL-15/IL-15RA-P2A proteins occurs that might lead the skilled artisan to believe that the methods of Campbell would benefit from the method of Laux. Indeed, Campbell appears to make no mention of proteases, proteolysis, or clipping at all. As such, a person of ordinary skill in the art would have no reason to apply the method of Laux to the already-successful production of IL-15/IL-15RA-P2A proteins described in Campbell. The skilled artisan would accordingly lack motivation to combine these references for at least this reason as well.
Applicant argues that the combination of references do not solve the same technical problem of producing IL-15/IL-15Rα complexes with the unique glycosylation profile recited in the pending claims. Applicant argues that there is no reasonable expectation of success in producing IL-15/IL-15Rα complexes with the unique glycosylation profile recited in the pending claims. Applicant argues that Laux describes deglycosylation of proteins produced according to the method of Laux.
Response to Arguments
Applicant’s arguments have been fully considered but they are not 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, it is the combination of Campbell and Laux that make the instant claims obvious. The references were not used in an anticipatory reference, and therefore, the arguments regarding the deficiencies of each reference alone, are unpersuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case Campbell et al. teach an isolated human IL-15/IL-15Rα heterodimeric protein have the claimed sequences. Campbell et al. do not teach that the complex is produced in CHO cells altered to impair the function of matriptase and having α(2,6) O-linked glycosylation. However, Laux et al. teach a CHO cell line having impaired matriptase for producing recombinant proteins. Laux et al. teach that the cell line advantageously reduces clipping of the secreted polypeptide and improves the recombinant production of the polypeptide of interest, thereby increasing the yield of the polypeptide. Therefore, it would have been obvious to produce the claimed human IL-15/IL-15Rα using the technique of Laux. Laux et al. teach that the method advantageously reduces clipping of the secreted recombinant polypeptide of interest and increases yield of the polypeptide of interest. One of ordinary skill in the art would have recognized that applying the known technique of Laux et al. to prepare the isolated IL-15/IL-15Ra heterodimer of Campbell et al. would have yielded the predictable result of a recombinantly produced IL-15/IL-15Ra heterodimer and a CHO cell comprising an expression plasmid encoding a human IL-15/IL-15Ra heterodimer, and provided the advantage reduced clipping of the heterodimer, and thus, increased the yield of the heterodimer.
Furthermore, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991)
In response to Applicant’s argument that there is no reasonable expectation of success, one of ordinary skill in the art would have a reasonable expectation of success because Laux et al. teach that the altered CHO cell can be used as a universal host cell for expressing different polypeptides of interest. Furthermore, it should be noted that the glycosylation of the claimed IL-15/IL-15R alpha complex necessarily flows from producing the complex in the CHO cells with impaired matriptase. Given that the combination of references teach producing the complex in the required cells, the resultant complex would have the same glycosylation pattern. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674