DETAILED ACTION
Election/Restrictions
Applicant’s election of Group II and SEQ ID NO: 5744 in the reply filed on November 25 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). Claims 1-9, 11, 13, 15, 17, 20, 24, 28, 31, 41 and 60 are pending in the application. Claims 1-9, 11, 13, 15, 17, 31, 41 and 60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 November 25 2025. Accordingly, claims 20, 24 and 28 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US2021/022582 (03/16/2021) which claims benefit of 63/047,209 (07/01/2020) and claims benefit of 62/990,111 (03/16/2020) as reflected in the filing receipt issued on April 6 2023.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62990111, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically claims 20, 24 and 28 require a RNA polynucleotide of SEQ ID NO: 5744. This sequence does not appear to be supported in the prior filed application.
While prior-filed application, 63047209, does not expressly state SEQ ID NO: 5744, contains Figure 4B which clearly teaches the sequence corresponding to SEQ ID NO: 5744.
Therefore, the effective filing date of claims 20, 24 and 28 is July 1 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 12 2022 and March 18 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to for the following two reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."” In the current case, the view numbers for Figures 1-16 are preceded by the word "Figure" instead of the abbreviation "FIG.".
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” In the current case, the view numbers for the partial views for Figures 2, 3, 4, 6, 8, 9, 11, 12, 13, that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: on page 6 in the brief description of Figure 3 it states that Figure 5A discloses SEQ ID NOS: 5742-5744. However, there is no Figure 5A. There is only figure 5 and this does not disclose these sequences. Figure 4D discloses the sequences.
Appropriate correction is required.
Claim Rejections - 35 USC § 112-Enablement
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 20, 24 and 28 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 modifying a genetic target in prokaryotic cells, does not reasonably provide enablement for modifying a genetic target in eukaryotic cells. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
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 those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and Nature of the Invention
The instant claims are directed to a system for modifying a genetic target in cells the system comprising a first set of transposon genes encoding type I-F3 CRISPR-Cas proteins wherein said genes are tnsA, tnsB, tnsC and tniQ and Cas genes cas8f, cas5f, cas7f and cas6f and an RNA polynucleotide comprising the sequence of SEQ ID NO: 5774.
The instant claims are also directed to a method comprising introducing the system above into cells.
Therefore, the instant claims are broad and encompass the modification or the introduction in any cell which is inclusive of both prokaryotic and eukaryotic cells.
It is noted that while the recitation for modifying a genetic target in cells is an intended use, the enablement of compositions limited by a particular use must be considered. See In re Vaeck, 947 F.2d 488, 20 USPQ2d 1438 (Fed. Cir. 1991) and In re Gardner, 427 F.2d 786, 166 USPQ 138 (C.C.P.A. 1970). Note: MPEP 2164.01(c).
The amount of direction or guidance provided and the presence or absence of working examples
The specification fails to include an explanation or example of how the CRISPR/Cas type I-F system is capable of being successful in eukaryotic cells. While the specification contemplates use in vitro or in vivo such as in a prokaryotic or eukaryotic cell (see page 4, 17, 25, 30, 70, 72-74, 80-81 and 85 ). The specification that’s that modifications of the system may include adapting the expression system to allow expression in eukaryotic hosts (page 30). The specification provides working examples in E. Coli (BL21) (see pages 99-100) but never actually shows how the system is to be used in eukaryotic cells. No specific guidance for using the system in eukaryotes is provided and no working examples that demonstrate the efficacy of the system in eukaryotes are provided.
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The relative skill of those in the art is high, that of an MD or PHD with experience in molecular biology. However, the art, with regards to the use of CRISPR/Cas type I-F systems in eukaryotic cells establishes unpredictability.
Zheng et al (Nucleic Acids Research, 2019) provide a discussion of the capabilities of the CRISPR/Cas Type I-F system in prokaryotes vs eukaryotes. Zheng teaches that CRISPR/Cas Type I-F is a class I system, which is a multicomponent system (Page 11461, right column), whereas Class 2 systems, such as CRISPR-Cas9 and CRISPR-Cas12a are simpler systems widely developed for gene editing in eukaryotes and prokaryotes (Page 11462, left column, 1st paragraph). Zheng teaches that the CRISPR-Cas I-F system has not been developed yet for non-model industrial micro-organisms, providing that it has not been tested or deemed capable of another organism besides Z. mobilis at the time of the published literature (Page 11462; bridging columns 1 and 2). Based on these teachings one skilled in the art would have recognized the underdeveloped state of the art with regard to the use of CRSIPR Type I-F systems in eukaryotic cells.
Zetsche et al (Cell. 2015) and Chen et al (Nat Commun, 2017) teaches that the Cas9 system was the first to be found successful in eukaryotic cells with the later use of a Cpf-1 family protein (Abstract). Zetsche teaches the identification of eight different Cpf1-family proteins and their guide RNAs and demonstrates the effectiveness of each Cpf1-family protein in cleaving DNA in vitro (Page 764, bridging columns 1 and 2). However, only two out of the eight proteins provided a successful result when tested in cultured human cells after codon optimization and the addition of a nuclear localization signal (NLS), demonstrating how variable in success the systems can be for mammalian cells (Page 764, bridging columns 1 and 2). Chen et al (Nat Commun 8, 14958 (2017) teaches that many CRISPR-CAS systems have been explored for mammalian gene editing and were found inactive in the cells even though they were active in bacteria or on purified DNA substrates (Page 2; Column 1). Given the unpredictability with simpler Class 2 CRISPR Cas systems, one skilled in the art would have recognized the unpredictability in adapting a Class 1 from use in a prokaryote to a eukaryote.
In the instant case, the claims encompass the use of the CRISPR/Cas type I-F system in both prokaryotes and eukaryotes and the specification fails to show how the claimed system can be used to modify a target gene in any cell or practice the claimed methods in any cell. Neither the claims nor the specification provide the steps or function of how the system is used in eukaryotic cells due to no evidence of the type I-F system being capable of successful use within eukaryotic cells.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to modify a target in any cell as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 20, 24 and 28 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.
Claims 20 and 24 as currently written are vague and indefinite. Claim 20 recites the system comprising a set of transposon genes encoding type I-F3 CRISPR-Cas proteins wherein said genes are tnsA, tnsB, tnsC and tniQ, and Cas genes cas8f, cas5f, cas7f and cas 6f. This seems to indicate that the set of transposon genes are tnsA, tnsB, tnsC, tniQ, cas8f, cas5f, cas7f and cas6f and all are included in the set. But claim 24 recites wherein the set of transposon genes or the cas genes or a combination thereof are present within a single recombinant polynucleotide that is introduced into the cells. This seems to suggest that the Cas genes are separate from the transposon genes but that is not what is recited in claim 20. Furthermore, claim 24 seems to indicate that what is introduced into the cells can only be the set of transposon genes or the cas genes but claim 20 requires that both are part of the system and the first line of claim 24 states the method comprises introducing the system into cells. Therefore, the scope of the system is unclear because claim 20 seems to indicate that all are transposon genes and part of the system but claim 24 seems to indicate the transposon genes are separate from the Cas genes and not both are introduced.
Claim 28 is included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 20 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
The claims recite laws of nature and natural phenomena. These judicial exceptions are not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception as explained below:
Subject Matter Eligibility Guidance
A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP § 2106:
Step (1). Is the claim directed to a process, machine, manufacture, or composition of matter?
Step (2A). Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea?
Prong 1 – Does the claim recite a law of nature, natural phenomenon, or an
abstract idea?
Prong 2 – If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application?
Limitations that are indicative of integration into a practical application include:
Improvements to the functioning of a computer, or to any other technology or technical field. See MPEP § 2106.05(a)
Applying the judicial exception with, or by use of, a particular machine. See MPEP § 2106.05(b)
Effecting a transformation or reduction of a particular article to a different state or thing. See MPEP § 2106.05(c)
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. See MPEP § 2106.05(d)
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. See MPEP § 2106.05(e)
Step (2B). If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly different than the judicial exception such that they provide an inventive concept? This step includes evaluation of the same considerations under Step (2A), Prong 2, as well as two additional considerations:
Adding a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; and
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
Analysis
Step (1): The answer to this step is yes since claim 20 is directed to a system (composition of matter), which is a statutory category.
Step (2A):
Product of Nature Definition
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See Myriad Genetics, Inc., 569 U.S. at 590-91, 106 USPQ2d at 1979.
Claim Analysis
Prong 1
The markedly different characteristics analysis is part of Step 2A Prong One, because the courts use this analysis to identify product of nature exceptions.
Claim 20 is directed to a system comprising a set of transposon genes encoding type I-F3 CRISPR-Cas proteins wherein said genes are tnsA, tnsB, tnsC and tniQ and Cas genes cas8f, cas5f, cas7f and cas6f and an RNA polynucleotide comprising the sequence of SEQ ID NO: 5744.
The appropriate counterpart to the currently claimed product of nature are: the naturally occurring type I-F3 CRISPR-Cas protein and guide RNA. As shown in Peters (Molecular Microbiology, 2019), figure 3, the major Tn7-like element families identified in sequence bacterial genomes include tnsA, tnsB, tnsC and tniQ and Cas genes cas8f, cas5f, cas7f and cas6. Figure 2 shows how target complexes are assembled at various preferred target sites with Tn7 and Tn-7 like which include gRNA-Cascade.
Petassi et al. (Cell, 2020) teaches in Figure 1, TN7-like Elements with I-F3 CRISPR-CAS systems found in Gammaproteobacteria which includes Aeromonas salmonicida S44. The instantly claimed SEQ ID NO: 5744 aligns with Aeromonas salmonicida S44 (GenBank: CP022176.1, 2017):
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Thus, the broadest reasonable interpretation of claim 20 is that the instantly claimed system does not possess any markedly different characteristics from the naturally occurring I-F3 CRISPR-Cas system. The examiner notes that the instant claims does not limit the spacer sequence and thus the instantly claimed SEQ ID NO: 5744 does not distinguish between the sequence in Aeromonas salmonicida S44.
Therefore, the answer to step 2A prong 1 is yes.
Prong 2:
The Prong Two analysis considers the claim as a whole. That is, the limitations containing the judicial exception as well as the additional elements in the claim besides the judicial exception need to be evaluated together to determine whether the claim integrates the judicial exception into a practical application.
The instant claim does not contain any additional elements.
Therefore, the answer to step 2A prong 2 is No.
Step (2B):
There are no additional elements.
Therefore, the answer to step (2B) is No.
Conclusion
Claim 20 is directed to a judicial exception and does not qualify as eligible subject matter under 35 U.S.C. § 101.
Claims 24 and 28 are NOT directed to a judicial exception and DO qualify as eligible subject matter under 35 U.S.C. § 101. The method claims practically apply the nature-based products recited in the claims. These claims are eligible under the streamlined analysis described in MPEP 2106.06.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The closest prior art Sternberg et al. (USPGPUB No. 20200283769; WO 2020181264 (cited on PTO Form 1449) is directed to RNA guided DNA integration using TN7-like transposons. Sternberg et al. teaches a system for RNA-guided DNA integration comprising one or more vectors encoding a CRISPR-Cas system comprising Cas5, Cas6, Cas7 and Cas8 and transposons TnsA, TnsB, TnsC and TniQ (claim 1) wherein the system is a Type I-F CRISPR-Cas system (claim 3). Sternberg et al. also suggests a guide RNA (claim 6) and donor DNA to be integrated (claim 7). While Sternberg et al. suggests there are many computational tools to facilitate gRNA design (paragraph 0301) and that the gRNA can be designed as a repeat-spacer-repeat array (paragraph 0123, 0124, 0604-0605), Sternberg et al. does not teach a RNA polynucleotide of SEQ ID NO: 5744 as claimed.
While the instantly claimed SEQ ID NO: 5744 aligns with Aeromonas salmonicida (GenBank: CP022176.1, 2017):
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there is no motivation within these references or the art as a whole to select this portion of the Aeromonas salmonicida sequence and specifically the first and second repeat sequences represented in SEQ ID NO: 5744. Therefore, absent hindsight, one skilled in the art would not have been motivated to combine the instantly claimed RNA polynucleotide of SEQ ID NO: 5744 with the Type I-F CRISPR-Cas system.
The examiner additionally notes pursuant to MPEP 821.04(a), rejoinder will only occur when non-elected inventions that depend from or otherwise require all the limitations of an allowable claim.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636