The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
1. The Office acknowledges the receipt of Applicant’s Request for Continued Examination filed April 21, 2025. Claims 1-17 are pending and are examined.
All previous rejections not set forth below have been withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
2. Claims 1-17 are objected to because of the following:
In claim 1, “and” should be inserted before the second “wherein” clause.
Dependent claims are included.
Appropriate correction is required.
Double Patenting
3. Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,538,775 (hereafter ‘775). Although the claims at issue are not identical, they are not patentably distinct from each other because SEQ ID NO:1 and a fragment of at least 200 contiguous nucleotides of SEQ ID NO:1 having transcriptional terminator activity in the ‘775 claims render obvious SEQ ID NO:1 and a sequence of at least 100 contiguous nucleotides of SEQ ID NO:1 having transcriptional terminator activity in the claims of the instant application. The claims of the instant application are broader than the claims of ‘775. The ‘775 claims are considered a species of the broader genus claims of the instant application. The species (patented claims) renders obvious the genus (claims of the instant application). An operably linked promoter, plant, monocot, maize, seed and method of use are set forth in the claims of the ‘775 patent.
Applicant requests that the rejection be held in abeyance until allowability is indicated.
Accordingly, the rejection is maintained.
Claim Rejections - 35 USC § 112, first paragraph
4. Claims 1-17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant discloses a Sorghum bicolor gamma kafirin terminator (SB-GKAF) identified as SEQ ID NO:1 having 459 nucleotides that shows better GUS reporter gene expression and more complete termination than the PINII terminator (Table 1, Figs. 3-5). Page 2, lines 5-17, of the specification discloses the state of the prior art:
“The terminator sequences play a key role in mRNA processing, localization, stability and translation (citation omitted). The 3’ regulatory sequences contained in terminator sequences can affect the level of expression of a gene. Optimal expression of a chimeric gene in plant cells has been found to be dependent on the presence of appropriate 3’ sequences (citation omitted). Read through transcription through leaky terminator of a gene can cause unwanted transcription of one transgene from promoter of another one. Also, bidirectional, convergent transcription of transgenes in transgenic plants can occur due to leaky transcription termination of separate convergent genes or from genomic promoters. Convergent, overlapping transcription can decrease transgene expression, or generate antisense RNA (citation omitted).”
In Example 2, Applicant states “Since improper termination can lead to improper processing of the 3’ end of mRNA, and hence affect RNA stability, terminators have been found to affect protein expression levels.” Applicant discloses that the construct comprising SEQ ID NO:1 (SB-GKAF) has about 35% more expression than that of the PINII terminator construct (Table 1). Figure 5 shows the presence of transcripts that had proceeded through the terminator (readthrough transcription) was lower for SB-GKAF than for the PINII terminator.
Applicant has no working example of a nucleotide sequence of at least 100 contiguous nucleotides of SEQ ID NO:1 and functions as a transcriptional terminator in a plant cell.
The claimed invention lacks adequate written description for the following reasons. Applicant does not disclose a representative number of sequences having at least 100 contiguous nucleotides of SEQ ID NO:1 and transcriptional terminator function in a plant cell. In fact, no sequence having less the full-length SEQ ID NO:1 has been shown to have transcriptional terminator activity. It is highly unpredictable that a truncated terminator having only 22% of the 459 nucleotides of SEQ ID NO:1 would have the transcriptional terminator activity shown for the full-length sequence. Read through transcription due to a leaky terminator of a gene would result in expression of a non-functional protein, because the transcription process would continue beyond its usual endpoint into other gene-encoding regions. The disclosure of the structure of the full-length kafirin transcriptional terminator having 459 nucleotides does not allow one skilled in the art to predict which “at least 100 contiguous nucleotides” of SEQ ID NO:1, if any, would also have transcriptional terminator function. The state of the prior art does not teach a particular core structures or motifs for transcriptional terminators to allow one skilled in the art to determine which sequence(s) having at least 100 contiguous nucleotides of SEQ ID NO:1 must be retained and which can be deleted without affecting its functional activity. Kriz et al. (US Publication No. 20050250938 (Applicant's IDS)) discloses SEQ ID NO:22 which has 239 contiguous nucleotides of SEQ ID NO:1 (positions 1912-2150 of SEQ ID NO:22). However, SEQ ID NO:22 is disclosed in Kriz as a sorghum gamma kafirin promoter and has no known transcriptional terminator functional activity [0042].
Accordingly, there is lack of adequate description to inform a skilled artisan that Applicant was in possession of the claimed invention at the time of filing. See Written Description guidelines published in Federal Register/ Vol.66, No. 4/ Friday, January 5, 2001/ Notices; p. 1099-1111.
Applicant traverses primarily that (1) reduction to practice is not required; (2) the structure (at least 100 contiguous nucleotides) and function (transcriptional terminator) are defined; and (3) one skilled in the art would have been able to envision 100 contiguous nucleotides of SEQ ID NO:1.
Applicant’s traversals have been considered but are deemed unpersuasive for the following reasons. With regard to traversal (1), this traversal is not on point because “reduction to practice” is an enablement issue rather than a written description issue. With regard to traversal (2), because Applicant does not disclose a single working example of “at least 100 contiguous nucleotides of SEQ ID NO:1” that functions as a transcriptional terminator, one skilled in the art cannot predict the structures of the claimed genus having transcriptional terminator activity as commensurate in scope with the claims. With regard to traversal (3), while one skilled in the art can readily generate a population of sequences having at least 100 contiguous nucleotides of SEQ ID NO:1, it is unpredictable which “at least 100 contiguous nucleotides of SEQ ID NO:1” would have transcriptional terminator function in a plant cell.
The state of the prior art indicates that the 3’ regulatory sequences contained in terminator sequences can affect the level of expression of a gene, and optimal expression of a chimeric gene in plant cells has been found to be dependent on the presence of appropriate 3’ sequences. Applicant does not identify any sequence having at least 100 contiguous nucleotides of SEQ ID NO:1 that contains the 3’ regulatory sequences necessary for gene expression. Applicant distinguishes the claimed invention from the prior art, stating that Applicant’s terminator sequence having SEQ ID NO:1 shows better gene expression and more complete termination than the PINII terminator. Applicant states that prior art terminators have been shown to be leaky, causing unwanted transcription of one transgene from promoter of another one, as well as bidirectional, convergent transcription of transgenes in transgenic plants. Applicant further states that leaky termination can decrease transgene expression or generate antisense RNA. These problems can result in the production of non-functional proteins. There is no evidence that the disclosures for SEQ ID NO:1 would be applicable to a sequence having “at least 100 contiguous nucleotides of SEQ ID NO:1”. It is unpredictable which 78% of SEQ ID NO:1 can be deleted and still retain transcriptional terminator activity in a plant cell, let alone overcoming the problems of prior art terminator sequences.
Accordingly, the rejection is maintained.
5. Claims 1-17 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant’s disclosure is as set forth above. Applicant distinguishes SEQ ID NO:1 from other terminators such as the PINII terminator because SEQ ID NO:1 shows increased gene expression and reduced leaky read-through transcription.
The “at least 100 contiguous nucleotides” of SEQ ID NO:1 is not enabled because there is no guidance and no working example of any sequence having at least 100 contiguous nucleotides of SEQ ID NO:1 having transcriptional terminator function. The breadth of “at least 100 contiguous nucleotides” encompasses deleting 78% of SEQ ID NO:1 and still retains functional transcriptional terminator activity. The specification and the state of the prior art do not teach which region(s) of SEQ ID NO:1 or of a transcriptional terminator must be conserved or can be deleted while still retaining functional activity. It is not known whether any at least 100 contiguous nucleotides of SEQ ID NO:1 can function as a transcriptional terminator. Kriz et al. (US Publication No. 20050250938 (Applicant's IDS)) discloses SEQ ID NO:22 which has 239 contiguous nucleotides of SEQ ID NO:1 (positions 1912-2150 of SEQ ID NO:22). However, Kriz identified SEQ ID NO:22 is a sorghum gamma kafirin promoter and has no known transcriptional terminator functional activity [0042]. While terminator truncations are known in the art, it is not known whether SEQ ID NO:1 truncations would be operable and if so, which truncations would retain their transcriptional terminator activity. Applicant provides no guidance as to how operable embodiments can be readily identified, or how inoperably embodiments can be readily eliminated, without resorting to random trial and error requiring undue experimentation. While one skilled in the art can generate a population of sequences having at least 100 contiguous nucleotides of SEQ ID NO:1, further guidance is needed as to what sequence(s), if any, within the population would retain its functional activity as a transcriptional terminator. Thus, a sequence having “at least 100 contiguous nucleotides of SEQ ID NO:1” is not enabled as commensurate in scope with the claims without undue experimentation. Accordingly, one skilled in the art cannot make and use sequences of at least 100 contiguous nucleotides of SEQ ID NO:1 having transcriptional terminator functional activity without undue experimentation.
Weighing all the Wands factors based on the totality of the record as discussed above, the Office determines that it would require undue experimentation for a person of ordinary skill in the art to make and use the invention as claimed.
Applicant traverses primarily that (1) the “at least 100 contiguous nucleotides” sequence is only required to have transcriptional terminator activity, and is not required to have increased gene expression or undesirable leaky read-through transcription; and (2) the application provides different techniques that one skilled in the art can use to determine whether a nucleotide sequence comprising 100 contiguous nucleotides of SEQ ID NO:1 can function as a transcriptional terminator in a plant cell.
Applicant’s traversals have been considered but are deemed unpersuasive for the following reasons. With regard to traversal (1), the rejection above has been modified to not require increased gene expression or undesirable leaky read-through transcription. However, there is no working example or evidence in the prior art to support that “at least 100 contiguous nucleotides” of SEQ ID NO:1, or a terminator sequence that has been truncated by 78%, could retain its function as a transcriptional terminator. It is possible that no 100 contiguous nucleotides of SEQ ID NO:1 is capable of functioning as a transcriptional terminator in a plant cell. With regard to traversal (2), before one skilled in the art can test a sequence for transcriptional terminator activity, one skilled in the art must be able to make said sequence comprising at least 100 contiguous nucleotides of SEQ ID NO:1 without undue experimentation. However, no guidance is provided with regard to which sequence having at least 100 contiguous nucleotides of SEQ ID NO:1 has the 3’ regulatory sequences necessary for gene expression and can function as a transcriptional terminator. Given the lack of guidance, lack of working examples, state of the prior art, and lack of predictability in the art, the quantity of experimentation necessary to practice the claimed invention would be excessive and undue. Accordingly, the rejection is maintained.
Claim Rejections - 35 USC § 102
6. 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.
7. The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
8. Claims 1-17 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Kovalic et al. (US Pub. No. 20070271633 (A)). Kovalic teaches a recombinant construct comprising a polynucleotide sequence operably linked to a heterologous nucleic acid sequence, wherein the polynucleotide sequence comprises 169 contiguous nucleotides of SEQ ID NO:1 and functions as a transcriptional terminator in a plant cell (claim 3, [0011], SEQ ID NO:14599). It should be noted that the gene sequence comprising SEQ ID NO:14599 of Kovalic has 923 nucleotides, and the last 169 contiguous nucleotides of SEQ ID NO:14599 (positions 755-923) has 100% sequence identity to 169 contiguous nucleotides of Applicant’s terminator having SEQ ID NO:1 (positions 1-169). Thus, the 169 nucleotides of Kovalic is inherently the transcriptional terminator of the disclosed gene sequence. The specification defines “operably linked” as “the association of nucleic acid fragments in a single fragment so that the function of one is regulated by the other” (p. 10). Thus, the sequence of Kovalic is not required to be immediately preceded by and physically attached to a heterologous nucleic acid. The heterologous nucleic acid sequence can be a heterologous promoter [0018], heterologous marker [0061], heterologous enhancer [0059], and heterologous transit peptide [0063] in the recombinant construct. Kovalic further teaches a plant comprising the recombinant construct (claim 3), monocot and maize plant [0055], seed (claim 3), and method of expressing a heterologous nucleic acid sequence in a plant (claim 3, [0055]). Accordingly, the claimed invention is anticipated by the prior art.
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Conclusion
9. No claim is allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG T BUI whose telephone number is (571)272-0793. The examiner can normally be reached M-F 8am-5pm.
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/PHUONG T BUI/Primary Examiner, Art Unit 1663