CTNF 18/260,017 CTNF 99262 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 12-151 AIA 26-51 12-51 Status of Claims Claims 1-8, 10, and 12-20 are pending. Priority Claims 1-8, 10, and 12-20 are a 371 of PCT/EP 2021/087887 filed on December 30, 2021, which has priority to SPAIN P202031322 filed on December 30, 2025. Double Patenting 08-30 AIA A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co. , 151 U.S. 186 (1894); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert , 245 F.2d 467, 114 USPQ 330 (CCPA 1957). A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101. Applicant is advised that should claim 1 be found allowable, claim 12 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 12 recites “wherein the target nucleotide is a target DNA sequence”. Claim 1 recites “recognition and cleavage of a target nucleotide”. The limitation represents an obvious choice of only two alternatives, i.e. DNA or RNA. Thus, despite a difference in wording, the claims have substantially the same scope. Claim Rejections - 35 USC § 112 07-30-01 AIA 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. 07-31-02 AIA Claim s 1-8, 10, and 12-20 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. Nature of the Invention: The invention involves the formation of a functional Cas complex where the crRNA is replaced with a guide peptide nucleic acid (crPNA) where a CRISPNA complex is formed where the crRNAs or sgRNAs are replaced with a PNA, an artificially synthetic oligonucleotide that is capable of directing Cas proteins to their DNA or RNA targets. Breadth of Claims: The claims encompass any Cas system that utilizes a tracrRNA where the crRNA or sgRNA is replaced with a PNA and is capable of binding to the tracrRNA and targeting sequence. Amount of Direction or Guidance Present in the Application: The specification provides several examples of several types of Cas systems along with a tracrRNA where the tracrRNA consists of the respective nucleic acid sequences listed in the specification [pg. 11-12]. Applicant’s specification further lists Cas systems, e.g. Cas 5 and Cas 13, where the specification lists tracrRNA sequences where the sequence maintains a certain amount of nucleotide bases from the 5’ end and lacks a certain number of bases from the 3’ end [Id.]. However, Cas5 systems do not use a tracrRNA, but instead uses an effector complex called a CRISPR-associated complex for antiviral defense, also known as a cascade [Introduction, Nam et al., Cas5d protein processes pre-crRNA and assembles into a cascade-like interference complex in subtype I-C/Dvulg CRISPR-Cas system, Structure , 2012]. The specification further provides single examples for a Cas9 system and a Cas12 system where the tracr sequence is provided. However, no guidance is provided for designing functional tracrRNA-PNA complexes for other Cas systems [Id.]. Additionally, Kumar et al. discloses that simple backbone modifications in PNAs can have strong negative effects on binding to structured nucleic acids such as RNAs [Introduction, Triplex-forming peptide nucleic acids with extended backbones, Chembiochem , Aug. 2020]. Kumar et al. showed that extending the PNA backbone in fact destabilized triplex formation with RNA [Id.]. This would lead a person of ordinary skill to infer that PNA interaction with RNA is highly structure-sensitive and unpredictable. Presence of Working Examples: Applicant’s specification discloses working examples for Cas9 and Cas13. However, there are no working examples provided for Cas5 or Cas 7 where tracrRNA is not used, and no method is disclosed to create a functional PNA-tracrRNA complex in those systems other than what is listed in the specification where it states for Cas5, Cas7, Cas12, and/or Cas13 where a 25-60 nt tracrRNA derived from the above systems where the first 18-22 nts from the 5’ end for binding Cas5, Cas7, Cas12, and/or Cas13 protein; and lacks the last 15-25 nts from the 3’ (guide domain), and includes a 5-15 nts sequence for binding the guide PNA. Again, Cas5 and Cas7 systems do not use a tracrRNA. Relative Skill in the Art: It is argued that the relative skill in the art, is that of a scientist with several years’ experience in the field, but that the Art itself is a recognition of what is understood by the Artisan, and thus, as seen below, does not make the breadth of the claims more predictable. The Predictability or Lack thereof in the Art: As stated above, Kumar et al. demonstrates that small changes in PNA backbone geometry or sequence can affect RNA binding [Introduction]. Kumar et al. further states that PNA-RNA interactions are highly sensitive and unpredictable, and since small changes in PNA design can dramatically affect affinity, the specification or the available art do not provide a reliable method to predict which PNA designs will successfully bind tracrRNA [Table 1]. Additionally, given the specification only provides two examples that disclose PNA sequences along with tracrRNA sequences for a Cas9 and Cas13 system, the broad scope of the claim being applicable to all Cas systems cannot be practiced without undue experimentation. Conclusion: Based on the above, the specification only provides enablement for the provided the Cas9 and Cas13 systems listed in the specification. However, because claim 1 also encompasses all Cas systems, including Cas systems that do not use tracrRNA, the specification fails to provide sufficient disclosure to allow one or ordinary skill in the art to make and use the claimed invention without undue experimentation . 07-31-01 Claims 10 and 20 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. Claim 10 uses the generic phrase “…prevention, amelioration, treatment or monitoring of a disease or disorder…” as it relates to administering the complex made up of a Cas system polypeptide or polynucleotide encoding a Cas polypeptide, tracrRNA, and a guide PNA. Claim 20 uses the generic phrase “…prevention, amelioration, treatment or monitoring of a disease or disorder…” as it relates to administering the complex made up of a Cas system polypeptide or polynucleotide encoding a Cas polypeptide, tracrRNA, and a guide PNA. The specification provides antecedent basis for “prevention, amelioration, or treatment of a disease or disorder” [pg. 13 ¶ 4]. Applicant’s specification states that CRISPNA complex or system is for the “prevention, amelioration or treatment of a disease or disorder” [pg. 13 ¶ 4]. It states this again on pg. 22 at number 16. However, the specification does not mention “prevention, amelioration or treatment” again. On pg. 2 of the specification, Applicant briefly describes how CRISPR systems have been used in the treatment of sickle cell disease, B-thalassemia, AIDS, and acute lymphoblastic leukemia. The specification also discusses how Cas9 utilizes an RNA molecule as a guide that can navigate towards a targeted DNA sequence, can then edit the sequence modifying the sequence in a way that either deactivates the gene or inserts a desired sequence to achieve a certain behavior, and that its most promising application is to genetically modify cells to overcome genetic defects, and possibly cure diseases like cancer [Background of the Invention ¶ 3]. On pg. 13, the specification references the potential for the claimed invention to be used to correct mutation causing diseases such as dystrophies and/or microsatellite expansion diseases [¶ 5]. The specification then cites the possibility of the claimed invention being used in the treatment of infectious diseases [pg. 13 ¶ 8]. The specification also states the claimed invention could be used to monitor diseases or disorders [pg. 15 Para starting with “Another aspect ”]. However, the specification does not provide any examples of the claimed invention being used to prevent, ameliorate, treat, or monitor diseases. Additionally, Figure 8 only demonstrates the proof-of-concept in generic cells and does not show how the system would work in a claimed diseased context. Moreover, how would CRISPNA be able to prevent, ameliorate, treat, or monitor diseases that are multifactorial such as heart disease where multiple genes are involved. Example 2, where it references Figure 4 which only provides a structure of the CRISPNA, states the efficiency will be determined as described in Figure 4 and also by flow cytometry. However, there is no mention of the results in Figure 4. The same is true for examples 3 and 4. The only other examples provided in the specification are related to diagnostic analysis for the detection of KRAS mutations, depleting of abundant sequences, and identification of SARS-CoV2 [pg. 25-26]. These examples relate to molecular detection and enrichment techniques and not therapeutic prevention, amelioration, treatment, or monitoring of a disease or disorder. Furthermore, the specification does not identify any specific diseases or disorders, other than general references to known Cas9 applications, nor does it describe therapeutic mechanisms, treatment protocols, monitoring methods, or how it would be beneficial in diseases that such as heart disease or diabetes where several genes are involved. This is further emphasized by Khoshandam et al. where the authors discussing current day challenges of CRISPR technology that include such things as genome editing with limitations of PAM, delivery system limitations, issues with delivery to specific tissues and organs, etc. [Chapter Ten – CRISPR challenges in clinical development, Progress in Molecular Biology and Translational Science , 2025]. Based on this and the number of diseases, a person of ordinary skill would not understand how the claimed invention would be implemented given the number of diseases and diseases with multiple genes being involved. Given the generic phrase “…prevention, amelioration, treatment or monitoring of a disease or disorder…” as it relates to administering the complex made up of a Cas system polypeptide or polynucleotide encoding a Cas polypeptide, tracrRNA, and a guide PNA, and the absence of teachings of what diseases could be therapeutically treated, an Artisan would not understand Applicant to be in possession of the full scope of a method for the prevention, amelioration, treatment, or monitoring of a disease or disorder using the claimed invention. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claims 1-8, 10, and 12-20 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 recites “tracrRNA of a) and capable of binding the target…”. However, there is no previous recital of the element “a)” in the claim. The only enumerated elements are (i) and (ii). Because of this, a person of ordinary skill would not understand what is being referenced. Claim 1 recites the limitation "the target nucleotide sequence" in Line 9. There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Because of dependency, claims 2-8, 10, and 12-20 are also rejected. Claim 2 recites the limitation "the target sequence" in Lines 7 & 9 . There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Claim 3 recites the limitation "the target sequence" in Lines 7 & 9 . There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Claim 5 recites the limitation "the target sequence" in Line 4/5. There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Claim 8 recites “a target cell transformed with the non-viral system of claim 6”. However, it is unclear what is meant by “transformed”. The specification does not explain or describe the term “transformed”. Does this include physical changes? Does it only include the DNA of the cell being modified in some way? Because of this, a person of ordinary skill would not be able to determine what context “transform” is referring to. Claim 10 recites “or monitoring of a disease or disorder”. As written, the term “monitoring” is unclear. Is this referring to detection of a biomarker, diagnostic confirmation, treatment response evaluation, or another specific measurable outcome. As written, a person of ordinary skill would not understand what is meant by “monitoring” given the nature of the invention. Claim 17 recites the limitation "the target sequence" in Line 2. There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Claim 18 recites the limitation "the target sequence" in Line 2. There is insufficient antecedent basis for this limitation in the claim. The only previous reference is “a target nucleotide”. Claim 20 recites “or monitoring of a disease or disorder”. As written, the term “monitoring” is unclear. Is this referring to detection of a biomarker, diagnostic confirmation, treatment response evaluation, or another specific measurable outcome. As written, a person of ordinary skill would not understand what is meant by “monitoring” given the nature of the invention. Claim Rejections - 35 USC § 112 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim 19 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 19, which depends from claim 4 which expressly limits the claimed system to Type II, Type V, and Type VI Cas systems, includes Cas systems that are outside the scope of claim 4. Claim 19 includes Cas systems such as Csy1, Cse2, Scn2, and related proteins, which are components of Type I CRISPR Cas systems. Because of this, Claim 19 conflicts with the scope of Claim 4 . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Conclusion No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JOHN DAVID MOORE/Examiner, Art Unit 1638 /ROBERT M KELLY/Primary Examiner, Art Unit 1638 Application/Control Number: 18/260,017 Page 2 Art Unit: 1638 Application/Control Number: 18/260,017 Page 3 Art Unit: 1638 Application/Control Number: 18/260,017 Page 4 Art Unit: 1638 Application/Control Number: 18/260,017 Page 5 Art Unit: 1638 Application/Control Number: 18/260,017 Page 6 Art Unit: 1638 Application/Control Number: 18/260,017 Page 7 Art Unit: 1638 Application/Control Number: 18/260,017 Page 8 Art Unit: 1638 Application/Control Number: 18/260,017 Page 9 Art Unit: 1638 Application/Control Number: 18/260,017 Page 10 Art Unit: 1638 Application/Control Number: 18/260,017 Page 11 Art Unit: 1638 Application/Control Number: 18/260,017 Page 12 Art Unit: 1638