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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-18, in the reply filed on 7/17/2025 is acknowledged.
Claims 19-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/17/2025.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 20. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim suggestion
Claim 2 states "the gene editing system integrated the first and second vectors into
the tumor DNA". Use of present tense is more appropriate in claim language, thus following is recommended” "the gene editing system integrates ... ".
Claim Rejections - 35 USC § 112(b)
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 1-18 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.
Claim 1, 4, 6 and 8 recite the term “fusions”. It is unclear what a “fusion” is: a fusion of a DNA and amino acid sequence, a fusion of more than one DNA sequence, a fusion of a DNA sequence and a RNA sequence? Claim 1 recites targeting the “fusions” using a “gene editing system” and claim 5 recites targeting sequences in gRNA that bind fusions. Furthermore, on page 13, the specification presents that “Tumor-specific genomic material (e.g., fusions) specific to tumor cells is identified” and on page 29 it states that “Fusions may be contiguous sequences of DNA formed by the "fusion" of two previously separate contiguous sequences of DNA. […] fusions or fusion genes”. Therefore, for the purpose of compact prosecution, the claims are interpreted as to state "fusiongenes".
Claims 1, 2, 6, 7, 9 and 10 recite the term “tumor DNA”. The specification does not define this term. It is unclear if the term refers to any portion of the genomic DNA from the tumor cell or the entire genomic DNA from the tumor cell or a specific portion of a cell’s DNA that is tumor-causing/associated DNA. Owing to the lack of clarity regarding this term, it is further unclear how “tumor DNA” is obtained from a subject. The specification states that “The invention relies on expression of gRNAs and Cas-related endonucleases in tumor cells by targeting fusions found only in tumor genomes. […] The exogenous gRNAs bind at or near known repeat sequences in tumor cells and Cas-related endonucleases cleave the known repeat sequences therein, resulting in fragmentation of tumor DNA” (page 2, para 2). Therefore, for the purpose of compact prosecution, the term “tumor DNA” is interpreted as “genomic from the tumor cell”.
Claim 1 recites “Cas-related endonucleases”. Neither the claims nor the specification provide any guidance regarding the meaning of this term. It is unclear what endonucleases are considered related to Cas enzymes and what type of relation is considered (i.e. evolutionary, functional, structural). The only Cas-related endonucleases disclosed in the specification are Cas endonucleases (page 15-16).
Claim 1 recites “a common region within a repetitive sequence present in the human genome” and claims 9 and 10 recite “repetitive sequences”. The metes and bounds of the term "repetitive sequence" is unclear since it is unclear how many nucleobases must repeat for a sequence to be considered ‘repetitive’. For example, an ordinary artisan recognizes that most genes have two alleles i.e. at least two repeats and thus could be considered “repetitive sequences”. Further, it is unclear what is a common region within a repetitive sequence. For example, is it a repeated sequence within “a repetitive sequence” or is it a sequence common across the plurality of “a repetitive sequence”.
Claim 1 is directed to a method of inducing tumor cell death comprising delivering two vectors that encode a gRNA and a Cas-related endonuclease separately. The gRNA targets ‘a common region within a repetitive sequence present in the human genome” “wherein expression of said gRNA and said Cas-related endonuclease result in cleavage of said tumor DNA”. The method also delivers a gene editing system that targets ‘fusions’. Although the vectors result in cleavage of ‘tumor DNA’ and thus are expected to induce tumor cell death, the function of the gene editing system in this method is not clear since the purpose of targeting ‘fusions’ is unclear. No clear relation between the vectors and the gene editing system is recited. Further, it is unclear what the fusions are being targeted for? It appears that the claim is incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are recited in claim 2. This evident from the statement in the specification “The invention relies on expression of gRNAs and Cas-related endonucleases in tumor cells by targeting fusions found only in tumor genomes” (page 2, para 2).
Claims 4, 6 and 8, each recite "normal sequences" from "heathy, non-tumor cells" however neither claims nor the specification provide any guidance for these terms. It is unclear if a specific criteria exists that identifies sequences as normal and cells as healthy. Are all non-tumor cells considered healthy and are all sequences obtained from non-tumor cells normal? For the purpose of compact prosecution, the claims are interpreted as "genomic sequences from
Claim 7 recites "said analyzing step". There is insufficient antecedent basis for these limitations in the claim. For the purpose of compact prosecution, claim 7 is interpreted to be dependent on claim 6 that recites "analyzing".
Claim 8 recites "normal DNA" and "tumor sequences". There is insufficient antecedent basis for these limitations in the claim. For the purpose of compact prosecution, claim 8 is interpreted as “genomic sequences” and “genomic from the tumor cell” (this interpretation incorporates the interpretation presented for claims 1 and 6 above).
In claim 10, it is unclear what the "portion thereof" is referring to within the claim. For
the purpose of compact prosecution, the claim is interpreted as "portion the repetitive
sequences",
Claims 2-18 is/are rejected due their dependence on claim 1 because they do not clarify the 112b issue noted with claim 1.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Claim Rejections - 35 USC § 112(a)
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 1-18 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
A method of inducing tumor cell death, the method comprising:
identifying one or more fusion genes in the genomic DNA of the tumor cells obtained from a subject;
delivering directly to the tumor in the said subject a gene editing system, a first vector comprising DNA encoding a guide RNA (gRNA) capable of hybridizing with sequences within genomic transposable elements in the human genome, and a second vector comprising DNA encoding a Cas9 endonuclease;
wherein said gene editing system targets one or more of said fusion genes for the insertion of the DNA encoding gRNA and the DNA encoding Cas9; and wherein expression of said gRNA and said Cas9 endonuclease result in cleavage of said genomic DNA of the tumor cells that induces tumor cell death.,
does not reasonably provide enablement for a method wherein the gene editing system and the vectors are delivered by any means of administration and wherein the gene editing system and the vectors comprise elements as claimed. In addition to issues of indefiniteness noted above, the elements as claimed lack enablement. For example, a gene editing system targeting any fusion in a genomic DNA in a tumor cell or a Cas-related endonuclease/gRNA targeting any repetitive sequence in the human genome are not enabled for a method that induces tumor cell death in a subject (i.e. in vivo cancer gene therapy).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Considering the numerous indefiniteness issues identified in the claims, the interpretations presented in the U.S.C. 112b rejections above are followed to construe the claims for the purpose of this analysis.
The claims as currently drafted encompass methods that induce death of any type of tumor cell(s) anywhere in the subject by delivering the gene therapy elements to the subject by any means of administration (such as direct tissue injection, intravenous, intrathecal etc.).
The gene therapy elements are recited also have an expansive breadth. Claims embrace a gene editing system that appears to target any fusion oncogene in the DNA from any tumor cell without limitation to the means of delivery to this gene editing system. The Cas endonucleases and gRNA encoded by the vector also broadly target any repeated sequence in the human genome. Claims 12-14 limit these repeated sequences to interspersed retrotransposons, such as LINE and SINE but do not limit the tumor type or the means of administration.
Claim 16 limits the delivery agent of the vectors to lipid nanoparticles. It does not recite a delivery agent for the gene editing system nor does it recite a tumor cell type or a means of administration.
Consequently, the breadth of the claims is expansive.
(B) The nature of the invention: The invention is in the field of cancer gene therapy by identifying and targeting fusion oncogenes for the insertion of cell death inducing agent.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Chromosomal aberrations are a recurrent and consistent finding in several cancers that result at chromosomal breakpoints, aberration such as translocation of sequences resulting in fusion oncogenes. Rabbitts (NATURE · VOL 372 · 10 NOVEMBER 1994) lists several gene fusions in Table 1. They note that “Translocations or inversions can be divided into those consistently found in certain tumour types (specific) and those observed only in the tumour from one patient (idiopathic)” yet it is clear that identification of such fusion oncogenes had become routine in the art with Rabbitts stating that “Molecular studies of breakpoints from specific aberrations have now reached a watershed.” (Introduction, para 2). Martinez-Lage et al (NATURE COMMUNICATIONS, (2020) 11:5060) is a post-filing art that also notes that “FOs have also been found in epithelial cancers, including prostate, colorectal, breast or melanoma, and over 350 recurrent FOs involving >300 different genes have been identified to date.” (Introduction, para 2, FO=fusion oncogene). Furthermore, fusion oncogenes targeting by gene editing methods to reduce/knockout their expression is an increasingly attractive therapeutic approach. For example, Chen et al (Nature biotechnology, Vol 35 No. 6 JUNE 2017) used a Cas/gRNA based approach to insert a gene encoding the prodrug-converting enzyme herpes simplex virus type 1 thymidine kinase (HSV1-tk) in the TMEM135-CCDC67 and MAN2A1-FER fusion oncogenes which are found in prostrate tumors (Introduction, para 4-5). This results in ganciclovir-induced death of fusion oncogene comprising cancer cells in vitro even though the integration efficiency remained less than 30% (Figure 3, Table 1). In vivo, the strategy works to achieve partial remission when the gene editing agents targeting the fusion oncogenes are delivered directly to the tumor engrafted in mice (Figure 4). Regarding alternate approaches to induce cell death, use of Cas9/gRNA targeting of transposable elements such as LINE and SINE was known in the art. Smith et al (bioRxiv 574020; doi.org/10.1101/574020) shows that targeting LINE-1 results in 7-fold increase in cell death in vitro (Figure 2, S3).
Yet, although the prior art teaches the potential of targeting fusion oncogenes for the insertion of sequences that encode cell killing agents to kill cancer cells, the prior art does not provide enabling guidance regarding how to deliver such agents in vivo i.e. to a subject, aside from direct injection into the tumor. Chen et al (Cancer Letters 447 (2019) 48–55; here in after Chen 2019) highlight the key challenges in in vivo application of this approach. They state that “Due to the heterogeneity of cancer, genomic aberration profiles are different not only in tumors among patients, but also in tumors during different stages or from different sites within a patient, which renders (epi)genome manipulation in cancer highly challenging. Moreover, this strategy requires fairly high editing efficiency because the unedited cells possess growth advantage over the edited ones. The former proliferates more rapidly than the latter, nullifying the therapeutic effect quickly. Also, it is of importance to select the appropriate delivery methods, especially in vivo delivery.” (emphasis added; page 49, col. 1-2 bridging para). A skilled artisan could not predict the therapeutic outcome of a method wherein the gene editing agents are not delivered directly into the tumor. There is no guidance regarding achieving tumor-specific targeting of the claimed cell killing agents.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The specification does not disclose any specific tumor type or any specific fusion oncogene. The specification only identifies “Repetitive elements 603 in the human genome include satellite DNA, tandem repeats, transposons, interspersed retrotransposons (e.g., long interspersed repetitive elements (LINEs), and short interspersed repetitive elements (SINEs)).” (page 20) but does not disclose any common region within any of these repetitive elements that could be targeted. The specification prophetically discloses that “Compositions may be formulated for delivery by any route of administration. For example, compositions may be formulated for oral, enteral, parenteral, subcutaneous, intravenous, or intramuscular administration.” (page 26, para 3).
The specification does not provide any working examples directed to the claimed method.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its unpredictability with regards to therapeutically efficacious means of delivery of the claimed gene therapy elements, and the lack of guidance in the form of varied working examples in the specification.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claim1-18, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1-18 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed method to its full scope.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Luo et al (US 20170240924 A1, Publication dates August 24, 2017) and Smith et al (bioRxiv 574020; doi.org/10.1101/574020, April 4, 2019).
Regarding claims 1 and 2, in view of the 112b issues noted above, Lou teaches that in case of prostate cancer "a genome editing technique that specifically targets a fusion gene can induce cell death in a cancer cell that carries the fusion gene" (abstract). Examples 1, 4 and 7 are pertinent since they cover Lou's method of identifying subject and tumor specific fusion oncogenes (= claimed identifying step) (Example 1, specifically [0115] and [0121]), targeting these sites (breakpoints/ fusion sites) with a CRISPR/Cas system (= claimed delivery of gene editing system that targets fusion oncogenes) to insert HSV-1 TK which when expressed induces cell death in response to ganciclovir in vitro (= clamed insertion of the vector at the fusion oncogene site as recited in claim 2) (example 4, specifically [0223]) and in vivo in mice by direct administration to the xenografted tumor (example 7, specifically [0273]). A detailed description for fusion gene detection is provided in [0137].
Regarding claim 3, in view of the 112b issues noted above, Lou teaches use of AAV and suggests lentivirus as an alternative [0223].
Regarding claims 4 and 5, in view of the 112b issues noted above, Lou teaches a Cas/gRNA to target fusion sites (example 4, [0223]) which they identified in example 1. Lou teaches a detailed method in example 1 for identifying patient specific fusion genes using sequencing, analyzing these sequences in comparison with matched adjacent benign prostate tissue (includes alignment) and then in example 4 and 7, targeting them with CRISPR/Cas (= claimed targeting fusion sites in tumor cells and not found in matched sequences from non-tumor cells).
Regarding claims 6, 7 and 8, in view of the 112b issues noted above, Lou teaches a detailed method in example 1 for identifying patient specific fusion genes using sequencing (=as required for claim 7 and 8-sequencing step), analyzing these sequences in comparison with matched adjacent benign prostate tissue (includes alignment, as required for claim 8-aligning step) to identify tumor specific fusion sites (as required by claim 9-identfying step).
Regarding claim 17 and 18, Lou teaches a doxycycline-inducible promoter [0092], CMV promoter [02224], and suggests use of other promoters known in the art [0095].
Lou does not teach using a second CRISPR/Cas system to target "a common region within a repetitive sequence present in the human genome" to “result in cleavage” of the DNA of the tumor cell wherein the repetitive sequence is located throughout the human genome (as recited in claim 9) adjacent to a PAM (as recited in claim 10) such as an interspersed retrotransposon sequence (as recited in claim 11) such as SINE or LINE (as recited in claim 12-14).
Smith teaches a method comprising two plasmid vectors encoding Cas9 and sgRNA that target transposable elements such as Alu and LINE-1 and that results in cleavage of DNA of a cell resulting in cell death (=claimed first and second vector, gRNA targeting repetitive element) (See section: High copy-number CRISPR/Cas9 editing induces cellular toxicity and inhibits survival of edited cells, Materials and Methods: Transposable element gRNA design, SpCas9 and gRNA plasmids used for genome editing, Figure S3).
Regarding claim 9, Smith targets Alu, LINE-1 which are repetitive element that are present plurally throughout the human genome (page 2, para 3) and the gRNA taught by Smith cleaves the plurality of LINE-1 to induce cell death (page 3, para 3).
Regarding claim 10, Smith teach gRNA that target PAM-adjacent LINE-1 sequences (page 3, para 2; Figure 1D).
Regarding claims 11, 13 and 14, Smith teaches LINE-1 (i.e. L1) (Figure S3)
Regarding claim 12, Smith teaches gRNA targeting Alu sequences (See section: gRNA design and copy number estimation of transposable elements).
Regarding claim 15, Smith teaches Cas9 endonuclease (Materials and Methods: SpCas9 and gRNA plasmids used for genome editing).
Regarding claim 16, Smith teaches the use of lipofectamine i.e. lipid nanoparticle for delivery of vector (Materials and Methods: Maintenance and transfection of HEK 293T cells).
Regarding claim 17, Smith teaches CMV promoters (Materials and Methods: SpCas9 and gRNA plasmids used for genome editing).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention, to substitute the sequences encoding the cell killing elements (i.e. gene encoding HSV-tk) in Lou’s method with Smith’s cell killing elements (i.e. sequences encoding Cas9/gRNA that target transposable elements such as LINE-1). An ordinary artisan would be motivated to make such a substitution because it would allow for targeted killing of the tumor cells without any additional requirement for ganciclovir infusion. Furthermore, while Lou’s method only results in 20% cell death at maximum ganciclovir dose (Figure 31A), Smith’s method results in 70% cell death (Figure S3). An ordinary artisan would reasonably expect to substitute Smith’s cell killing elements in Lou’s method because Smith provides the Cas9 and sgRNA sequences that would be substituted in Lou’s vector that comprises the gene encoding HSV-tk. Lou also teaches method for constructing donor vectors to be used in their fusion oncogene targeting method ([0261-0266]).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632