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 .
Application Status
This action is written in response to applicant’s correspondence received on 6/9/2026. Claims 9-12, 14-17, 23, 26, and 29-30 are pending. Claims 9-10, 14-17, 23, 26, and 29-30 have been amended. Claims 1-8, 13, 18-22, 24-25, and 27-28 have been cancelled. All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Election/Restrictions
Applicant’s election without traverse of a 1000kb sequence of SEQ ID NO: 27 with at least 95% identity to SEQ ID NO: 27 and SEQ ID NO: 43 for the gene not encoded by the second sequence in the reply filed on 2/3/2026 is acknowledged. The elected species are considered for the following rejections.
Claim Rejections - 35 USC § 112 – Maintained/Updated in Response to Amendment
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.
Claims 26 and 29 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.
Regarding claim 26, claim 26 recites “the at least one second item is formate.” However, no “at least one second item” is previously recited in the claim. Thus, recitation of “the at least one second item” lacks proper antecedent basis in the claim. This is a new rejection necessitated by amendment.
Regarding claim 29, claim 29 recites a method of producing a vaccine comprising using the nucleic acid of claim 9. Claim 29 is therefore a “use” claim, where the specific use of the recited elements of the claim are not clearly defined or articulated. The metes and bounds of the claim are therefore not clearly defined in the claim. This rejection is maintained.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered with respect to claim 29 and are not persuasive. The Applicant argues that a person of ordinary skill in the art would interpret the “use” claim of claim 29 to mean that the second nucleic acid sequence would encode a vaccine, and further argues that the claim broadly encompasses in vitro and in vivo transcription methods, and methods which rely on cis or trans configuration with respect to the host cell. These arguments are not persuasive because these elements are not recited in the claim itself. Claim 29 simply recites that the nucleic acid is used in a method without any method steps articulated or clearly defined.
Claim Rejections - 35 USC § 102 - Maintained
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.
The following is a quotation of the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 29 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meijrink (US patent 10,590,436 B2, first published 7/14/2016, issued 3/17/2020, of record).
Regarding claim 29, claim 29 recites in the alternative “using the first nucleic acid sequence of claim 9,” and therefore does not require the second nucleic acid sequence of claim 9. Claim 29 is therefore broadly drawn to the first nucleic acid sequence itself (e.g., Applicant’s elected SEQ ID NO: 27). The only actionable step of claim 29 appears to be providing a nucleic acid sequence such as SEQ ID NO: 27. Note that the preamble “a method of producing a vaccine” does not add structural limitations or guidance in the claim itself. As such, as claim 29 is generally unclear, it is here being interpreted that such a method can be drawn most broadly to simply providing SEQ ID NO: 27. Meijrink teaches SEQ ID NO: 4, which comprises at least such a portion of SEQ ID NO: 27 as to read on the first nucleic acid sequence of claim 9 because SEQ ID NO: 4 of Meijirink matches 100% with instant SEQ ID NO: 27 (see first two pages of Meijrink for alignment of instant SEQ ID NO: 27 and SEQ ID NO: 4). Meijirink, by simply teaching SEQ ID NO: 4 which is a 100% match to SEQ ID NO: 27, therefore anticipates claim 29, which is broadly drawn to a method of providing/”using” the first nucleic acid sequence of claim 9.
Response to Arguments
The Applicant’s arguments filed 6/9/2026 have been considered and are not persuasive. The Applicant’s amendments are sufficient to obviate the original 102 rejection with the exception of the 102 rejection of claim 29. Claim 29 is broadly drawn to only the first nucleic acid sequence of claim 29, which is taught and anticipated by Meijirink. Thus, the rejection of claim 29 is maintained.
Claim Rejections - 35 USC § 112 – Maintained/Updated in Response to Amendment
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 9-12, 14-17, 23, 26, and 29-30 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claim 9, claim 9 is broadly drawn to a genus of nucleic acids which are recited to be capable of functioning as inducible promoters, where the promoters are inducible by the introduction of formate. Furthermore, the recited genus of nucleic acids are recited to “comprise or consist” of a “portion” of a sequence selected from a list of SEQ ID numbers, or to comprise a “portion” of a sequence selected from a group of SEQ ID numbers, where a percentage of 95% of the sequence identity is required. This claim language is problematic. Firstly, the applicant is claiming a genus of uncharacterized promoter sequences, where the sequences are recited with functional requirements (i.e., they must function as promoters which can be induced by formate in non-methylotrophic yeast). The genus of promoter which the applicant is claiming encompasses variations of the SEQ ID numbers which were not reduced to practice. The applicant has not characterized “portions” of the sequences, where such “portions” can be interpreted to be any portion of the sequences (for instance, 10 base pairs of SEQ ID NO: 27). The Applicant has not shown functional embodiments of “portions” of the recited sequences commensurate in scope with what is being claimed. Furthermore, the Applicant has not demonstrated possession of variations of the recited promoter sequences, which allow for 5% variation in the promoter sequences. The promoter sequences recited are between 1 and 1.5 kb, which encompasses promoters with between 50-75 mutations. As is known in the art and discussed further below, promoter sequences are critical to their function, where minor changes can have drastic and unpredictable effects on the functionality of the promoter (see discussion on state of the art, below).
Regarding the guidance provided in the specification, the applicant offers examples 1-3. Example 1 describes identifying putative promoters (16 promoters), where 10 of these putative promoters for FDH genes show an increased expression level after exposure to sodium formate, where qPCR is used to establish expression levels. Note that, given the fact that not all 16 of the putative promoters function in the same manner is evidence of unpredictability concerning such sequences that are identified. Example 2 details an experiment where a 1500 bp region of one of the promoters is cloned into an expression construct linked with a reporter GFP gene, where the reporter appears to display increased expression in the presence of sodium formate. Example 3 tests different growth medias, where two putative promoters are measured (strains comprising S29008 and p15032). Thus, in total, two promoters have been tested in full length, while a 1500 bp “portion” of one promoter (YALI0E14256, Example 2) was tested.
The Applicant has not identified any core structure-function relationship which would identify common structural features of the promoters and the functional requirement that these sequences act as inducible promoters. For instance, the Applicant has not characterized elements of the promoters through mutagenesis or identified transcription factor binding sites which confer any characteristics on the promoters. The Applicants have therefore not shown possession of what “portions” of the recited sequences are functional, and/or which portions can be mutated or deleted in order to retain the recited functionality of the promoters, where the present claim language allows for upwards of 5% variation in the promoter sequences. Furthermore, the Applicant has only identified 10 putative promoters with such functionality, and was therefore not in possession of any promoters with, for instance, “95%” sequence identity to SEQ ID NO:18. Thus, the Applicant was not in possession of either promoters comprising 95% sequence similarity to the recited sequences and much less “portions” of these sequences, which could comprise as few as 10 base pairs. For instance, the applicant has not established or shown possession of what a minimum “portion” of any of the promoters would be, where such a “portion” must still retain the functionality of a promoter which is formate-inducible, let alone if it would be possible to have a portion as small as, for instance, 10 bp, which could function as an inducible promoter.
Regarding the state-of-the art, it is known in the art that promoters are relatively uncharacterized, where such sequences comprise binding sites for transcription factors, where such binding sites are not fully characterized. For instance, Zhu (Zhu C et al. Genome Res. 2009 Apr;19(4):556-66) teaches that:
“Transcription factors (TFs) regulate the expression of genes through sequence-specific interactions with DNA-binding sites. However, despite recent progress in identifying in vivo TF binding sites by microarray readout of chromatin immunoprecipitation (ChIP-chip), nearly half of all known yeast TFs are of unknown DNA-binding specificities, and many additional predicted TFs remain uncharacterized. To address these gaps in our knowledge of yeast TFs and their cis regulatory sequences, we have determined high-resolution binding profiles for 89 known and predicted yeast TFs, over more than 2.3 million gapped and ungapped 8-bp sequences (‘‘k-mers’’). We report 50 new or significantly different direct DNA-binding site motifs for yeast DNA-binding proteins and motifs for eight proteins for which only a consensus sequence was previously known; in total, this corresponds to over a 50% increase in the number of yeast DNA-binding proteins with experimentally determined DNA-binding specificities,” (Abstract)
Zhu further teaches that such transcription factors bind to promoters (e.g., page 564, right column, final paragraph). Thus, Zhu teaches that transcription factor binding in yeast cells and their promoters is complex and unpredictable, where such transcription factor binding sites are largely unknown and must be characterized by empirical data and experimentation. The application has not shown any such characterization, where it is unknown and unpredictable what sequences of the recited SEQ ID numbers are conferring the functionality of being inducible promoters.
Similarly, Tang (Tang H et al. Metabolites. 2020 Aug 6;10(8):320) is a research article which focuses on promoter engineering in yeast cells (Title, Abstract, and throughout). Tang teaches that there is inherent unpredictability and complexity within endogenous promoters, teaching that:
“Alper created a library based on the TEF1 promoter and obtained a series of synthetic promoters with a wide range of activities; the best candidate showed a two-fold higher activity than the native PTEF1. These promoters were used to regulate efficient glycerol production by driving the rate-limiting enzyme expression in S. cerevisiae,” (page 8, thir paragraph).
Thus, Tang teaches that random mutagenesis libraries create promoters with a “wide range” of activity. Furthermore, as seen above, Tang teaches that such activities must be validated empirically.
Thus, given that promoters and their architecture, along with the binding sites which they comprise for transcription factors, are widely uncharacterized and unpredictable, and where furthermore such components are known to affect the functionality of the promoters, the applicant can not be said to have been in possession of the genus of promoters presently recited, as they have not performed any mutagenesis studies to identify structural elements of the promoters required for functionality or identified any transcription factor binding sites or essential functional regions of the promoters, and have at best only generated one “portion” of one of the promoters which comprised at least 1500 bp of one of the putative promoters.
Furthermore, given that the promoters themselves, which were inducible showed a range of induciblity from 2.9-38.6 depending on the promoter (Table 1 of the specification), the data appears to show wide range of variability across the promoters identified. There is therefore no indication that testing one “portion” of 1500 bp of one of the promotes would reasonably show possession of the remaining, untested promoters, as the identified promoters appear to show highly variable results (table 1 of specification).
Claims 10-12, 14-17, 23, 26, and 29-30 depend from claim 9 and do not resolve this 112(a) issue and are therefore also rejected under 112(a).
Furthermore, regarding claim 29, claim 29 recites a method of producing a vaccine using the nucleic acid of claim 1. However, the Applicant has not demonstrated or recited any such method to produce a vaccine in the specification or drawings. The Applicant has therefore not shown possession of any method of vaccine production using the nucleic acid of claim 1, let alone the unpredictable genera recited in claim 1, which further adds unpredictability and complexity to a method of vaccine production.
Response to Arguments
The Applicant’s arguments filed 6//9/2026 have been considered but are not persuasive. The Applicant argues that the claims have been amended to require 800 bp selected from any of the recited sequences, or that the promoter has at least 95% identity to the recited sequences. This argument is not persuasive because the present claims do not require 800 base pairs of the recited sequences, where the claim in fact recites that the first nucleic acid sequence “comprises or consists of a portion of a sequence” selected from SEQ ID NOs 2-33. Thus, the nucleic acid sequence presently recited encompasses a portion (e.g., 25 base pairs) of SEQ ID NO: 2, where the sequence is recited with the functionality of acting as a formate inducible promoter. The Applicant is therefore arguing limitations not actually recited in the claim by arguing that the claim requires 800 base pairs.
Furthermore, the Applicant argues that it is known by a person of ordinary skill in the art that a promoter can be significantly truncated and still remain functional. The Applicant makes this argument without evidence of record, and is therefore an argument of counsel. MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record. For instance, as discussed above in the 112(a) rejection, it is known that promoters comprise transcription factor binding sites and regions which are highly unpredictable and uncharacterized in yeast cells (see discussion of Zhu, above. Thus, there is evidence in the art which supports the argument of unpredictability, where the Applicant has not addressed the merits of the rejection or supplied any evidence to support the claim that promoters can be significantly truncated and retain there functionality.
The Applicant makes a similar argument with respect to making mutations within promoters, stating that it is known that promoter sequences tolerate mutations and retain their functionality. This is another argument of counsel which can not take the place of actual evidence of record. For instance, Zhu teaches that there are regions which bind transcription factors (proteins which control promoter expression) which specifically bind to sites within a promoter, and further teaches that such transcription factors and there binding regions are highly uncharacterized and unpredictable (see 112(a) rejection discussion of Zhu). Thus there is evidence of record which teaches unpredictability in the art which places a higher burden on the Applicant to show possession of the claimed invention.
The Applicant makes the argument that a person of ordinary skill in the art could generate mutations and/or truncations and test them to then determine the functionality of the promoters, and that such experiments are routine. This argument is not persuasive. The argument that a person could determine truncations/mutations is not the same as actually performing experiments necessary and sufficient to show that the Applicant has possession of the claimed scope of the invention. The Applicant has not performed any such experimentation or testing , and the mere fact that the Applicant or another person of skill in the art could perform mutation/truncation is not persuasive in the absence of reduction to practice or teachings regarding what such mutations and/or truncations might be to render functional promoters which respond to formate. For instance, the Applicant’s position that significant truncations can be made without affecting the functionality of the promoter is not supported in the specification or the art, where the Applicant has no way of determining if, for instance, residues 102-196 of SEQ ID NO: 5 (a portion which presently reads on the claims) is in fact a formate-inducible promoter in non-methylotrophic yeast cells. Furthermore, even if the claims required 800 bp of the recited promoters with 95% sequence identity, which the claims do not, such a genus is still undefined because the Applicant has not identified which 200 bps can be removed or mutated to render formate-inducible promoters.
The Applicant argued that Tang performed mutagenesis experimentation to identify promoters with enhanced performance, and that because other artisans have mutated promoters it would not be fair to restrict the scope of the present claims. This argument is not persuasive because 1) Tang was mutating and evaluating different promoters from those presently recited 2) the fact that other groups have performed experiments is not sufficient to render obvious mutations in entirely different promoters and 3) what Tang teaches is that actual experimental/empirical reduction to practice is required in order to identify promoters with a desired characteristic.
The Applicant argues that they were in possession of methods involving the use of the uncharacterized genus of promoter. This argument is not persuasive because as discussed above the key element of claim 29, i.e., the promoters in question, were not shown to be in possession by the Applicant at the time of filing. The Applicant was therefore not in possession of the “use” of such promoters in various undefined methods of use of such promoters in vaccine production (see 112(b) rejection and 112(a) rejections above).
Furthermore, as discussed in the above 112(a) rejection, the Applicant has not in fact reduced to practice all of the recited promoters and their response to formate, where such lack of evidence with respect to each recited sequence places a higher burden on the Applicant to shown possession of the recited genus of promoters including potential residues which tolerate mutations and/or truncations.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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