Notice of Pre-AIA or AIA Status
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 June 22, 2026. Claims 1-17 are pending and are examined in the instant application.
All previous rejections not set forth below have been withdrawn.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.
Applicant’s earliest priority benefit for the claimed invention is PCT/US12/47901, filed July 23, 2012. Provisional Application No. 61/514055, filed August 2, 2011, does not disclose “a nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1”.
Specification
2. The disclosure is objected to because of the following: p. 20, ln. 6-7, discloses that SEQ ID NO:1 has 465 bp. Applicant’s Sequence Listing discloses that SEQ ID NO:1 has 459 nucleotides.
Clarification and/or 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 a recombinant construct comprising SEQ ID NO:1 or 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 125 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 genus claims of the instant application. The species (patented claims) renders obvious the genus (claims of the instant application). Because the 125 contiguous nucleotides “functions as a transcriptional terminator”, said sequence is inherently operably linked to the 3’ end of a heterologous nucleic acid sequence in the construct (p. 12, lns. 20-23). 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 claims contain 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 125 contiguous nucleotides of SEQ ID NO:1 that functions as a transcriptional terminator in a plant cell.
A nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1 that functions as a transcriptional terminator is understood by the Office to be a functional fragment of at least 125 contiguous nucleotides of SEQ ID NO:1, wherein said function is transcriptional terminator. The specification defines a “functional fragment” as follows.
A "functional fragment" of the terminator is defined as any subset of contiguous nucleotides of the terminator sequence disclosed herein, that can perform the same, or substantially similar function as the full length terminator sequence disclosed herein. A "functional fragment" with substantially similar function to the full length terminator disclosed herein refers to a functional fragment that retains the ability to terminate transcription largely at the same level as the full- length terminator sequence. A recombinant construct comprising a heterologous polynucleotide operably linked to a "functional fragment" of the terminator sequence disclosed herein exhibits levels of heterologous polynucleotide expression substantially similar to a corresponding recombinant construct comprising a heterologous polynucleotide operably linked to the full length terminator sequence. (p. 13, lns. 11-21).
Thus, from Applicant’s definition, a nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1 in a recombinant construct would have “substantially similar function” and would result in “substantially similar” levels of expression of a heterologous polynucleotide as the full-length terminator sequence having SEQ ID NO:1.
The claimed invention lacks adequate written description for the following reasons. Applicant does not disclose a representative number of sequences having at least 125 contiguous nucleotides of SEQ ID NO:1 and transcriptional terminator function in a plant cell as defined for “functional fragment”. In fact, no sequence having less than the full-length SEQ ID NO:1 has been shown to have transcriptional terminator activity. It is highly unpredictable that any “at least 125 contiguous nucleotides of SEQ ID NO:1” has the “appropriate 3’ sequences” for transcriptional terminator function to allow “substantially similar” levels of expression of a heterologous polynucleotide as shown for SEQ ID NO:1. As stated above, Applicant’s admitted prior art discloses that the structure of the terminator sequence affects gene expression. 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. It is unpredictable that any 125 contiguous nucleotides of SEQ ID NO:1 would have the essential components necessary for proper transcriptional terminator function. A transcriptional terminator is simply not any non-coding region at the 3’ end of a transcribed sequence. 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 125 contiguous nucleotides” of SEQ ID NO:1, if any, would also have comparable transcriptional terminator function. While one skilled in the art can readily generate a population of sequences having at least 125 contiguous nucleotides of SEQ ID NO:1, it is unpredictable which “at least 125 contiguous nucleotides of SEQ ID NO:1” would have transcriptional terminator function in a plant cell when operably linked to the 3’ end of a heterologous nucleic acid sequence in a recombinant construct and allow for about 35% more expression and lower readthrough transcription than the PINII 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.
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’s Traversals
Applicant traverses primarily that the claims recite polynucleotides having defined structural features and function that are common to the members of the claimed genus.
Response to Applicant’s Traversals
Applicant’s traversals have been considered but are deemed unpersuasive for the following reasons. The claimed genus is nucleotide sequences having “at least 125 contiguous nucleotides of SEQ ID NO:1.” However, except for the full-length SEQ ID NO:1, no species within the claimed genus has been shown to have transcriptional terminator function. It is highly unpredictable that the at-least-125-contiguous-nucleotide fragments of SEQ ID NO:1 would produce “substantially similar” results shown for SEQ ID NO:1, given the fact that no essential structural component is recited for the fragment, and other full-length transcriptional terminators are known to be leaky and inefficient. While Applicant is in possession of nucleotide sequences having at least 125 contiguous nucleotides of SEQ ID NO:1, Applicant is not possession of nucleotide sequences having at least 125 contiguous nucleotides of SEQ ID NO:1 and have transcriptional terminator function, which is defined as “substantially similar function as the full length terminator sequence”. There is no evidence that Applicant is in possession of functional 125-nucleotide fragments of SEQ ID NO:1 that would allow for about 35% more expression and lower readthrough transcription than the PINII terminator. 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 claims contain 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.
Enablement factors to consider include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Applicant’s disclosure is as set forth above.
The “at least 125 contiguous nucleotides” of SEQ ID NO:1 is not enabled for the following reasons. The nature of the invention is a recombinant construct comprising SEQ ID NO:1 or a nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1 that functions as a transcriptional terminator in a plant cell. The breadth of the claims encompasses any fragment of at least 125 contiguous nucleotides of SEQ ID NO:1, so long as said fragment functions as a transcriptional terminator in a plant cell. As discussed above, a “functional fragment”, which includes a nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1, is defined as having “substantially similar function” as SEQ ID NO:1. Applicant’s working examples are directed only to SEQ ID NO:1. 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. There is no working example of a transcriptional terminator having at least 125 contiguous nucleotides of SEQ ID NO:1. Applicant provides no guidance as to what regions or motifs of SEQ ID NO:1 must be retained for transcriptional terminator function. As stated above, Applicant’s admitted prior art discloses that the structure of the terminator sequence affects gene expression, and the presence of appropriate 3’ sequences are required for optimal expression. 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 state of the art to date does not recognize that any 125 contiguous nucleotide fragment of a terminator would have the same functional activity as its full length terminator sequence. It is unpredictable that any 125 contiguous nucleotides of SEQ ID NO:1 would have the essential components necessary for proper transcriptional terminator function. It is unpredictable whether any of the at least 125 contiguous nucleotides of SEQ ID NO:1 can function as a transcriptional terminator at a level “substantially similar” to the full-length sequence comprising SEQ ID NO:1 as defined in the specification. While terminator truncations are known in the art, it is not known what regions of SEQ ID NO:1 can be deleted, what regions of SEQ ID NO:1 must be retained, and what core components present in SEQ ID NO:1 are required for transcriptional terminator function. 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 theoretically generate a population of sequences having at least 125 contiguous nucleotides of SEQ ID NO:1, with truncations from the 3’ end, the 5’ end, or both the 3’ and 5’ ends, further guidance is needed as to what sequence(s), if any, within the population would retain comparable transcriptional terminator function to SEQ ID NO:1. Thus, a sequence having “at least 125 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 125 contiguous nucleotides of SEQ ID NO:1 having transcriptional terminator functional activity without undue experimentation.
Given these difficulties, notwithstanding a relatively high level of ordinary skill of those in the art, the amount of experimentation would likely be extensive and undue. 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’s Traversals
Applicant traverses primarily the following: (1) The relevant inquiry is not whether it is possible that none of the claimed fragments are functional, but whether the specification, together with the knowledge of the skilled artisan, enables a person of ordinary skill to identify operable fragments without undue experimentation. (2) The mere possibility that some fragments within the claimed genus may prove inoperative does not render the claims non-enabled, particularly where the specification directs the skilled artisan to the sequence of SEQ ID NO:1 associated with transcriptional termination and provides routine assays (Examples 2 and 3) for confirming whether a given fragment retains that function. (3) The experimentation required to identify functional fragments would involve routine techniques known to one skilled in the art, such as systematic deletion analysis by creating and testing 5’ and/or 3’ truncations of the SEQ ID NO:1. (4) Example 2 describes transient GUS/MUG expression assay (Table 1, Fig. 3), and Example 3 describes expression analysis and read-through transcription assays in stably transformed maize (Figs. 4-5). (5) Confirmatory screening is routine, not undue.
Response to Applicant’s Traversals
Applicant’s traversals have been considered but are deemed unpersuasive for the following reasons.
With regard to traversal (1), Applicant is claiming a genus of functional fragments of SEQ ID NO:1 having at least 125 contiguous nucleotides when none of the claimed fragments have been shown to have transcriptional terminator function that is “substantially similar” to SEQ ID NO:1. One skilled in the art cannot predict whether any of the fragments of SEQ ID NO:1 have comparable function to SEQ ID NO:1. The specification provides no evidence that fragments of SEQ ID NO:1 are functional.
With regard to traversal (2), Applicant has no evidence to support the assertion that there is “a mere possibility that some fragments within the claimed genus may prove inoperative”. Applicant has not shown any operable fragment of SEQ ID NO:1. Examples 2 and 3 are not on point because they are directed to SEQ ID NO:1 and do not address fragments of SEQ ID NO:1.
With regard to traversal (3), it is not routine experimentation to identify functional fragments because no fragment has been shown to be comparable to SEQ ID NO:1. No guidance is provided as to what the appropriate 3’ sequences are required for optimal expression, how to avoid leaky transcription, and how to prevent the formation of RNA antisense. Systematic deletions of SEQ ID NO:1 from the 5’ and/or the 3’ to generate all possible fragments having at least 125 contiguous nucleotides of SEQ ID NO:1, and screen each and every fragment for about 35% more expression and lower readthrough transcription compared to the PINII terminator, is not routine experimentation. The results shown for the full-length SEQ ID NO:1 do not allow one skilled in the art to predict that the functional activity of its fragments.
With regard to traversal (4), Examples 2 and 3 are directed to SEQ ID NO:1 and do not address fragments of SEQ ID NO:1. These examples do not address how one skilled in the art can reasonably predict which nucleotide sequence of at least 125 contiguous nucleotides of SEQ ID NO:1 would have “substantially similar” transcriptional terminator function as SEQ ID NO:1.
With regard to traversal (5), before one skilled in the art can screen for terminator function, one skilled in the art must be able to make functional fragments without resorting to random trial and error requiring undue experimentation.
Accordingly, the rejection is maintained.
Conclusion
6. No claim is allowed.
7. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amjad Abraham can be reached on 571-270-7058. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PHUONG T BUI/Primary Examiner, Art Unit 1663
Prosecution Insights