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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on 03/02/2026. Claims 1, 3-4, 6-12, 14-20, and 22 are currently pending. Claims 1, 6-8, 14, and 17 have been amended by Applicant’s amendment filed on 03/02/2026.
Election/Restrictions
Applicant’s election of Group I, which include claims 1, 3-4, 6-12, 14-19, and election of species for Group I, a promoter TBG-S1-Fl13 (SEQ ID NO: 7) in the reply filed on 08/28/2025 was previously acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6 and 8-11 were previously withdrawn from further consideration by Applicants pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 20 and 22- 24 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
The requirement for restriction between Groups I-III was previously made final
Therefore, claims 1, 3-4, 7, 12 and 14-19 are subject to examination to which the following grounds of rejection are applicable.
Priority
The instant application is a 371 of PCT/US21/29403 filed 04/27/2021. PCT/US21/29403 has priority to PRO 63/016,139 filed 04/27/2020
Thus, the earliest possible priority for the instant application is 04/27/2020.
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments
Claim Objections
The objection of claims 14 and 17 for improperly using the article “a” are withdrawn in view of applicants’ amendments.
Applicants’ arguments with regard to a withdrawn objection/rejection are moot.
Claim Rejections - 35 USC § 102
The previous rejections of claims 1, 3-4, 7, 12 and 14-19 as being anticipated by Wilson et al. are withdrawn in view of applicants’ amendments.
Applicants’ arguments with regard to a withdrawn objection/rejection are moot.New rejections/objections in response to Applicants’ arguments or amendments
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, 3-4, 7, 12 and 14-19 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.
Claims are directed to a gene cassette, comprising a genus of regulatory sequences with a promoter operably linked to a nucleic acid encoding a nuclease, wherein said promoter has a level of transcription less than the level induced by TBG-Sl. The claims are broadly but reasonably interpreted as comprising a genus of promoter having a level of transcription which is less than the level induced by TBG-Sl
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
Thus, the claims encompass a genus of cassettes comprising any nucleic acid comprising a sequence encoding a nuclease, operably linked to any number of regulatory sequences comprising any promoter that is “a promoter which has a level of transcription less than the level induced by TBG-S1” in any suitable in vitro or in vivo model as well as in any cell or tissue. (See also 112b rejection with respect to this recitation).
The specification teaches three promoter variants of TBG-S1; TBG-Sl -F64, TBG-Sl-Fl 13, and TBG-Sl-Fl40. The specification teaches three additional promoters, CCL16 promoter,
SCLC22A9 promoter, and CYP26Al promoter (Pg. 1, lines 25-30). The promoters are described as low transcription weak promoters (Pg. 4, line 11 – Pg. 5 line 7).
The applicant is on record as stating that the TBG-S 1 promoter in Wilson et al. (US 2018/0110877 Al) is actually a strong promoter and the definition of a promoter having low transcriptional activity at page 4, lines 12-19 of the application as filed (page 5 of Applicants’ remarks). Claim 1 recites “A gene targeting nuclease expression cassette comprising a nucleic acid comprising a nuclease coding sequence which is operably linked to regulatory sequences which direct expression of the nuclease following delivery to a host cell having a sequence to which the nuclease is targeted, wherein the regulatory sequences comprise a promoter which has a level of transcription less than the level induced by TBG-S1”
The specification does not identify what changes, mutations, fragments, regulatory sequences, or sequences encoding additional proteins, etc. could be used within a gene targeting nuclease expression cassette that would be encompassed by the structural limitations of claim 1 and still be able to produce a nuclease in a host cell at levels below that of TBG-S1 promoter.
The instant specification does not provide a sufficient representative sampling of structures that could encompass all of the possible species of the instant claim.
Specification Disclosure
The specification teaches three promoter variants of TBG-S1: TBG-Sl -F64, TBG-S1-Fl 13, and TBG-Sl-Fl40. The specification teaches three additional promoters, CCL16 promoter, SCLC22A9 promoter, and CYP26Al promoter (Pg. 1, lines 25-30). (Relevant figure 1 of instant application provided below).
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The promoters are described as low transcription weak promoters (Pg. 4, line 11 – Pg. 5 line 7). Introduction of the promoters is shown to result in less expression of a specific gene of interest compared to the TBG-S1 promoter in liver (Pg. 56, Table 2). The specification details the removal of increasing lengths of the TBG-S1 promoter to obtain the TBG-S1 promoter variants (Pg. 57 lines 1-3).
However, the specification does not actually describe a protocol by which any number of regulatory sequences which include at least one promoter (other than the 6 that are listed) could be identified or predicted, produced, and validated to have “less transcriptional activity” than the TBG-S1 promoter in any cell type or tissue in vitro and in vivo.
In summary, the specification describes a minimal species (6) within the claimed genus – cassettes comprising any nucleic acid comprising a sequence encoding a nuclease, operably linked to any regulatory sequence comprising any promoter that is “a promoter which has a level of transcription less than the level induced by TBG-S1”. The specification does not provide predictability for a nucleic acid sequence encoding for all possible products and retaining the claimed function of the instant application.
Claims 12 and 14-19 recite limitations upon the cassette of claim 1 that do not serve to remedy these issues.
Guidance Provided by the Art
A thorough search of the art failed to uncover any gene cassettes containing regulatory sequences including promoters specifically designed to produce less transcription than the TBG-S1 promoter. The prior art was generally searched for promoter engineering protocols, TBG promoter engineering, weak promoters, and regulatory sequence engineering as a whole.
The art detailed the complexity of regulatory systems, for example Artemyev et al. (Cells vol. 13,23 1963. 27 Nov. 2024) discusses “…promoter activity in one tissue or condition may significantly differ from its function in another context due to factors such as chromatin accessibility and nucleosome positioning. Moreover, promoters are integral parts of regulatory networks, interacting with transcription factors, enhancers, and other regulatory elements.”
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Barshad et al. (Genome research vol. 35,6 1277-1286. 2 Jun. 2025) teaches there is ongoing debate with respect to enhancer-promoter communication and the effect on gene regulation. Several factors play a role in the how gene regulation is affected by this relationship, including transcription-associated proteins (TAPs), such as transcription factor (Pg. 1279, TAPs have properties that facilitate hub formation), other proteins such as CTCF and cohesion (Pg. 1279-1280, CTCF and Cohesin: indirect players in enhancer promoter loop formation), enhancer-promoter distance (Pg. 1280-1281, Distances between enhancer–promoter DNA during interactions). Multiple models have been published in an attempt to characterize how varying factors affect the communication relationship, such as the bridge and hub models (Fig. 2 of Barshad provided below).
Due to the complexity of this system, multiple questions remain. Barshad discusses that “Although significant progress has been made in understanding the dynamics, distances, and models of enhancer–promoter communication, several key questions and debates remain unresolved. First, when during the transcription activation cycle does communication happen? The prevailing model suggests that communication occurs during a transcriptional burst; however, it is also possible that communication immediately precedes a burst, and interactions are released before the burst completes. Moreover, just as enhancer–promoter interactions can influence the transcription cycle, transcription can also influence contacts, as seen by recent studies showing that Pol II in general (Zhang et al. 2023), and even Pol II pausing (Barshad et al. 2023; Penagos-Puig et al. 2023), can affect enhancer–promoter interactions. Determining when communication occurs during the transcription activation cycle could provide critical insights into the regulation of gene expression and the mechanisms underlying transcriptional bursts. Second, do interactions better resemble a structural bridge or hub? The two models are not mutually exclusive. Although the literature appears to provide more and more support for hubs of some variety, evidence also suggests that enhancer–promoter pairs come into close apposition, and it remains possible that hubs support the formation of a transient protein bridge during transcriptional activation. Understanding how elements of the structural bridge and hub models might coexist or function together could reshape our understanding of the molecular mechanisms governing enhancer–promoter communication.” (Pg. 1283, Future outlooks and open questions). It is therefore evident that the field of synthetic biology with respect to regulatory sequences and promoters is highly complex and continues to evolve. Taken together, the art fails to provide predictability for a nucleic acid sequence encoding for all possible products, especially regulatory sequences, and retaining the claimed function of the instant application in any tissue/cell/model context.
Conclusion
Considering the large variation in the genus, the minimal species described in the specification, and the lack of predictability provided by the specification and art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Maintained and modified rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (b)
This rejection has been modified in response to the applicants’ amendments filed 03/02/2026.
Claims 1, 3-4, 7, 12 and 14-19 remain 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 1 recites “A gene targeting nuclease expression cassette comprising a nucleic acid comprising a nuclease coding sequence which is operably linked to regulatory sequences which direct expression of the nuclease following delivery to a host cell having a sequence to which the nuclease is targeted, wherein the regulatory sequences comprise a promoter which has a level of transcription less than the level induced by TBG-S1”. The recitation “regulatory sequences “ allows for multiple regulatory sequences. Therefore, metes and bounds are unclear and would not be readily apparent to one of ordinary skill in the art and this renders the claim indefinite.
It is unclear what the applicants’ intended meaning for the phrase “wherein the regulatory sequences comprise a promoter”. Does the applicant intend for the recited multiple regulatory sequences to include only a single specific promoter? Note that transcriptional activity of promoters is specific to the type of promoter used and transformed host cells with specific transcription factors. This lack of clarity renders the claim indefinite.
Additionally, it is unclear what the applicants’ intended meaning with respect to the transcription. The regulation of gene expression is highly context specific. Is the reduction in transcription meant to be solely for the encoded nuclease compared to the TBG-S1 promoter in the context of specific cells/tissues? In the context of the comparable promoters having the same regulatory elements? The metes and bounds are unclear and would not be readily apparent to one of ordinary skill in the art and this renders the claim indefinite.
Claims 3-4, 7, 12 and 14-19 are also rejected as they depend from claim 1.
Please note: The sequences of SEQ ID NOs: 6 and 7 (which are truncated sequences of the TBG-S1 promoter) appear to be free of the prior art.
Conclusion
1, 3-4, 7, 12 and 14-19 are rejected.
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 KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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, Maria G. Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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