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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on October 24, 2025.
Currently, claims 4-5, 7-13, 15, 17, 22-23, and 25-34 are pending in the instant application. Claims 28-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Accordingly, claims 4-5, 7-13, 15, 17, 22-23, and 25-27 are under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
Claims 4-5, 7-13, 15, 17, 22-23, and 25-27 remain rejected under 35 U.S.C. 103 as being unpatentable over Camire et al. in view of Sun et al., Stafford et al., Jenny et al., and Sabatino et al. for the reasons as set forth in the Office action mailed on June 25, 2025 and for the reasons set forth below.
Applicant's arguments filed on October 24, 2025 have been fully considered but they are not persuasive. Applicant asserts that the claims are not obvious because the cited references in combination does not suggest the claimed nucleic acid molecule encoding the synthetic protein. Applicant did not elaborate on the assertions but instead pointed out and reiterated the §1.132 declaration filed on October 24, 2025. Since applicant’s entire argument is provided entirely by referring to the declaration, the examiner will address the declaration in addressing applicant’s argument.
The declaration under 37 CFR 1.132 filed on October 24, 2025 is insufficient to overcome the instant rejection for the following reasons:
The declarant states that it was “highly unpredictable” to select and use an appropriate linker that would provide the protein-encoding “performance” and “therapeutic efficacy” as there is “no evidence or suggestion in the prior art that a deleted B-domain in an FVa protein combined with a linker would be desirable for use.” See paragraphs 4-6. The declarant further points out that the proteins of the cited art in the instant rejection are not identical to and are structurally different from what is claimed in the instant case. In response, it is noted that the instantly claimed “furin cleavage motif” linker of RKRRKR (SEQ ID NO:49) that is placed between the heavy chain and the light chain of the FVa protein is not invented or created by the instant co-inventors. Rather, the RKRRKR linker claimed in the instant case had long been well-recognized and well-utilized in the relevant art for the very same purpose of linking two different chains of a coagulation factor protein and/or for producing an active form of a coagulation factor protein for years prior to the effective filing date sought in the instant application (April 26, 2018) as clearly evidenced by Stafford (priority date of June 25, 2009) and Sun (online publication date of May 5, 2017). Note that Stafford cites the “2004” reference in paragraph 0110 as following: “The vector may also contain the RKRRKR sequence described by Margaritis et al. that causes the Factor VII to be secreted in the active form, i.e., Factor VIIa.” (emphasis added). See also paragraph 0147 of Stafford disclosing “a wild type-mouse Factor VII with an RKRRKR sequence to cause the polypeptide to be secreted in the two-chain, active form (FVIIa)” (emphasis added). There is no teaching in Stafford or in Sun that the “RKRRKR” linker can only be used for linking two chains of FVII or for producing an active form of FVIIa to the extent that the RKRRKR linker cannot be used when making a construct for expressing an active form of FV (FVa). As such, the “highly unpredictable” nature of using the instantly claimed linker is not objectively, factually supported by the declarant’s statements. The declarant did not provide any objective, factual evidence supporting that one of ordinary skill in the art as of the effective filing date in the year of 2018 would have deemed using the claimed linker as being “highly unpredictable” because the protein of Stafford and Sun is different from the protein claimed in the instant application.
In fact, very interestingly, the teachings of Stafford and Sun pertaining to the appropriate use of the RKRRKR linker appear to be the work of the instant applicant, The University of North Carolina at Chapel Hill. Even more interestingly, it is found that the Sun reference is co-authored by the instant co-inventors of this application. As such, it is unclear to the examiner whether the declarant has attempted to criticize and dismiss on the record the very work of the applicant or declarant’s own work in actively selecting and using the RKRRKR linker for the purpose of linking two chains of a coagulation factor protein and/or for the purpose of producing an active form of a coagulation factor protein. It is bewildering as to how or why the teachings and the work of Stafford and Sun can possibly be deemed to be unsupportive of using the same linker, RKRRKR, claimed in the instant case for effectively producing an active form of the instantly claimed coagulation protein, especially in light of the examiner’s finding that the work of Stafford and Sun is the work of the instant applicant/co-inventors.
The declarant even goes further to assert that there is no evidence that the RKRRKR linker “will operate better relative to other linkers in the encoded protein as claimed.” In response, the examiner fails to understand the relevance of the existence of other linkers. The examiner also fails to understand why the RKRRKR should “operate better” compared to others in order to be included in the instant claimed nucleic acid molecule. There is no claim limitation requiring that SEQ ID NO:49 should “operate better relative to other linkers”.
The declarant states that it would have been “highly unpredictable” that the claimed structure “can treat hemophilia in a meaningful way, let alone completely correct a hemophiliac phenotype.” The declarant repeats again that it would have been “highly unpredictable” that the claimed elements in combination “would provide improved function” by pointing out “the complete phenotypic correction” described in the instant application. In response, applicant’s attention is directed to the fact that the rejected claims are not directed to treating hemophilia, nor do they require a “complete phenotypic correction”, which appears to mean the “improved function”. The rejected claims are merely directed to a product, a nucleic acid molecule. Hence, the examiner fails to understand the relevance of the alleged “highly unpredictable” nature pertaining to treating or completely curing hemophilia phenotype.
In paragraph 9, the declarant lists three prior art references, wherein no legible copy of each of the three references has been submitted for examiner’s consideration. Hence, the examiner will solely rely on the brief summary of each reference as provided in the declaration. The declarant states that Weldon teaches changes in furin cleavage linkers can cause cytotoxicity thus cannot predict “the desired therapeutic effects of furin cleavage mutations.” In response, it is noted that the instantly claimed linker, SEQ ID NO:49, was known and taught by Stafford and Sun and the claimed linker does not appear to comprise “mutations”. Furthermore, “therapeutic effects” are not claimed or required by the claimed nucleic acid molecule. Hence, the description of Weldon as provided by the declarant is far from teaching the repeatedly alleged “highly unpredictable” nature of using the claimed linker in producing an active form of coagulation factor. The declarant states that Liu teaches the 2A self-cleaving peptides have limited applications and Chng teaches that cleavage efficiency of 2A peptides should be evaluated for different proteins. In response, it is noted that the claimed nucleic acid molecule does not appear to require a 2A peptide. Hence, it is unclear from the brief summary of Liu and Chng as provided in the declaration whether the two references teach the declarant’s repeatedly “highly unpredictable” nature of using the claimed linker, RKRRKR (SEQ ID NO:49). Further, it appears that none of Weldon, Liu, and Chng criticizes the use of the RKRRKR linker taught by Stafford and Sun for linking the two chains and/or for producing an active form of a coagulation factor protein. Again, note that the examiner cannot verify the teachings of the three references as applicant did provide a legible copy of each reference for examiner’s consideration.
In paragraphs 10-11, the declarant asserts that the effects of the cleavage site were “not predictable” and “unclear” thus need to be tested for its performance for the claimed FVa, which “would result in complete phenotypic correction of hemophilia in mice.” In response, as already noted above, the rejected claims in the instant rejection are merely directed to a nucleic acid, not a method of curing hemophilia or providing a complete phenotypic correction of hemophilia. Hence, the features pertaining to the alleged unpredictable, unclear nature are irrelevant to the rejected claims. Most importantly, there is no objective, factual evidence in the declaration that supports the alleged “highly unpredictable” nature of using the art-recognized RKRRKR linker for producing an activated form of the protein as already practiced by the instant applicant and/or the instant co-inventors as evidenced by Stafford and Sun as explained in detail above.
In view of the foregoing, the §1.132 declaration is not found persuasive to support applicant’s asserted nonobviousness of the rejected nucleic acid molecule claims.
Accordingly, this rejection is maintained.
Conclusion
No claim is 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 DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635