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 .
Claims Status
Claims 95-98 and 112-113 are amended.
Claims 1-94 and 99-111 are canceled.
Claims 114-118 are new.
Claims 95-98, and 112-118 are under examination.
Edited Rejections Necessitated by Claims Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 95-98, and 112-118 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a nucleic acid encoding a dominant negative Zbtb20 (DN Zbtb20), where the DN Zbtb20 comprises one or more Zbtb20 C-terminal zinc-finger domains but lacks at least a portion of a Zbtb20 N-terminal comprising the BTB domain. Claim 97 specifies the function of the claimed DN Zbtb20 as being capable of binding the endogenous Zbtb20 binding sites within DNA, preventing endogenous Zbtb20 form binding to said binding sites.
According to the specification, a “dominant negative “ is any variant of endogenous Zbtb20 which is capable of suppressing the activity of endogenous Zbtb20 by acting as a competitive inhibitor of Zbtb20. For example, the dominant negative would be any variant of the endogenous Zbtb20 that can bind to endogenous Zbtb20 binding sites within DNA, preventing the binding of endogenous Zbtb20 to said binding sites.(See paragraph [98]). While the specification provides the SEQ ID NOs defining the nucleic acid/ amino acid sequences of the DN Zbtb20 (e.g. SEQ ID 39/40, respectively); however, Applicants have not demonstrated a reduction to practice that the claimed DN Zbtb20 will produce a stable and functional variant that can perform the claimed function (e.g. to reduce the activity of endogenous Zbtb20 by acting as a competitive inhibitor of Zbtb20).
In the instant case, the specification defines the dominant negative Zbtb20 as the variant comprising one or more Zbtb20 C-terminal zinc-finger domains but lacking at least a portion of a Zbtb20 N-terminal comprising the BTB domain. The specification also contemplates that the said variant is capable of acting as a competitive inhibitor of Zbtb20 upon delivery to the cell, suppressing the activity of the endogenous Zbtb20.(See paragraph [98]). Prior arts by Cordeddu et al and Stellacci et al had identified dominant negative variants of Zbtb20 occurring in patients with Primrose syndrome. The identified variants comprise of full-length Zbtb20 with missense mutations affecting the C-terminal domain of Zbtb20 (i.e. the DNA binding domain), resulting in the production of stable but dysfunctional protein. ( See Fig.1A, and Fig.2B provided by Stellacci et al ). On the other hand, prior art by Sutherland et al demonstrated that removing exon 6 encoding the BTB domain from endogenous Zbtb20 resulted in a knockout rather than the production of a dominant negative mutant. (See Sutherland et al , Results section- 1st paragraph on page 2805, and Fig.1D). Therefore, one with ordinary skill in the art would expect that a nucleic acid encoding the Zbtb20 ‘s C-terminal domain but lacking the BTB domain would not produce a stable and functional protein capable of serving as a competitive inhibitor. Applicants have not reduce to practice that truncating the N-terminal domain comprising the BTB domain from the full Zbtb20 will result in a stable and functional protein that is capable of acting as a competitive inhibitor of the Zbtb20. Accordingly, Applicants have not provided sufficient description of the invention to support they were in possession of a dominant negative Zbtb20 comprising one or more Zbtb20 C-terminal zinc-finger domains but lacking at least a portion of a Zbtb20 N-terminal comprising the BTB domain.
Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc.,525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
Furthermore, it should be noted that the claims as currently recited covers a broad genus of all proteins comprising one or more zbtb20 C-terminal zinc finger domains and lacking “ all or a portion” of the BTB domain. It should be emphasized that even if one specific truncation were shown to be dominant negative, the specification would still need to support the broader range of all or partial BTB deletions encompassed by the claim. To begin with, the specification does not provide a written description for obtaining stable and functional DN Zbtb20 from the claimed SEQ ID NO: 39/40, nor does it provides a written description for obtaining stable and functional DN Zbtb20 to cover all possible variants of the human DN Zbtb20 that would result in a sequence with as little as 90% identity to the claimed sequence of SEQ ID NO:39/40 and producing a stable and functional protein imparting a dominant negative human Zbtbt20 activity. Furthermore, the specification does not identify what changes, deletion, fragments, etc. could be made to SEQ ID NO: 39/40 that would still produce a stable and functional dominant negative variants of the human Zbtb20. Accordingly, Applicants have not provided sufficient description of the invention to support they were in possession of all variants comprising one or more zbtb20 C-terminal zinc finger domains and lacking “ all or a portion” of the BTB domain.
Taken together, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph. Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant's arguments filed 04/10/2026 have been fully considered but they are not persuasive.
Applicant argue the basis of the rejection under 35 U.S.C. § 112(a) for failing to comply with the written description requirement. Specifically, Applicants argue that Sutherland et al provide no basis for concluding that the claimed dominant negative Zbtb20 protein, based on its structure, will not bind to endogenous human or mouse Zbtb20 protein when expressed in a cell which endogenously expresses human or mouse Zbtb20.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants appear to argue that Zbtb20 protein comprising one or more C-terminal zinc finger domains while lacking all or part of the N-terminal BTB domain constitutes a dominant negative zbtb20 protein. This argument is not persuasive because the issue under 35 U.S.C 112(a) for written description is whether the instant disclosure conveys to a person of ordinary skill in the art that the inventors are in possession of the claimed dominant negative zbtb20 protein. As previously discussed, the specification does not provide any experimental data, representative species, or other technical evidence demonstrating that the deletion of all or a portion of the BTB domain results in a dominant negative zbtb20 protein. Rather, the specification appears to assume that the removal of the BTB domain necessarily produce dominant negative zbtb20 protein. Such a stance is evident in Applicant’s remark, which states that “ Essentially, members of this family are all transcriptional repressors, and the BTB domain is required for dimerization of such transcriptional repressors, which in turn is necessary to recruit other factors that act to repress transcription of target genes. Based thereon, disruption of the BTB domain, e.g., by mutation or removal prevents this dimerization and accordingly the repressive activity the BTB-ZF family member”. ( See 2nd paragraph on page 9 of Applicant’s remarks). It should be noted that the cited prior art by Sutherland et al was for the purpose of providing a scientific evidence showing that the disruption of the BTB-containing region may abolish zbtb20 function altogether, generating a complete knockout of the zbtb20 protein rather than a truncated protein that would function in a dominant negative way. In other words, Sutherland et al report deletion of exon 6, which encodes the BTB domain, resulting in zbtb20 null animals, which translate to a complete loss in the protein rather than the production of a truncated protein that may function in a dominant negative manner. Thus, Sutherland does not establish that the removal of BTB domain predictably would produce a dominant negative protein as opposed to a nonfunctional or null protein. Accordingly, because multiple outcomes were plausible in the art, including loss of the protein function, loss of protein stability, or generation of a null phenotype, the disclosure does not reasonably convey possession of the full scope of the claimed genus of dominant negative zbtb20 proteins defined by deletion of all or a portion of the BTB domain. Applicants assertion that such proteins are dominate negative is unsupported by evidence in the instant disclosure and therefore does not cure the deficiency in written description. The point from citing Sutherland et al is to demonstrates that BTB-domain disruption was associated with null phenotype, creating unpredictability regarding the result of BTB domain deletion. Applicants need to show scientific evidence represented by assays, data, characterization of dominant negative activity to demonstrate that Applicants are in possession of the claimed invention. Furthermore, it should be noted that the claims as currently recited covers a broad genus of all proteins lacking “ all or a portion” of the BTB domain. It should be emphasized that even if one specific truncation were shown to be dominant negative, the specification would still need to support the broader range of partial BTB deletion encompassed by the claim. In addition, Applicants argument that Sutherland rely on a transgenic mice generated by homologous recombination rather than expression of a recombinant truncated proteins, and therefore do not provide relevant support for the claimed dominant negative zbtb20 proteins is also not persuasive. This is because under 112 (a) written description, Sutherland et al is not cited to show how to make a recombinant protein. Rather it was cited to show what happens to zbtb20 when the BTB domain is removed in its native context. So, even that Sutherland et al do not teach recombinant protein expression, such argument does not cure the 112 (a) written description deficiency. In other words, regardless of the experimental system used, Sutherland et al still fails to provide evidence of possession of all the claimed genus of the dominant-negative zbtb20 proteins.
Applicant further argue relying on prior arts by Schaffer et al (2000), Seto et al (2011), Melnick et al (2000), and Takeda et al (2003) to traverse the rejection under 35 U.S.C. 112 (a) for lack of written description.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because, as discussed previously, Sutherland et al provide that zbtb20-specific evidence that deletion of the BTB/POZ domain results in loss of zbtb20 function consistent with null or knockout phenotype. The office agrees with Applicants, that Sutherland et al does not disclose expression of zbtb20 derived polypeptides lacking all or part of the BTB domain, nor does it demonstrate that such polypeptides suppress endogenous zbtb20 activity in a dominant-negative manner. The additional references cited by Applicants do not remedy the deficiency because they do not provide zbtb20 specific structure-function disclosure or presentative species within the claimed genus. For example, Schaffer and Seto relate to engineered dominant-negative constructs of BCL6 and describe gene-specific mechanism of inhibition that rely on constructs distinct in structure function from the presently claimed zbtb20 derived proteins. Specifically, these two references do not establish that deletion of all or part of the BTB domain in zbtb20 results in negative dominant suppression of endogenous zbtb20. On the other hand, Melnick et al disclose point mutation analysis of thePLZF BTB/POZ domain and identify residues required for transcriptional repression. However, Melnick et al does not disclose deletion of all or part of the BTB domain, and therefore does not provide guidance regarding the functional properties of the claimed zbtb20 deletion variants. Takeda et al similarly describes BCL6 mediated transcriptional regulation and functional inhibition in the IL-18 pathway, but does not disclose zbtb20-derived truncated proteins establish a generalizable relationship between BTB domain deletion and dominant negative activity of zbtb20. Even if Applicants argue that the BTB domain is conserved among the BTB-zinc finger family, such argument only show structural similarity at a high level, and it does not show that deletion of the BTB in zbtb20 yields dominant negative activity. It also does not show that all of the generated truncated zbtb20 proteins lacking all or portion of the BTB domain would produce stable and functional proteins. Neither it shows that all of these truncated proteins would suppress the endogenous WT zbtb20, or even behave similarly. Therefore, the argument that BCL6 and zbtb20 are both BTB-zinc finger transcription factors is not persuasive. Because, 112(a) requires possession of zbtb20 specific dominant negative proteins and not a general knowledge extrapolated from BTB-ZF family behavior. Consistent with this, the teachings of Sutherland et al showing that disrupting the BTB domain in zbtb20 resulted in a complete knockout and not a truncated protein that would function in a dominant negative manner. Thus , even within the BTB-zinc finger family the functional consequences of BTB-domain disclosure are not predictable across different family members. Accordingly, teachings derived from BCL6 or other BTB-family proteins do not establish that deletion of all or part of the BTB domain in ZBTB20 yields dominant negative activity. Accordingly, the cited references alone or in combination fail to provide representative species or reasonable correlation between the claimed structural genus and the asserted dominant negative function required to satisfy the written description for the full scope of the claimed zbtb20-derived proteins.
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 FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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