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 8/21/2026. Claims 1-12, 15-26, and 30 are pending. Claims 12 and 30 have been amended. Claims 13-14 and 27-29 have been cancelled. All pending claims are currently under examination.
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant’s amendment of the claims since the office action mailed 5/21/2026. Therefore, this action is not final.
Claim Objections
Claims 10 and 19-20 are objected to because of the following informalities:
Claims 10 and 19 recite “a mRNA” which should be changed to “an mRNA” as the use of a/an is determined by pronunciation.
Claim 20 recites “a viral vectors” which should be amended to “a viral vector.”
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Figures 19A-C and 20A-20B contain nucleotide sequences that are not identified by sequence identifiers (i.e., SEQ ID NOs) in the drawings or in the brief description of the drawings. Drawings containing nucleotide sequences must be accompanied with their proper SEQ ID numbers, either in the drawings themselves or in the brief description of the drawings in the specification. For instance, the brief description of Figures 19A-C do not include SEQ ID NOs for the sequences listed in Figure 19. Additionally, SEQ ID numbers of the sequences shown in Figure 19 are not shown in the figure itself. The remaining figures listed above have similar deficiencies, wherein the figures contain nucleotide sequences that are not identified with SEQ ID numbers and have no corresponding SEQ ID numbers recited in the brief description of said figures.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112 – New Rejection
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 9-11, 18-20, and 23-25 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 9, claim 9 recites in the alternative “the composition of claim 1 or a polynucleotide encoding the Cas protein and/or guide molecule.” Recitation of “the Cas protein and/or guide molecule” lacks proper antecedent basis because it is not referenced back to claim 1. Amending claim 9 to recite “the Cas protein and/or guide molecule of claim 1” would be remedial. Claims 10-11 depend from claim 9 and are also rejected because they do not resolve this issue.
Similarly, claim 18 suffers from the same 112(b) issue, where claim 18 recites ““the composition of claim 12 or a polynucleotide encoding the Cas protein and/or guide molecule,” where “the Cas protein and/or guide molecule” lacks proper antecedent basis and can be addressed with a similar amendment. Claims 19-20 depend from claim 18 and do not resolve this issue and are also rejected.
Regarding claim 23, claim 23 recites that “the Cas protein makes an A>G or C>T base edit.” This claim language is confusing because the deaminase, and not the Cas protein, is what is presumably making the edit.
Regarding claim 24, claim 24 recites “a method of treating a disease associated with splicing, transport, localization, translation, and/or turnover” and later in lines 3-4 recites “the composition modulates splicing, transport, localization, translation, and/or turnover associated with the disease.” Claim 24 is unclear because lines 3-4 do not recite “RNA” in association with for instance localization. It is unclear what molecule types claim 24 requires which the claimed composition modulates, or if the claim is meant to encompass for instance localization of any molecule which could be acted upon as such.
Claim 25 depends from claim 24 and does not resolve this 112(b) issue and is therefore rejected.
Claim Rejections - 35 USC § 112 – Maintained/Updated to Clarify the Rejection
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.
Claims 5, 24-26 and 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.
Regarding claim 5, claim 5 recites that the Cas protein is associated with one or more “functional domains.” Thus, claim 5 is broadly drawn to a genus of “functional domains” where furthermore such functional domains can comprise any number of combinations or embodiments (“one or more” functional domains). This claim language is problematic because it is known in the art that protein functional domains can comprise diverse and unpredictable functions, where the complexity and unpredictability of the recited functional domains is compounded by the fact that the claim language includes embodiments where functional domains are combined (“one or more”). The specification does not demonstrate possession of the genus “functional domains” as presently recited.
Regarding the specification, the specification does not offer a clear definition for “functional domain,” thus the plain meaning of the term in this context is taken to mean a protein domain with any given function. Thus, recitation of ‘functional domain” broadly includes any protein domain with a function. With regards to reduction to practice, the specification offers Examples 1-4. Examples 1-2 relate to detection methods using systems described in the specification, where Example 2 describes the characterization of novel Cas enzymes. Example 3 characterizes exemplary small Cas proteins. In Example 3, the Applicants fused the novel Cas enzymes with deaminases functional domains and demonstrated that such fusions were capable of site-specific base conversions (paragraphs 1162-1163). Example 4 is directed to identical subject matter as Example 3. Thus, the Applicant describes fused deaminase domains with the recited Cas proteins and demonstrated functionality of such fusions.
Regarding the state of the art, it is known that functional domains of proteins are complex and unpredictable. For example, Goodacre (Goodacre NF et al. mBio. 2013 Dec 31;5(1):e00744-13) is a research article which focuses on protein domains of unknown function within bacteria (Title, Abstract, and throughout). Goodacre teaches that:
“More than 20% of all protein domains are currently annotated as “domains of unknown function” (DUFs). About 2,700 DUFs are found in bacteria compared with just over 1,500 in eukaryotes. Over 800 DUFs are shared between bacteria and eukaryotes, and about 300 of these are also present in archaea. A total of 2,786 bacterial Pfam domains even occur in animals, including 320 DUFs,” (Abstract).
Thus, Goodacre teaches that the genus of protein “functional domains” is known to be uncharacterized and by extension unpredictable because it is known in the art that large portions of protein domains are not functionally characterized across multiple organisms (Goodacre, above). Furthermore, the issue of uncertainty and complexity are compounded by the fact that, given that thousands of protein functional domains are undefined, their functionality with a “Type VI Cas protein,” and/or how such unknown protein domains may influence or interfere with such a Cas protein is similarly unpredictable. In addition, such unpredictability is compounded by the fact that claim 5 recites that “one or more” functional domains may be present which includes combinations of undefined protein domains.
The Applicant has not shown possession of the genus “functional domain” because it is known as taught by Goodacre that such a genus is uncharacterized, where furthermore the Applicant’s specification has not demonstrated possession of this genus. Claim 5 is therefore rejected.
Regarding claim 24, claim 24 recites a method of treating a disease associated with RNA splicing, transport, localization, translation, and/or turnover, comprising administering a composition of claim 1, where the composition modulates splicing, transport, localization, translation, and/or turnover associated with the disease. Claim 24 therefore requires the claim limitations of claim 1, where claim 1 recites a composition comprising a Cas protein which forms a complex with a guide sequence which directs the complex to a target sequence. Claim 24 therefore establishes a structure-function relationship between the guide sequence of claims 1 and 24 and the target sequences of the guide sequence recited in the claims: the target sequences must be associated with causing a disease, and the guide sequence which targets a target sequence must be functionally capable of having the overall effect of treating a disease associated with, for instance, RNA splicing, transportation, localization, translation, and/or turnover. As such, the guide sequence and its target sequence carry functional weight in the claims based upon the structure of the guide sequence and target sequence (i.e., the nucleic sequences), where a guide sequence targets a target sequence which is associated with a disease and act as a target to have the effect of “treating” said disease. As such, the target sequences must be bona fide target sequences which are associated with a given disease. Claim 24 broadly recites “target sequence” and “guide sequence” where furthermore the claim recites that a disease is treated by the administering of the composition of claim 1, which requires a “target” to be bound by the complex of claim 1.
Claim 24 therefore broadly recites the genus of “target sequence” and “guide sequence” which can be targeted to affect a change/treatment in a disease associated with, for instance, RNA splicing, transport, localization, translation, and/or turnover. As discussed further below, the Applicant was not in possession of the broad genus of such targets/guides as those recited with the specific function of treating a disease associated with RNA splicing because, as it was known in the art at the time of filing, RNA splicing variants and targets associated with diseases were known to be an unpredictable genus (see the discussion on Truty, below). The Applicant has not demonstrated possession of the claimed genus of “target sequences” and the guide sequences which target such sequences with sufficient reduction to practice or guidance to show possession of the claimed genus as a whole because the species the Applicant recites in the specification are not representative the of the genus as a whole because the art teaches that the targets, and by extension guide sequences which would target the targets, are unknown (see below). The Applicant further does not establish a structure-function relationship between the targets and their recited function (e.g., the Applicant does not establish a core sequence which could be used as a target in a method of treating a splice-associated disease). Such targets and sequences to be targeted to treat disease are furthermore not predictable, as taught in the art (see discussion, below). The application therefore does not show possession of the claimed subject matter (see below).
With regards to the specification, the Applicant has not shown possession of the claimed subject matter. The Applicant has classified and characterized a few Cas enzymes and reduced their functionality to practice. For instance, the Applicant recites Example 4 and demonstrated that the smaller Cas proteins identified can act as RNA base editors (paragraphs 1265-1274). The Applicant has reduced to practice such methods in HEK293 reporter constructs and endogenous transcripts (paragraph 1269). The Applicant has not taught and reduced to practice specific targets using their methods for treatment of diseases such as cancer and AMD (as recited in claim 25). The Applicant recites RNA knockdown and editing assays (e.g., paragraphs 1299-1304). The Applicant also offers Table 10 which includes a list of diseases and genes associated with said diseases which could potentially be targeted by their systems (Table 10, paragraph 962). The specification does not sufficiently characterize the scope of the claims by showing representative species or a core structure-function relationship between target sequences and guide sequences which would have the effect of treating a splice associated disease because it is known in the art that such target sequences and their complementary guide sequences are unpredictable. The mere fact that the Applicant can make a guide sequence to target a target sequence does not mean that they have characterized the presently claimed subject matter, as the Applicants were not in possession of specifically which “target sequences’ or “guide sequences” would be used to treat diseases associated with RNA splice variants (see below for a discussion on the unpredictability of the recited genus).
However, with regards to the state-of-the-art, it is known that targets for diseases associated with RNA splicing are complex and unpredictable. For instance, Truty (Truty R et al. Am J Hum Genet. 2021 Apr 1;108(4):696-708) is a research article which focuses on RNA splicing variants and their association with disease (Title, Abstract, and throughout). Truty teaches that:
“The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs,” (Abstract).
Truty further teaches that natural variations of splicing confound the clinical relevance of splice variants (Abstract).
Truty teaches that:
“Variants that may alter RNA splicing can be computationally predicted, and these predictions can be confirmed by RNA analysis. However, assessing the clinical consequences of abnormal splicing can be challenging because of an incomplete understanding of alternative splicing and normal RNA expression profiles across tissues. Some studies have revealed previously unrecognized variety in RNA transcript isoforms associated with well-studied genes, including BRCA1 and BRCA2, showing that our understanding of naturally occurring alternative splicing of disease gene transcripts is still evolving. Recent studies have also illuminated how differential expression of transcript isoforms can influence whether certain sequence variants are tolerated. As a result of this underappreciated complexity, variants that allow biologically viable alternative
splicing may be incorrectly classified as disease causing. Therefore, investigating both the spectrum of variants predicted or assumed to cause abnormal splicing
across a broad variety of genes and their contribution to naturally existing genomic variation is essential to understanding their overall involvement in hereditary disease,” (Introduction, first paragraph).
Thus, Truty teaches that there is known unpredictability when attempting to define RNA splicing associated with diseases, where large cohort models and direct RNA analysis are required in order to help clinical interpretation (Abstract, and Introduction).
Truty further teaches that:
“Several computational tools are used to predict the potential splicing effects of variants encountered during clinical genetic testing for hereditary disease. However, these tools often do not have a high positive predictive
value when used individually, particularly for variants outside the essential splice site(s) (ESS). Therefore, their predictions are often not considered usable evidence for variant interpretation unless there is consensus among them,” (Introduction, first paragraph).
Truty therefore teaches that prediction methods for the effects of RNA splice variants and their clinical roles are unpredictable, where Truty further teaches that previously identified variants with unknown significance can be classified as pathogenic splice variants or benign based upon further analysis (Introduction, first paragraph, final sentence).
Truty further teaches that:
“Furthermore, the challenge of interpreting splicing variants is not limited to hereditary cancer and has been noted in other disease areas, such as inherited retinal diseases. To avoid negative outcomes, it is essential to consider a variety of types of evidence for variant interpretation and to use appropriate control samples during RNA analysis. Compounding the challenge of accurately interpreting the effects of a splicing variant is the conundrum of defining which one or a subset of transcript isoforms may be affected. This has implications for identifying molecular etiologies of disease through genetic testing because clinical laboratories may sometimes choose a single reference transcript when reporting observed variants. In some cases, the chosen reference transcript may not be fully relevant to the disease in question (and the prediction of splicing effects can be dependent on the transcript chosen), leading to missed diagnoses. It is expected that clinical interpretation of variants identified during genetic testing for inherited disease will eventually consider the individual expression patterns of specific transcripts for each disease gene and how those patterns may affect the manifestation of disease. Various studies have shed light on the complexity of gene expression through discovery of novel exons, complex interactions between splicing variants and tissue-specific effects, the effect of cellular context on splicing in the absence of variants that affect splicing (e.g., in the progeria-related LMNA gene [MIM:150330]), and quantitative effects of transcript isoforms on clinical phenotypes,” (page 704, left column, paragraphs 1-2).
Truty therefore teaches that RNA splice variants and their exact roles in diseases – including cancer and retinal diseases such as those recited in instant claims 25 and 30 – are complex and undefined. Given that such uncertainty and complexity exists concerning the classification and roles of specific RNA splice variants in disease, the effects of targeting such an RNA in the context of a given disease are also unpredictable. The Applicant was therefore not in possession of the genus “target sequence” or “guide sequence” as recited in claim 1 and by extension claims 24-26 and 30 as such a genus is unpredictable. Furthermore, the teachings of Truty generally teach that the genus of target in the context of what such a target would be in order to act as a treatment in the context of disease is largely undefined (see specific passages quoted above, and throughout Truty). In short, the genus of “target sequence” and “guide sequence” in the context of splicing-associated disease is known to be unpredictable; the Applicant has not characterized this genus or defined and recited specific targets commensurate in scope with what is claimed.
Furthermore, it is known in the art that complex disease states such as cancer are associated with aberrant RNA splicing, export/localization, and translation. For instance, Borden (Borden KLB. Biochem Soc Trans. 2022 Oct 31;50(5):1447-1456) is a review article that focuses on how cancer produces changes in RNA processing (Title, Abstract, and throughout). Borden teaches that:
“mRNA processing is a critical determinant for the protein-coding capacity of mRNAs since these physical changes impact the efficiency by which a given transcript can be exported to the cytoplasm and translated into protein. While many of these mRNA metabolism steps were considered constitutive housekeeping activities, they are now known to be highly regulated with combinatorial and multiplicative impacts i.e. one event will influence the capacity to undergo others. Furthermore, alternative splicing and/or cleavage and polyadenylation can produce transcripts with alternative messages and new functionalities…In all, dysregulated RNA metabolism in cancer gives rise to an altered proteome that in turn elicits biological responses related to malignancy. Studies of these events in cancer revealed new mechanisms underpinning malignancies and unearthed novel therapeutic opportunities. In all, cancer cells coopt RNA processing, export and translation to support their oncogenic activity,” (Abstract)
Borden therefore teaches that cancer yields altered RNA processing in cells in combinatorial, multiplicative mechanisms, where such alterations affect export, translation, and RNA splicing (above). Furthermore, with respect to therapeutic targeting and the identification of targets which affect RNA processing, Borden teaches that:
“eIF4E has been a focal point for development of cancer therapeutics targeting RNA metabolism…eIF4E phosphorylation inhibits RNA export and may have impacts on translation although this is highly debated. Phosphorylation may also modulate other eIF4E activities although this is yet to be determined. Thus, it is not yet known if inhibition of its phosphorylation will impact on multiple eIF4E activities. The last group including 4GI-1 may only impact eIF4E-dependent translation which may limit its clinical utility; however, its ability to inhibit other eIF4E activities has not yet been investigated and given the proximity of 4GI-1 to the cap-binding site may well have inhibit other functions,” (page 1451, final paragraph).
Borden therefore teaches that the specific potential therapeutic targets such as eIF4E have undetermined roles in RNA processes such as translation in the context of cancer target therapeutics, where further investigation is required to identify the exact role such targets may have in translation. Borden therefore teaches that overall RNA processing in cancer is a complex process where individual targets and proteins which may be involved in such processing are unresolved (Abstract, page 1451).
Regarding claim 25, as discussed above, Truty further teaches that genes associated with hereditary cancer and the role of splice variants are unpredictable. Borden further teaches the complexity and unpredictability of identifying targets for cancer therapeutics which affect RNA processing such as translation and export (above). The Applicant has not shown possession of such splice variants and their role in cancer (see rejection of claim 24).
Regarding claim 26, claim 26 is broadly drawn to a method of treating a disease, which includes for instance the diseases associated with RNA splicing. The scope of 26 therefore broadly encompasses the claim limitations of claim 24. As claim 26 recites a larger genus of diseases to be treated, which includes RNA splice associated diseases, the Applicant has not shown possession of claim 26 for the same reasons as those given in the rejection of claim 24 above. Thus, claim 26 is rejected for at least the reasons outlined in the rejection of claim 24, above.
Regarding claim 30, claim 30 broadly includes diseases such as cancer, where hereditary cancer genes and their unpredictability with respect to splice variants is discussed above in the rejection of claim 24 with respect to Truty. Borden further teaches the complexity and unpredictability of identifying targets for cancer therapeutics which affect RNA processing such as translation and export (above). Claim 30 encompasses the claim limitation of claim 25 and is therefore rejected for the same reason. Thus, claim 30 is rejected for at least the reasons outlined in the rejection of claim 24, above.
Response to Arguments
The Applicant’s arguments filed 8/21/2026 have been considered and are not persuasive.
As an initial matter, the Applicant has not addressed the 112(a) rejection of claim 5 by either argument or amendment. The rejection of claim 5 is therefore maintained.
The Applicant argues that the Office has not met the burden of establishing a 112(a) rejection based upon unpredictability. This argument is not persuasive. The 112(a) rejection above establishes that 1) the Applicant is claiming a genus of “target sequences” and “guide sequences” which are recited in claims 24 and 26 with functional limitations because they are recited to be used in a method to treat a disease, where the compositions of claims 1 and 12, from which claims 24 and 26 depend, respectively, have a structure-function relationship (i.e. the target and guide sequences are recited in a method to treat a disease), 2) the specification provided by the Applicant offers a limited number of target sequences of the guide sequences, where the species recited in the specification are not sufficient to show possession of the claimed genus because 3) it is known in the art that target sequences for treating diseases, such as diseases associated with splice variants, is a highly unpredictable genus comprising unknown target sequences and their complementary guide sequences which could be used in such a method. Each of these three elements are addressed in the 112(a) written description rejection, above.
The Applicant argues that:
“[t]hat the claims do not recite specific targets, that the specification "offers only a few targets," and that Applicant "has not reduced to practice the treatment of disease" appear in a single sentence that returns to where the ground began, in the conclusion that "the evidence in the art teaches unpredictability and demonstrates the lack of possession of the presently recited subject matter of claims 24-28 and 30." None of the three is accompanied by the comparison of claim scope to the scope of the description that a genus finding requires.”
This argument is not persuasive because the 112(a) rejection is accompanied by an analysis of the scope of the claims (paragraph beginning “Regarding claim 24”) as well as what guidance is provided in the specification (paragraph beginning “with regards to the specification”). There is therefore a comparison between what is claimed versus what is described in the specification, as well analysis as to why the specification is insufficient in light of the unpredictability known in the art to show possession of the claimed genus of target/guide sequences.
The Applicant argues that the rejections rests on a “general allegation of unpredictability.” This argument is not persuasive because it is a mischaracterization of the rejection. The position of the Office is that the Applicant is claiming possession of a genus which they have not shown possession of, where it is furthermore known in the art that the claimed genus of targets/sequences are unpredictable. The argument of unpredictability supplied by the Office is not simply a “general allegation of unpredictability” but is based upon scientific research and findings as taught by Truty. Truty teaches direct statements which speak to the lack of predictability in the art with respect to the recited genus of targets/guide sequences (see discussion of Truty, above). The Office therefore does not provide a general allegation, but instead provides an argument based upon knowledge of the art with respect to diseases associated with RNA splicing.
The Applicant argues that “[t]he Office identified no structural feature distinguishing the described species from the alleged genus, made no comparison of "the scope of the claim with the scope of the description," made no "determination of the field of the invention and the level of skill and knowledge in the art," and conducted no review "from the standpoint of one of ordinary skill in the art at the time the application was filed." This argument is not persuasive because the 112(a) rejection in fact performed this analysis. The Office has made a comparison of the scope of the claims with respect to the description, and has furthermore made a factual finding to determine knowledge in the field, where the knowledge in the field (i.e., Truty) teaches that the genus of sequences recited, which require a functional limitation of being a component of a composition to treat a disease associated with splice variation, is an unpredictable genus because the effects of splice variants and their role in disease is unknown. Thus, the Applicant does not know what to target, and the guidance in the specification does not resolve this gap in knowledge in the art. The Applicant was therefore not in possession of “target sequences” or “guide sequences” which would bind to such targets to affect a treatment of a disease associated with RNA splicing. The specification is inadequate to show possession of the scope of the claimed subject matter because the state-of-the art teaches unpredictably with respect to the claimed subject matter which the specification does not address or resolve, namely, what a practitioner would actually target to treat a disease.
The Applicant argues that there is a presumption of adequacy of the description unless shown otherwise, and that the Office did not meet the burden of showing the inadequacy of the description. This argument is not persuasive because the Office has demonstrated unpredictability of the recited sequences because the art, Truty, teaches unpredictability. The burden has now shifted to the Applicant to show that their specification is adequate in view of the unpredictability known in the art.
The Applicant argues that the Office’s rejection does not rest on a reasonably basis or preponderance of evidence. The Applicant argues that the rejection relies only on one reference, Truty. This argument is not persuasive because the mere fact that Truty is only reference does not speak to its inability to demonstrate a preponderance of evidence. For instance, Truty teaches that they have based their findings of a study of ~680,000 patients (Abstract). Such a large cohort is a “preponderance of evidence,” and it is irrelevant that such a large study was performed and described in a single publication.
The Applicant argues that Truty does not relate to the present technology because it does not mention Cas or RNA therapeutics. This argument is not persuasive because 1) Truty relates to RNA splice variants and their relationship to disease (Title), which is the subject matter recited in claim 24, and is furthermore related to diseases as broadly encompassed by claim 26, and 2) Truty teaches uncertainty with respect to the role a variant may play in disease, where such variants are what would be targeted in the recited method. Truty teaches that in general the art is unpredictable with respect to what role a splice variant may play in disease. Because RNA splice variants are targets in the recited method, the teachings of Truty are directly relevant to what is claimed, as a person in the art would be uncertain as to what to target in RNA splicing associated diseases based upon the teachings of Truty, who further teaches unpredictability in hereditary cancer genes. The Applicant argues that Truty’s RNA splice variants “bear on the weight given a variant in clinical classification, not on whether a target sequence can be described.” This argument is not persuasive because if a sequence cannot be classified for clinical significance, as Truty teaches, it is unpredictable as to whether such a variant would be a “target” in a method to treat disease. The teachings of Truty therefore have direct bearing over the claimed subject matter, which requires bona fide targets which can be targeted to treat a disease. The fact that Truty teaches that a person of ordinary skill in the art does not know whether or not a variant is actually associated with a disease certainly bears on the unpredictability of using such a sequence as a target/guide sequence in the recited method.
The Applicant argues that guide sequence and target sequence complementarity is a known structure-function relationship, and that guide sequences can be designed and used to functionally to target a sequence. The Office agrees that a practitioner can design a guide sequence. However, the ultimate question is to what the guide sequence is complementary in order to result in the treatment of a disease, as presently recited. In other words, the issue is the target sequence, which informs the guide sequence, wherein the specification does not offer sufficient guidance to show possession of the claimed scope of such sequences, and wherein the art further teaches that such targets are unpredictable.
The Applicant argues that the Office did not analyze the entity of paragraph 1269. The Office acknowledges that, for the purposes of the rejection, only half of the paragraph was cited. The Applicant quotes the remaining half of the paragraph, which is still not sufficient to show possession of the scope of the claimed subject matter because, although the second half of paragraph 1269 discusses targeting endogenous genes it does not show possession of which endogenous genes can be targeted to treat RNA splicing associated diseases. The argument is therefore not persuasive, although the inclusion of the second half of the paragraph, which is directed to targeting endogenous genes, has been incorporated into the rejection simply for the sake of completeness. The Office acknowledges that the Applicant can target an endogenous gene, but the question is whether or not the Applicant has shown possession of the claimed subject matter, which requires targeting of specific sequences to treat diseases. The Applicant has not shown possession of such target sequences and guide sequences for the reasons outlined in the rejection, above.
The Applicant argues that the Office’s account of allowable subject matter contradicts the present rejection. This argument is not persuasive because the present rejection is based upon specific limitations recited in the claim, namely, that treatment of a disease occurs, wherein such treatment functionally requires sequences which would target a sequence using a guide sequence to treat the disease, wherein the Applicant has not characterized such target sequences or guide sequences. The Office acknowledges that the Applicant could target a sequence; however, the Applicant was not in possession of the present claim limitations, where hybridization of guide sequences to their complementary targets would have the effect of treating a disease as recited because the genus is unpredictable as taught in the art. The Applicant’s specification has not resolved the unpredictability in the art, wherein the sequences that are targeted by the Applicant are not representative species of sequences which could treat a disease as such sequences are unpredictable as taught by Truty.
The Applicant argues that claims 25, 26, and 30 were not addressed because they were tied into the rejection of claim 24. This argument is not persuasive. Claim 26 broadly encompasses the treatment of any disease, which includes the diseases of claim 24. The scope of the claim is what is at issue in the analysis, not what is specifically recited (see MPEP 2163, “ "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention”). Claim 26 recites the treatment of a disease, which reasonably includes the diseases recited in claim 24. The analysis of claim 24 therefore applies to claim 26 and also claim 30, as discussed previously. Nonetheless, separate paragraphs to clarify these points have been added to the rejection.
In conclusion, the arguments are not persuasive, the Applicant has not shown possession of the genus of target sequences and guide sequences which have the functional requirement of treating diseases, including splice variant diseases. Truty, while being a single reference, does in fact offer a preponderance of evidence because Truty is directed to a study of over 680,000 people (i.e., a preponderance of evidence). Further the teachings of Truty are directly relevant to the claimed subject matter because Truty teaches uncertainty and unpredictability concerning what an actual target sequence should be which would render the functional requirement of treating a disease, as presently recited. The mere fact that the Applicant can make a guide sequence to target a target sequence does not mean that they have characterized the presently claimed subject matter, as the Applicants were not in possession of what “target sequences’ or “guide sequences” would be used to treat diseases associated with RNA splice variants.
Claim Rejections - 35 USC § 112 – Enablement/New Rejection Not Necessitated by Amendment
Claims 21-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for in vitro cleaving of target RNA (claims 21-23), does not reasonably provide enablement for in vivo use to treat the broad genera of diseases recited (claims 21-26 and 30). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They 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 these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of the Invention/Breadth of Claims
Regarding claims 21-23, these claims broadly encompass in vivo methods of cleaving a target RNA. This claim language is problematic because the breadth of the claim includes targeting specific in vivo cells in any specific context, including for instance targeting and delivery of reagents in diseases such as cancer. As will be discussed further below, the Applicant has not provided sufficient guidance in the specification to the effect that a practitioner would be able to use the broadly recited method in in vivo specific contexts to target RNA (see discussion below on prior art Shembrey).
Regarding claim 24, claim 24 is broadly drawn to a method of treating a disease associated with RNA splicing by administering the composition of claim 1. Claim 1 comprises a Cas enzyme and heterologous guide sequence which forms a complex to bind a target sequence. Thus, claim 24 recites as an active element of the claim a composition of a Cas enzyme and guide sequence which targets a target sequence, where said composition is recited with the capacity to treat a disease associated with RNA splicing. This claim language is problematic because 1) the Applicant has not reduced to practice the treatment of any diseases 2) the Applicant has not identified which target sequences/guide sequences shall be used to have the effect of treating a disease associated with RNA splicing and 3) the art teaches unpredictability with respect to which sequences qualify as bona fide targets which could be used to treat a disease associated with RNA splicing, turnover, transport, and/or translation. See discussion below.
Guidance in the Specification
With regards to the specification, the Applicant has classified and characterized a few Cas enzymes and reduced their functionality to practice. For instance, the Applicant recites Example 4 and demonstrated that the smaller Cas proteins identified can act as RNA base editors (paragraphs 1265-1274). The Applicant has reduced to practice such methods in HEK293 reporter constructs and targeted endogenous transcripts (paragraph 1269). The Applicant has not taught and reduced to practice specific targets using their methods for treatment of diseases such as cancer, RNA splicing, and AMD (as recited in claims 24 and 25). The Applicant recites RNA knockdown and editing assays (e.g., paragraphs 1299-1304). The Applicant also offers Table 10 which includes a list of diseases and genes associated with said diseases which could potentially be targeted by their systems (Table 10, paragraph 962). The specification does not reduce to practice the treatment of any diseases using in vivo testing methods.
State of the Art
Regarding the state of the art, it is known that targets for diseases associated with RNA splicing are complex and unpredictable. For instance, Truty (Truty R et al. Am J Hum Genet. 2021 Apr 1;108(4):696-708) is a research article which focuses on RNA splicing variants and their association with disease (Title, Abstract, and throughout). Truty teaches that:
“The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs,” (Abstract).
Truty further teaches that natural variations of splicing confound the clinical relevance of splice variants (Abstract).
Truty teaches that:
“Variants that may alter RNA splicing can be computationally predicted, and these predictions can be confirmed by RNA analysis. However, assessing the clinical consequences of abnormal splicing can be challenging because of an incomplete understanding of alternative splicing and normal RNA expression profiles across tissues. Some studies have revealed previously unrecognized variety in RNA transcript isoforms associated with well-studied genes, including BRCA1 and BRCA2, showing that our understanding of naturally occurring alternative splicing of disease gene transcripts is still evolving. Recent studies have also illuminated how differential expression of transcript isoforms can influence whether certain sequence variants are tolerated. As a result of this underappreciated complexity, variants that allow biologically viable alternative
splicing may be incorrectly classified as disease causing. Therefore, investigating both the spectrum of variants predicted or assumed to cause abnormal splicing
across a broad variety of genes and their contribution to naturally existing genomic variation is essential to understanding their overall involvement in hereditary disease,” (Introduction, first paragraph).
Thus, Truty teaches that there is known unpredictability when attempting to define RNA splicing associated with diseases, where large cohort models and direct RNA analysis is required in order to help clinical interpretation (Abstract, and Introduction). Truty teaches that our understanding of even well-characterized genes such as BRCA1 and BRCA2 with respect to splice variants and their relationship to disease are still evolving (above) and therefore teaches unpredictability with respect to what may constitute a bona fide target for treatment of disease.
Truty further teaches that:
“Several computational tools are used to predict the potential splicing effects of variants encountered during clinical genetic testing for hereditary disease. However, these tools often do not have a high positive predictive
value when used individually, particularly for variants outside the essential splice site(s) (ESS). Therefore, their predictions are often not considered usable evidence for variant interpretation unless there is consensus among them,” (Introduction, first paragraph).
Truty therefore teaches that prediction methods for the effects of RNA splice variants and their clinical roles are unpredictable, where Truty further teaches that previously identified variants with unknown significance can be classified as pathogenic splice variants or benign based upon further analysis (Introduction, first paragraph, final sentence).
Truty further teaches that:
“Furthermore, the challenge of interpreting splicing variants is not limited to hereditary cancer and has been noted in other disease areas, such as inherited retinal diseases. To avoid negative outcomes, it is essential to consider a variety of types of evidence for variant interpretation and to use appropriate control samples during RNA analysis. Compounding the challenge of accurately interpreting the effects of a splicing variant is the conundrum of defining which one or a subset of transcript isoforms may be affected. This has implications for identifying molecular etiologies of disease through genetic testing because clinical laboratories may sometimes choose a single reference transcript when reporting observed variants. In some cases, the chosen reference transcript may not be fully relevant to the disease in question (and the prediction of splicing effects can be dependent on the transcript chosen), leading to missed diagnoses. It is expected that clinical interpretation of variants identified during genetic testing for inherited disease will eventually consider the individual expression patterns of specific transcripts for each disease gene and how those patterns may affect the manifestation of disease. Various studies have shed light on the complexity of gene expression through discovery of novel exons, complex interactions between splicing variants and tissue-specific effects, the effect of cellular context on splicing in the absence of variants that affect splicing (e.g., in the progeria-related LMNA gene [MIM:150330]), and quantitative effects of transcript isoforms on clinical phenotypes,” (page 704, left column, paragraphs 1-2).
Truty therefore teaches that RNA splice variants and their exact roles in diseases – including cancer and retinal diseases such as those recited in instant claims 25 and 30 – are complex and undefined. Given that such uncertainty and complexity exists concerning the classification and roles of specific RNA splice variants in disease, the effects of targeting such an RNA in the context of a given disease are also unpredictable.
The teachings of Truty generally teach that targets and guide sequences which target such target sequences in the context of treatment of a disease are largely undefined (see specific passages quoted above, and throughout Truty). In short, the art teaches that “target sequences” and “guide sequences” in the context of splicing-associated disease is not fully understood. The Applicant has not characterized such sequences or defined and recited specific targets commensurate in scope with what is claimed.
Additionally, it is known in the art that with respect to Type VI Cas enzymes such as Cas13, there are known hurdles and challenges which exist in implementing such Cas enzymes for the in vivo treatment of diseases such as cancer. For instance, Shembrey (Shembrey C et al. Sci Adv. 2024 Dec 20;10(51):eadl0731) is a research article which teaches applications of Cas13 (a type VI Cas enzyme) in targeting oncogenic targets for treatment (Title, Abstract, and throughout). Shembrey teaches that:
“despite its potential, the major hurdle for these RNA-targeting tools lies in the absence of efficient and safe strategies for delivering large Cas13 enzymes and their crRNAs to hard-to-transfect patient-derived cancer cell lines and animal models. Although a key benefit of CRISPR-Cas13 technology is that it does not mutilate genomic DNA, this means that Cas13-based therapeutics will likely require repeated dosing for sustained RNA cleavage activity, a constraint applicable to all RNAi technologies. This is additionally complicated by the rapid degradation of crRNAs in cells, yielding only transient knockdown. Although a single dose of transiently delivered Cas13 and crRNA resulted in ~40% reduction in endogenous KRAS G12 expression and ~70% reduction of endogenous BRAF V600E, this was insufficient to produce sustained antiproliferative phenotypes in many of the cancer cell lines tested,” (page 13, right column, second paragraph).
Shembrey therefore teaches that application of such RNA-targeting tools as those recited in the present claims are known to face major in vivo hurdles owing to inefficient and safe delivery of the enzymes both to certain cell types and to animal models (above). Shembrey further teaches that the repeated dosing requirements and treatments have been shown to be insufficient for sustained antiproliferation phenotypes in cancer cell lines (above). Shembrey therefore teaches that it is known in the art that a method of in vivo delivery of Cas13 to cleave targets (claims 21-23) or treating a disease such as cancer (as encompassed by claims 24-26 and 30) suffers major hurdles which have yet to be resolved, where such treatments are known to be ineffective and challenging (above).
Shembrey further teaches that:
“Future work should focus on optimizing delivery methods that allow for efficient and sustained expression of Cas13 and crRNA in vitro and in vivo. To this end, important milestones have been met in the delivery of various CRISPR systems using Adeno-Associated Viruses (AAV) or through the delivery of Cas endonuclease mRNA encapsulated into lipid nanoparticles. Similarly, meaningful advances have been made to enhance the stability of crRNAs, with various chemical modifications improving their half-life in human cells. These delivery modalities lay a strong foundation for future studies in patient-derived cancer cell lines and animal models, which are needed for the further advancement of these SNV-specific Cas13 drugs,” (page 13, right column, third paragraph).
Shembrey therefore teaches that future work is required for optimizing both in vitro and in vivo and delivery methods of Type VI Cas enzymes (above). Shembrey teaches that while important foundational work has been performed in the area of delivery, future studies “are needed for the further advancement of these SNV-specific Cas13 drugs,” (above).
Furthermore, it is known in the art that complex disease states such as cancer are associated with aberrant RNA splicing, export/localization, and translation. For instance, Borden (Borden KLB. Biochem Soc Trans. 2022 Oct 31;50(5):1447-1456) is a review article that focuses on how cancer produces changes in RNA processing (Title, Abstract, and throughout). Borden teaches that:
“mRNA processing is a critical determinant for the protein-coding capacity of mRNAs since these physical changes impact the efficiency by which a given transcript can be exported to the cytoplasm and translated into protein. While many of these mRNA metabolism steps were considered constitutive housekeeping activities, they are now known to be highly regulated with combinatorial and multiplicative impacts i.e. one event will influence the capacity to undergo others. Furthermore, alternative splicing and/or cleavage and polyadenylation can produce transcripts with alternative messages and new functionalities…In all, dysregulated RNA metabolism in cancer gives rise to an altered proteome that in turn elicits biological responses related to malignancy. Studies of these events in cancer revealed new mechanisms underpinning malignancies and unearthed novel therapeutic opportunities. In all, cancer cells coopt RNA processing, export and translation to support their oncogenic activity,” (Abstract)
Borden therefore teaches that cancer yields altered RNA processing in cells in combinatorial, multiplicative mechanisms, where such alterations affect export, translation, and RNA splicing (above). Borden further teaches that novel alternative splice variants can display novel functionalities (Abstract). Furthermore, with respect to therapeutic targeting and the identification of targets which affect RNA processing, Borden teaches that:
“eIF4E has been a focal point for development of cancer therapeutics targeting RNA metabolism…eIF4E phosphorylation inhibits RNA export and may have impacts on translation although this is highly debated. Phosphorylation may also modulate other eIF4E activities although this is yet to be determined. Thus, it is not yet known if inhibition of its phosphorylation will impact on multiple eIF4E activities. The last group including 4GI-1 may only impact eIF4E-dependent translation which may limit its clinical utility; however, its ability to inhibit other eIF4E activities has not yet been investigated and given the proximity of 4GI-1 to the cap-binding site may well have inhibit other functions,” (page 1451, final paragraph).
Borden therefore teaches that the specific potential therapeutic targets such as eIF4E have undetermined roles in RNA processes such as translation in the context of cancer target therapeutics, where further investigation is required to identify the exact role such targets may have in translation. Borden therefore teaches that overall RNA processing in cancer is a complex process where individual targets and proteins which may be involved in such processing are unresolved (Abstract, page 1451).
Experimental Burden
As discussed above, the art teaches that there is uncertainty and unpredictability with respect to what guide sequences and target sequences would be efficacious in the treatment of diseases, including RNA splicing-associated diseases, cancer, and retinal diseases (Truty). Truty teaches that large-scale cohort studies are required in order to elucidate such splice variants, and even so, further testing and analysis is required in order to understand the role such RNA splicing variants play in a broad spectrum of diseases (above). The practitioner is therefore saddled with an undue experimental burden because they would be required to identify specific target sequences which guide sequences will target, wherein such target sequences would be required to be bona fide targets associated with any number of disease including splice variant associated-diseases.
Furthermore, the practitioner would face undue experimental burden with respect to treatment of diseases such as cancer because Shembrey teaches that it is known in the art that major hurdles exist when attempting to use Cas enzymes systems such as Type VI Cas enzymes in the treatment of diseases such as cancer (above). The practitioner would be required to overcome these known technical challenges without guidance provided in the specification in order to achieve the scope of the claimed subject matter (e.g., the treatment of cancer).
The Applicant has solved neither the problem of efficacious delivery of such enzymes in vivo to treat cancer or more broadly the known issue of identifying guide sequences/targets which would act as bona fide targets to treat diseases such as those associated with RNA splicing/variants.
Regarding claim 25, claim 25 recites a method of treatment, where one such disease to treat is cancer. Enablement issues with respect to the treatment of cancer, including hereditary cancers associated with gene splice variants, are addressed above in the discussion of Truty and Shembrey and apply to claim 25.
Regarding claims 26 and 30, these claims are broadly drawn to the treatment of disease, where such language encompasses RNA splicing associated disease and cancer (as cancer is also recited in claim 30, the dependent claim of claim 26). These limitations and the enablement issues associated with such limitations are addressed in the rejection of claim 24 and applied to claims 26 and claim 30 (above).
Allowable Subject Matter
Claims 1 and 12 and their dependent claims are drawn to Cas nucleases with 98% sequence identity to SEQ ID NOs 4628, 4693, 4741, 4752, 4753, and 5873. Both ABSS and NCBI BLAST (Patent and Cluster Databases) were searched. The search returned no prior art results for the recited sequences in the claims, nor a reasonable suggestion to arrive at such sequences, where the limitations of the claims require heterologous guide sequences which can form with the recited Cas proteins. Thus, claims 1 and 12 and their dependent claims are free of the art.
Furthermore, claims 1 and 12 recite a composition comprising Cas proteins and heterologous guide RNAs. Recitation of heterologous guide RNAs as a required limitation of the composition renders the claim subject matter eligible, as such a composition with heterologous guide RNAs would not be a naturally occurring product of nature. Claims 1 and 12 are therefore subject matter eligible.
Furthermore, the Applicants have identified six Cas13 enzymes, reduced to practice targeting of mammalian genes using two of the newly identified family of Cas13 enzymes, have performed HEPN domain mutational analysis to render catalytically dead/inactive forms of the Cas13 proteins, and fused the dCas13 proteins to active deaminases to direct A-to-I editing in mammalian targets (see Example 3). The Applicants have furthermore made mutational predictions and reduced to practice E620G and Q696L variants, where the mutants reduced off-target effects as predicted. Thus, the applicant was reasonably in possession of the claimed invention, where furthermore a practitioner is enabled without undue experimentation to make and use the invention of claims 1-4,6-12 and 15-23.
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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