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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/25/2026 has been entered.
Claims 14-20, 24, and 29-38 are under consideration in this office action.
Withdrawn Rejections
The rejection of claims 2-6, 8-9, and 11, on the ground of nonstatutory double patenting as being unpatentable over claim 4 of U.S. Patent No. 11, 608, 504, is withdrawn. The amendments to the cancel the above claims, rendering their rejection moot.
The rejection of claim(s) 2, 5-6, 8-9, and 11, under 35 U.S.C. 103 as being unpatentable over Weissenborn (Weissenborn et al. JBC 267(9):6122-6131, 1992; of record in IDS 3/23/2023), is withdrawn. The amendments cancel the above claims rendering their rejection moot.
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 29 is 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.
Claim 29 recites, “wherein the DNA sequence comprises a nucleic acid of SEQ ID NO:1”. This recitation lack sufficient antecedent basis and is indefinite because the claims recites two DNA sequences (i) and (ii). As such, it is not apparent to which DNA sequence this recitation refers. This will be interpreted broadly as referring the either (i), (ii), or both.
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 14-20, 24, and 29-38, as amended, previously presented, or newly added, 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.
When determining if a recited genus has adequate written description for a genus:
(1) the broadest reasonable interpretation of the genus is determined;
(2) the disclosure is examined to determine if the specification has provided a representative number of species to describe the complete structure of the genus;
(3) the disclosure is examined to determine whether a representative number of species have been sufficiently described by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus; and
(4) the state of the art is examined to the determine if it supports/supplement the genus description in the specification in a manner that would demonstrate the application was in possession of the claimed genus at the time of effectively filing.
Breadth of the Claims:
Amended claim 14 recites, “the DNA sequence has 23 to 54 nucleobases, is capable of forming a stem-loop structure and comprises a nucleic acid sequence having at least 90% identity with SEQ ID NO:1”.
Stating that the DNA sequence “has” 23 to 54 nucleobases means the same as “comprising” and “containing” 23 to 54 nucleobases. Thus the breadth of the DNA sequence is that it at least has 23 to 54 bp in length but can also have more bp and sequences present. Stating the DNA sequence “is capable of forming a stem-loop structure” is conditional language not requiring an actual stem-loop structure to be formed. Further, being capable of forming a stem-loop structure” means that any form of a stem loop structure comprising any number of bases in the loop and stem. Even further, this capacity form stem loop structures to form as claimed in not particularly limiting because all DNA “is capable” of at least transiently forming a type of stem loop structure. The genus “a nucleic acid sequence having at least 90% identity with SEQ ID NO:1” means that as much as 10% of the DNA sequence. The breath includes any addition, deletion or one or more changes in nucleotides in the primary sequence any wherein the sequence that has the overall effect of having 90-100% identity with SEQ ID NO:1. Thus the breadth of the claimed genus of DNA sequences is broad because it includes any type of any (deletion, addition, substitution) of any 2 or 3 nucleotides anywhere within the 23 bases of SEQ ID NO:1 plus any sequences between 24 to 54 nucleotide bases in length of any sequence. As such, the genus is quite large in the number of sequence and heterogenous primary sequence structure.
New claim 29 recites, “a nucleic acid sequence of SEQ ID NO:1”. The recitation of “a” includes any fragments of SEQ ID NO:1 of any length. As such, the breadth of the genus is very broad and heterogeneous.
Description in the Disclosure (citations from the pre-grant publication):
Regarding SEQ ID NO:1:
[0029] the invention relates to recombinant nucleic acid sequences, such as nucleic acid constructs, comprising an isolated nucleic acid consisting of SEQ ID NO: 1, or a variant thereof, wherein said variant is a nucleic acid sequence that has at least 80%, preferably, more than 80% sequence identity with SEQ ID NO:1 It was found that a transcript of the DNA sequence of SEQ ID NO: 1 is capable of forming a stem-loop (pin) structure that is associated with an increased stability of an RNA molecule that comprises this structure. Nucleic acid constructs comprising this DNA sequence of the invention can significantly increase efficiency of expression of genes operably linked to the constructs in recombinant cells by increasing the lifetime of genes transcripts (i.e. mRNA) and, consequently, the number of cycles of translation of the transcripts.
Therefore, while the specification contemplates a variant sequence with 90% identity to SEQ ID NO:1, it only provides one the full length species, SEQ ID NO:1. Further, the specification describes a newly identified function of the full length sequence, forming a step-loop (pin) secondary/tertiary structure that lead to the function of increasing stability of an RNA molecule. The specification provide no description of any nucleotide bases that can be added, deleted, or substituted. The specification provides no description of the nucleotide bases that are response for keeping the part of the stem-loop (pin) structure conserved to impart that functional property of increasing stability of an RNA molecule. Given the great breadth of all the possible structures of the genus of a variant sequence with at least 90% identity to SEQ ID NO:1, disclosure of one full length sequence with 100% identity to SEQ ID NO:1 fails to provide an adequate number of representative species to describe the complete structure of this broad and diverse genus. The specification also fails to describe a representative number of species of variants by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus.
State of the Art:
Regarding stem loop structures, Howe et al (Journal of Physical Chemistry 2023, 127:1586-1597) that changes in DNA or RNA sequence to include AU/AT pairs results in a change in stem loop structure melting and the pairs inclusion resulted in significant impairment of the stem loop structure refolding pathway when AU/AT pairs were placed at different points in the stem. (See abstract). Cheung (Virology 363 (2007):229-235) describes that alterations in DNA sequences that usually form stem loop structures causes mismatches that do not yield their stem loop structure (p. 230, col 2, last paragraph). As such, the art prior to the effective filing of the instant application and years after teaches that changes to DNA nucleic sequence structure alter their ability to function and form stem loop structures.
Regarding variants and fragments of promoter sequence, Rudge et al (ACS Synth Biol 2016 5:89-98) reports, “a major aim of synthetic biology is the rational design and construction of DNAs composed of genetic parts from various sources to achieve novel functions….However, characterization of promoters is problematic because their behavior can vary unpredictably in different context….DNA sequence local to genetic parts can also significantly affect their behavior. In particular, the activity of promoters has been shown to depend on the adjacent transcript sequence…The mechanistic details of these relationships are not fully understood. For the goal of characterization, this means that both the promoter of interest and any indirect (fluorescence, luminescence, colorimetric) reporter measurements of its activity are subject to unpredictable variation” See page 89, col 1 and page 89, col 2, last paragraph to p. 90 col 1, first paragraph. Ralston (2008 Nature Education 1(1):216 from Scritable website 2014. https://www.nature.com/scitable/topicpage/operons-and-prokaryotic-gene-regulation-992/#:~:text=For%20example%2C%20mutations%20affecting%20the,the%20genes%20in%20the%20operon. Pages 1-3) reports, “ Because of the common control mechanism for all of the genes in the lac operon, mutations in this operon can have multiple, or pleiotropic, effects. For example, mutations affecting the promoter can prevent all of the operon's genes from being expressed, because RNA polymerase will be unable to bind and commence transcription. Other mutations may affect expression of only some of the genes in the operon. For instance, nonsense mutations in the lac z gene encoding beta-galactosidase might interfere with expression of downstream permease and transacetylase genes by causing the ribosome to fall off prior to their translation. This kind of mutation is said to have a "polar" effect on the pathway in that it affects downstream genes but not upstream genes.”.
Thus the art teaches unpredictabilites in altering and varying promoter sequences as would occur in variants and fragments of the claimed promoter/regulatory regions.
In conclusion, the specification does not provide adequate description for the claimed variants and fragments of SEQ ID NOS:1 because the specification fails to describe any species variants and fragments and only provides the full length sequences of these SEQ ID NOS. The specification does not describe any relevant characteristics or traits of these variants and fragment. The specification does not describe any particular changes that can be made to these SEQ ID NOS that maintain the intended function of these particular sequences in the claimed invention. Further the state of the art teaches that variants and fragments as little as one base pair change can alter the structural/functional relationship of nucleic acid sequence, albeit stem loop structure formation or promoter function. Since the specification does not provide any description of the species in the claimed genus and the art teaches unpredictability in variants and fragments structural/functional relationship, one of ordinary skill at the time of effective filing would not believe there is sufficient description to demonstrate the application was in possession of vast number of structurally and functionally diverse variants and fragments of SEQ ID NOS:1.
Response to Arguments
Applicant's arguments filed 2/25/2026 have been fully considered but they are not persuasive.
Applicant submits that claim 14 has been amended to limit the length of the claimed DNA sequence to 54 nucleobases. Applicant submits that support for this amendment can be found on page 9, line 7. Claim 14 was also further amended to recite the function that the structure provides the capability tor form a stem-loop structure.
In response, Applicant is not giving the claim language its broadest reasonable interpretation. Amended claim 14 recites, “the DNA sequence has 23 to 54 nucleobases, is capable of forming a stem-loop structure and comprises a nucleic acid sequence having at least 90% identity with SEQ ID NO:1”.
Stating that the DNA sequence “has” 23 to 54 nucleobases means the same as “comprising” and “containing” 23 to 54 nucleobases. Thus the breadth of the DNA sequence is that it at least has 23 to 54 bp in length but can also have more bp and sequences present. Stating the DNA sequence “is capable of forming a stem-loop structure” is conditional language not requiring an actual stem-loop structure to be formed. Further, being capable of forming a stem-loop structure” means that any form of a stem loop structure comprising any number of bases in the loop and stem. Even further, this capacity form stem loop structures to form as claimed in not particularly limiting because all DNA “is capable” of at least transiently forming a type of stem loop structure. The genus “a nucleic acid sequence having at least 90% identity with SEQ ID NO:1” means that as much as 10% of the DNA sequence. The breath includes any addition, deletion or one or more changes in nucleotides in the primary sequence any wherein the sequence that has the overall effect of having 90-100% identity with SEQ ID NO:1. Thus the breadth of the claimed genus of DNA sequences is broad because it includes any type of any (deletion, addition, substitution) of any 2 or 3 nucleotides anywhere within the 23 bases of SEQ ID NO:1 plus any sequences between 24 to 54 nucleotide bases in length of any sequence. As such, the genus is quite large in the number of sequence and heterogenous primary sequence structure. As such, the DNA sequence is not limited to 54 nucleobases and limited by its recited capacity to form a stem-loop structure. Further, the breadth is significantly larger than Applicant’s interpretation.
Applicant respectfully submits that the Office has misinterpreted the scope of the claims. SEQ ID NO: 1 contains 23 nucleobases and the DNA sequence of claim 14 must have at least 23 nucleobases. To retain 90% identity to SEQ ID NO: 1, only one or two modifications can be made to SEQ ID NO: 1. However, any modification must not change the function of capable of forming a stem-loop structure.
In response as discussed above, 90% identity to SEQ ID NO:1 comprises 2 or 3 changes anywhere in the 23 nucleotide sequence of SEQ ID NO:1 but the sequence is not only limited to SEQ ID NO:1 and 90% identity thereto. It also can comprise another 1 to 31 nucleic acids to add up to a sequence length between 24 to 54 bases of any sequence. This is a large and heterogenous number of species sequences. The specification only describes one SEQ ID NO:1 and where it lies within the wildtype sequence. This would not be deemed an sufficient number of sequences to describe the complete structure of the genus and given the unpredictability of sequence to function when altered, one would not come to the conclusion that the disclosure of one sequence would lead one to understanding and conclusion of possession of the full genus.
Applicant submit that the Office's citation to Cheung further supports that the present claims satisfy the written description requirement. Cheung teaches that modifying the nucleic acid sequence can impair forming a stem-loop structure. The presently amended claims require that the claimed DNA sequence is capable of forming a stem-loop structure. Thus, any modifications to the nucleic acid sequence of SEQ ID NO: 1 that destroy the ability to form a stem-loop structure would be outside the scope of amended claim 14.
In response, Applicant is imply that the capacity to form stem loop structures in a sequence 23 to 54 sequence that also has a sequence with 90% identity to SEQ ID NO:1 limits any mutations that would hinder the one specific species of stem loop structure seen to occur in a sequence with 100% identity to SEQ ID NO:1. However, the claims DNA sequence is much larger than that and also the breadth of the capacity to form a stem loop structure is the capacity to form any stem loop structure transiently or consistently. Even further “capacity” is conditional language mean a stem loop structure is not required to be present only the capacity to form one which all nucleotide sequence have. As such, Applicant is not considering the full breadth of their claimed genus and one species disclosure does not adequately describe the complete structure of the DNA sequence genus of the claims.
Applicant submits only routine activities would be required to identify the modifications to SEQ ID NO: 1 that would still allow the formation of the stem-loop structure. The Office has already acknowledged that such structures were known in the prior art and Applicant has highlighted some of the immediately obvious modifications that could be made via this response. Given the small number of permissible changes and the routine nature of modifying SEQ ID NO: 1, Example 11A squarely supports that the instant claims satisfy the written description requirement.
In response, Applicant is not giving the claims the broadest reasonable interpretation. This argument solely focuses SEQ ID NO:1 and 90% identity, but the claims are significantly broader than that for reasons discussed above. While the means of designing possible mutation to the sequence are known in the prior art, predictable impact on function, such as stem loop structure and others as discussed by Cheng remains. As such, Applicant’s argument is not persuasive.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632