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 1-27 are pending, as originally filed, and are considered herein.
Claim Objections
Claim 2 is objected to because of the following informalities: Claim 2 recites “… genes that are either expressed … and are operatively linked …” (emphasis added). The elements listed after the term “either” utilize the conjunction “or”, in proper English. Applicant has the conjunction “and”. It is assumed this is a typographical error made during claim drafting. For substantive considerations, the term “either” will be given no weight. Appropriate correction is required.
Applicant is advised that should claim 1 be found allowable, claim 6 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 1 is drawn to a composition with a core promoter comprising a TSS, from a gene that is expressed at higher levels in cancer cells. Claim 6 requires the higher level to be determined by ChIP. However, the claims are to the composition, as seen in claim 1, and the method of finding out if it is expressed at higher levels is irrelevant to the structure being claimed. Thus, despite a slight difference in wording, these claims have substantially the same scope.
Claim Rejections - 35 USC § 112
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.
Claim 16-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 16-18 recite “or a reverse complement thereof” with respect sequence identifiers for enhancers. It is not clear what is being claimed. The enhancer is a double stranded sequence, the sequence itself, paired with its complement. The reverse complement, however, in its broadest reasonable interpretation is not the complement. It is reversed. Therefore, the Artisan would not understand what is claimed. Is Applicant claimed the complement sequence, where the 5’ to 3’ orientation is reversed? Or something else?
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 1-27 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 generic for a combination of (i) a generic core promoter including a TSS, from one or more cancer-responsive gene expressed at higher level in the cancer cell, versus non-cancer cell, and operatively-liked to an ORF and (ii) a generic plurality of enhancers that is not part of the gene from which the generic core promoter is found.
The specification teaches that the use is to provide synthetic cancer-specific promoters with high specificity and sensitivity (paragraph 4). The specification teaches that these promoters are designed through screening processes, carried out in both high- and low- throughput screens. For example a promoter may be chosen from -1000 to +1000 of the TSS of the gene and can then be adjusted based on ChIP data, removing TF binding sequences, and considering regions of high species conservation to arrive at a core promoter to be used (e.g., paragraph 100-101) and by other methods known in the art. Twelve examples of cancer-activated core promoters are provided (paragraph 129), in the context that the promoter may be specific for a single type of cancer, or form multiple cancer types (e.g., paragraph 131). The same is taught to be linked to synthetic response elements (TF/enhancer binding sites) and drive expression of proteins in cancer cells (e.g., paragraph 132). The approach to learning these structures that work in desired embodiments is found through complex screening processes, done with high throughput methods (e.g., Example 1). Here, bioinformatic analysis identifies endogenous cancer-activated promoters, and subsequent engineering to provide minimal promoters, bioinformatics is used to identify TFs which may be added, and further screening with enhancers provide for active synthetic promoters, through a massive screen to find working embodiments (e.g., figure 10). The complexity of this is even more than would appear to be required initially. The transcription factors are analyzed with different spacings, to find spacings that work, given the 10.4 nucleotide spacing of a single turn of dsDNA and are analyzed in tile libraries (e.g., Example 1). Such can be in Applicant’s example shown in Figure 13. Nevertheless Applicant’s massive screens have identified 1800 unique tiles in combination with two separate libraries, one with a core promoter of TATA-TSS and another using coreBIRC5 core promoter (paragraph 327). Many of these drove reporter gene expression at a level similar to baseline core promoter, however, a subset drove expression up to 80x higher (e.g., Id.). Also, several elements drove expression in specific contexts only, e.g., TCF7 and TP53 drove expression in only LXFL430 or LXFA586, which was confirmed in validation studies. In essence then, the methods are reliant on a screen and do not provide the needed structure required of any specific or general expression increased in either a single cancer cell context, or in a multiple cancer cell types. Example 2 demonstrates similar choice of specific promoters and response elements, in a modular fashion, for taking advantage of specific dysregulated pathways in cancer. Similar to Example 1, this utilizes screens to find the elements and combinations. Example 3 demonstrates HCC in orthotopic mouse models, utilizing another promoter specific the cancer (APF-3) and also uses different delivery formulations. Example 4 demonstrates benign vs malignant inflammation and specificity. All of these include screening to pan out particular promoter-enhancer-ORF combinations.
However, none of these teach a core promoter made of other promoters, nor the core structure required for any specific instance of expression desired in cancer(s) versus non-cancer cells. I.e., the Examiner is arguing that there are no instances of single promoter made of other promoters, as is seen in Claim 1, and further is arguing that the screening systems do not provide the knowledge know what the core structure of the core promoter, including TF sites, and enhancers, that will work in any specific instance. What is disclosed is specific instances of heterologous core promoter/enhancer combinations that provide the desired benefit.
The art does not provide more, to understand the core structures required in any particular instance.
In essence, Applicant has provided a method to find and pan out heterologous expression constructs that provide for increased expression in any specific cancer environment, with a minimal promoter. But where substantial variation exists in a genus, one must describe a sufficient variety of species to reflect the variation within the genus to a “representative number of species”, when the structure is not provided directly. Even when a selection procedure is provided, sufficient to enable an invention, the written description of 35 USC 112 is severable from its enablement provision. Ariad, 94 USPQ2d 1167, Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the ‘775 patent possessed such an antibody.) Simiarly, here, the heterologous expression constructs could be made, if they can exist, but that does not demonstrate possession of the heterologous promoter later found through selection processes.
Thus, beyond the specific minimal promoter and heterologous enhancers, the Artisan would not have understood Applicant to have been in possession of the generic core promoter made of more than one cancer-responsive gene, nor the scope of the generic core promoter and plurality of heterologous enhancers. The only thing understood as possessed, are those specific sequences disclosed in the combinations disclosed, for expression only in those cancer cells that they are shown to provide such increased expression.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638