DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/28/2025 has been entered.
Claims 1, 4, 8-10, 12-22 are currently under examination.
All previous rejection not reiterated in this office action are withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 8-10, 12-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “determining a determined germline DNA code of the whole genome DNA sequence of the organism using the whole genome sequencing procedure applied to the cell sample from the organism” renders the claim indefinite because it is unclear if a germline DNA code is already determined, what is this step try to accomplish using whole genome sequencing and statistical averaging methodology. The recitation of “match the considered germline DNA code of the site” renders the claim indefinite because it is unclear whether it means to have homology with the DNA code or base pairing with the DNA code. The recitation of “change agent material that causes the configuration of the DNA code at each of the two sites” renders the claim indefinite because it is unclear what configuration the agent is causing. The recitation of “DNA code that is considered to be germline for the site as determined by a whole genome sequencing procedure applied to a cell sample from the organism” renders the claim indefinite because it is unclear whether this “DNA code that is considered to be germline” means it is from whole genome sequencing from germ cells isolated from the organism at the time of the configuring, or the germ cells at the time the organism was developed from.
Dependent claims 9-10, 12-22 are rejected for same reason because they depend on claim 1 but does not remedy the indefiniteness.
Regarding claim 4, the word “match” in the context of the claim renders the claim indefinite because it is unclear whether it means to have homology with the DNA code or base pairing with the DNA code.
Dependent claim 8 is rejected for same reason because it depends on claim 4 and does not remedy the indefiniteness of claim 4. Further, the recitation of “determining the number of samples using an error rate of a sequencing method used to sequence at least one of the samples” renders the claim indefinite because it is unclear what number is being determined, and how the error rate of a single sequence method is being used. It is also unclear when this recited step occurs in the context of the method claimed in claim 4.
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, 4, 8-10, 12-22 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This rejection is rewritten to address the amendment.
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." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
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." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
Claim 1 is drawn to a method of configure a subsequence of a DNA sequence of one or more cells in an organism comprising: determining the whole genome DNA sequence of the organism using a whole genome sequencing procedure applied to a cell sample from the organism, preparing a treatment configured to cause the DNA code of subsequence to be configured to germline subsequence DNA code of the determined whole-genome DNA sequence code of the organism; and applying the treatment to the organism to cause a configuration of genetic code at two sites in the subsequence.
Claim 4 is drawn to a method of changing a DNA sequence comprising determining a desired DNA sequence to be changed in the organism; preparing a treatment configured to cause the organism DNA sequence to be changed to the desired DNA sequence; applying the treatment to the organism; wherein treatment is configured to change the organism DNA at two sites in the desired DNA sequence, wherein the desired DNA sequence is determined by sequencing a number of whole-genome DNA sequence samples of the organism and deciding at each of the respective nucleotide position in the desired DNA sequence, the desired sequence is the majority of the sample sequences.
The breadth of the claim
The scope of claim 1 is rather broad. It encompasses a method of configure whole genome subsequence DNA at any position(s) in the genome in a wide variety of high eukaryotic organisms, which includes human, and all types of the cells in the organism into germline sequence. It encompasses configure DNA code within genomic DNA in adult organism at any stage of the life. The claims also encompasses of wide variety “treatment” that can configure DNA sequence into germline DNA code and desired DNA code.
The teaching from the specification and the presence of working examples
The specification teaches cancer is caused by a wide spectrum of different cascading mutations and ultimately different and constantly evolving disease, and the same has been shown with aging. The specification teaches that no one has discovered a definitive cause of aging in humans or other animals, but current evidence points to aging being an emergent phenomenon resulting from failure of a large number of different pathways and processes (paragraph [0007]-[0009]). The specification teaches that the method named multiplexed homologous template repair (MMHTR) may be used to replace in every cell in an organism’s body, the current, mutagenic, whole-genome sequence of the cell with a pre-mutagenic copy of the organism’s whole-genome DNA sequence. The specification teaches that such as complete replacement will turn back the clock on the organism’s genome, removing any accumulated damage, and returning each cell and the entire organism, to a germline state. The specification teaches that only nuclear DNA sequence is replaced but the gene expression pattern would not be disrupted or altered (paragraph [0012]-[0013]). For the treatment, changing agent material, (that can change the mutagenic whole genome DNA to premutagenic DNA), the specification teaches it may be administered to one or more of the cells of the organism, and it is species specific (paragraph [0127]). The specification teaches that the agent may include a donor sequence or homology repair template (paragraph [0157]-[0159]). The specification listed a number of Cas nucleases as example to perform the method of whole genome DNA replacement (paragraph [0178]-[0185]). However, the specification does not teach or give example for configuring subsequence in whole-genome sequence at one or more desired DNA sequence site using the listed nucleases. Nor does the specification teaches other nucleases may accomplish such purpose. As such, whether using the listed nucleases or other changing agent and/or treatment as claimed can configure whole-genome DNA at any two sites for any organism, including human, is unpredictable.
The teaching from prior art and the level of predictability in the art
The state of prior art at the time of filing is underdeveloped with regard to providing treatment to whole genome subsequence by changing mutagenic nucleotide at desired location(s) in an organism in vivo for therapeutic purpose. As stated in the specification, prior methods of modifying DNA sequences using CRISPR are all directed to affecting small sub-sequences of DNA that are known to relate to a disorder or disease in a similar way for most members of a species of an organism. The prior art does not describe any changing agent that can accomplish whole-genome DNA replacement as intended by the application or a method of changing whole genome DNA in high eukaryotic cell such as human cell. In a summary written by Wang (Journal of Cellular Molecular Medicine, 2020, Vol. 24, pages 3256-3270), 4 years after the filing of the present application, it describes many advances in using class 2 CRISPR systems for molecular manipulations, including introducing insertion or deletions through targeted DNA cleavage followed by NHEJ repair, targeted sequence replacement via CRISPR induced HDR, transgenesis (pages 3263-3264). There is no mention that mutagenic whole genome sequences may be replaced by premutagenic whole genome sequence. Even for gene therapy that targets specific disorder, there exists a number of limitations including off-target effects, protospacer adjacent motif requirement (PAM), DNA damage toxicity, immunotoxicity, efficient delivery of CRISPR, are some the challenges remaining to be addressed for specific diseases based on trial and error (Uddin et al. Frontier in Oncology, 2020, Vol. 10, article 1387, pages 1-17, esp. pages 3-9). As such, whether the claimed method is achievable in an organism for changing genomic sequence at all potential “desired DNA” subsequence is unpredictable in the art at the time of filing, especially in human organism.
The amount of experimentation required
In summary, there is not teaching from prior art for treating an organism by replacing genome DNA at any position(s) to a desired DNA sequence in high eukaryotic organism including human by a “changing agent and/or treatment.” The skilled artisan would thus have to rely on the teaching solely from specification to practice the method as claimed. However, the specification does not teach or provide a single example that a method as claimed may be accomplished by any treatment. As discussed above, CRISPR genome targeting requires PAM sequences in the DNA region, the specification does not teach how to change “desired DNA sequences” that do not have PAM in the “desired region.” The specification also fails the address the art recognized technical challenges discussed above. The skilled artisan would thus engage in undue experimentation to practice the claimed method of claim 1 and 4 and their dependent claims. Therefore, the claimed method is not enabled by the present application.
Response to Arguments
Applicant argues amended claim 1 does not necessary for practice of the invention as claimed for a mutation to be known or even present. Applicant states if a mutation is present in the DNA code of the subsequence, the treatment causes the DNA code of the subsequence to be configured into the determined germline DNA of the subsequence, whereas if a mutation is not present, the treatment causes the DNA code of the subsequence to be configured into the determined germline DNA code of the subsequence. Applicant states that if there is no change to the DNA code when there is no mutation because the DNA code is the same before and after the treatment but the process of configuring still occurred to ensure the subsequence matches the germline DNA code of the subsequence.
Applicant asserts that claims are also amended that configuration of DNA code at 2 sites of a subsequence, which would have been predictable result and would not be the subject of undue experimentation. Applicant argues that the claim language does not require the method to address any disease or disorder but simply to configuring DNA code at 2 sites to determine the germline DNA code of the sites, which does not require determination of safety and efficacy. Applicant further states that claim 15 limits the targeted nuclease to CRISPR-Cas9. Applicant further argues that the issue of PAM site locations does not exist because the invention does not require specific PAM site location but any PAM site may be used. Applicant argues that the genetic payloads of the invention ae designed to match the PAM site location in a specific region of the genome being targeted, wherein said novel approach works because the relative number of PAM sites in a human genome is enormous. Applicant states that the sequence size was amended to sizes in examples Applicant included in the application, Figures 8-16. Applicant argues that there is no time limit for the treatment, wherein the result may be evaluated for any length of time.
The above arguments have been fully considered but deemed unpersuasive. With regard to there is no predetermined mutation in the sequence, it is rather confusing what DNA code needs to be configured to germline DNA code. As discussed in the 112 2nd rejection above, it is unclear whether the claim is referring to configure DNA code to germline at the time the sample is taken from the germ cells of the adult organism or the germ cells that the adult organism originally developed from. It is also unclear what “treatment” may be applied for such configuration so that it configures DNA code to germline when there is a change, but does not configure DNA code when there is not a change. The sequences listed in Figure 8-16 merely teaches the existence of PAM sites in a subsection of genomic DNA, and repair template that may be used for homologous recombination following Cas9 cleavage. The design of the repair template requires prior knowledge where the cleavage is going to take place and sequences adjacent to said cleavage site(s), even only 2 sites are edited. As discussed in previous office action, the term “subsequence” is not given a limiting definition in the specification. The teaching from the specification suggests “massively multiplexed homologous template repair” is intended for whole-genome replacement (paragraph [0012]), and “it is contemplated that the system and methods of the present invention can be used to replace, in every cell in an organism’s body, the current, mutagenic, whole-genome DNA sequence of the cell with a pre-mutagenic copy of the organism’s whole genome DNA sequence. It is contemplated such a complete replacement will ‘turn back the clock’ on the organism’s genome.” In light of the disclosure of the specification, the BRI of the “subsequence” of a whole genome DNA sequence clearly encompasses a large number of sequences of different size, ranging from a small coding sequence to a whole genome DNA sequence lack only a few nucleotides. The added limitation of “the subsequence is no longer than 2000 base pairs” does not limit the configuration to a DNA code that is no longer than 2000 base pairs because the whole genome of an organism, the chromosomal DNA is continuous. The “examples” listed in paragraphs as cited by Applicant simply describes prior art known technology generally for how to establishing dose requirements, selecting vehicle and nuclease, comparing base pair sequence to binding site sequence…” not specific examples for the claimed invention of configure DNA code of a subsequence of a whole genome DNA sequence in one or more cells of an organism to a germline state, by determining the whole genome sequence of the organism and preparing a treatment such as using CRISPR technology. Nor does the specification teaches any other “treatment configured to cause the subsequence to be configured to a DNA code of the determined whole-genome DNA sequence.” It is unclear what is the relevance of time limit with the claimed method as argued by Applicant. In view of the analysis of all wands factors as discussed above, it is determined that the present specification does not provide sufficient teaching to enable the method as claimed. This rejection is still considered proper and therefore maintained.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 4 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Cotta-Ramusino (US 11,680,268).
Claim 4 is drawn to a method of configuring DNA code of a subsequence of a whole genome DNA comprising: determining a desired DNA code of the subsequence by sequencing a number of whole-genome DNA sequence samples, and deciding the DNA code of the subsequence in a majority of the sample sequences; preparing a treatment configured to cause the DNA code of the subsequence to be configured to desired DNA subsequence; and applying the treatment to the organism, the treatment is configured to cause DNA code of the subsequence to be changed to desired DNA code of the subsequence at two sites; delivering to the organism at least one dose of said treatment.
Cotta-Ramusino teaches a method for improving CRISPR mediated genome editing by increase the likelihood that the break is repaired by homology directed repair (HDR) (abstract). Cotta-Ramusino teaches an embodiment that treating a subject by contacting the subject with a template nucleic acid to alter the sequence of target nucleic acid, wherein the method comprising acquiring knowledge of an undesired sequence in said subject by DNA sequencing (col.329, lines 49-56). Cotta-Ramusino teaches contacting the cell with Cas9 molecule, template nucleic acid and at least one gRNA, wherein the system may comprise two gRNA to generate two breaks (col.329, lines 59-62, and col.330, lines 35-39). Cotta-Ramusino teaches in some embodiments, the method if for treating a subject a disease caused by a target position in a nucleic acid for a particular mutation, and correct said mutation, such disease includes cancer (col.452, lines 52-60). Cotta-Ramusino teaches when two gRNA is used, the first and second breaks are configured to be within 65 nucleotides of one another. The teaching from Cotta-Ramusino meets the limitation of sequencing DNA sequence samples to determine desired sequence because an ordinary skilled in the art has to determine the DNA code/sequence of healthy subject, a diseased subject, wherein sequencing a specific disease causing gene meets the limitation of a subsequence, the desired sequence would have been the sequence from a healthy subject. Inherently, the desired sequence of healthy subject is the majority of the sample because only a fraction of the population has cancer mutation. The HDR method is intended to correct the mutation so that a treatment is applied to the diseased subject. Therefore, the teaching from Cotta-Ramusino anticipates the claimed invention of claim 4.
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/CELINE X QIAN/Primary Examiner, Art Unit 1637