Examiner of Record
The Examiner of record has changed.
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 the following invention
Group II (claims 42-67 and 91) drawn to a method for genetically modifying a cell in the reply filed on 16th Sept, 2025 is acknowledged.
Claims 1-18, 19-27, 28-32, 33-41, 68-83, and 84-90, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Status of Claims
Claims 42-67 and 91 are under consideration.
Since claim 91 requires the product of unelected claims 84 to 90, these claims will be examined to the extent they are required to practice the method of claim 91.
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international application PCT/US2020/054526, filed on Oct 07, 2020, which claims domestic priority under 35 U.S.C. 119(e) to U.S. provisional application no. 62/912,115, filed on Oct 18, 2019.
Claim Objections
Claims 50-67 and 91 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits. 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.
Appropriate correction is required.
Claim Rejections - 35 USC § 112a
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.
Scope of 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 42-49 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 for genetically modifying an animal cell in vitro, the method comprising introducing into the cell a donor DNA, at least one ssDNA binding protein or nucleic acid encoding the at least one single stranded DNA binding protein, and at least one nucleic acid cutting entity or a nucleic acid encoding the nucleic acid cutting entity
does not reasonably provide enablement for methods of modifying an animal cell in vivo (including all administration types, vector types, dosage types, and subject types).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Instant claims encompass:
“modifying”
This includes all types of genetic modification including all possible editing types such as but not necessarily limited to CRISPR, TALEN, ZFN or Mega nucleases.
“a cell”
This encompasses all possible types of cells in vitro from all possible species types or in vivo in all possible subject types.
“introducing in to a cell”
This encompasses all types of delivery in vitro or in vivo
Regarding in vivo delivery, this includes all possible routes of delivery.
“a donor DNA”
Regarding both in vitro and in vivo delivery, this encompasses all possible donor template types including but not necessarily limited to viral (such as but not necessarily limited to adenoviruses, lentivirus, or AAVS) and non-viral vector types (such as but not necessarily limited to LNPs or naked DNA).
Direction or Guidance Presented
While contemplating methods in vivo in subjects (para. [0105, 0140 - 0141, and 0151] see for example para [0140]: Some embodiments include compositions and methods designed to result in high efficiency of genome editing in cells (e.g., eukaryotic cells such as plant cells and animal cells, such as insect cells and mammalian cells, including mouse, rat, hamster, rabbit and human cells); applicant provides no guidance on in vivo methods.
Present Working Examples
Applicant discloses Examples 1-3 and 6, which appear to be drawn to in vitro gene editing of cells of a human cell line in vitro.
A description of Examples is discussed in the Written Description section.
in vitro Cell Types:
293FT cells (Examples 1-2, and 6) U2OS cells (Example 3) are described.
Nuclease Types:
CRISPR/Cas9 RNP (Examples 1 - 3) and variants of CRISPR/Cas9 RNP (Example 6) were tested. Nucleotides were introduced in to cells with a transfection reagent.
Electroporation of different single stranded DNA binding proteins on delivery of Cas9 ribonucleoprotein (RNP) into EmGFP cell line (having a disrupted EmGFP gene) with a single stranded donor DNA (approximately 100 nucleotides) was also performed and depicted in Fig. 1.
Absent Working Examples
Since the cells recited in claims are unlimited, the scope of the claims reads on cells within a subject. Importantly, no working examples are provided that are drawn to in vivo gene editing of cells, which is encompassed by instant claims.
State of the Art and Unpredictability of the Art
Providing to a cell and in vitro vs. in vivo
As stated above, while Applicant’s broad claim encompasses in vivo embodiments Applicant only provides working examples of gene editing in vitro.
Regarding translation of in vitro methods to in vivo methods, Applicant is directed to the post-filing art of Mattes (Current Opinion in Toxicology 2020, 23-24:114–118). Matts evidences that around the time of filing, and post-filing, translating in vitro data to in vivo data is unpredictable. Specifically, Mattes evidences “the challenge of validating a system’s performance and extrapolating it’s responses to those of an animal or human remains” (abstract) and “the question of relevance to the in vivo setting remains an issue” (Summary; pg. 116).
Accordingly, because translation of in vitro methods to in vivo methods is still unpredictable, Applicant cannot be enabled for instant claims, which encompass in vivo methods.
Applicant is also directed to the post-filing art of Zhang (J Cell Physiol. 2021 Apr;236(4):2459-2481.). Zhang teaches significant challenges also remain before CRISPR/Cas technology can be routinely employed in the clinic for treating different genetic diseases, which include toxicity and immune response of treated cells to CRISPR/Cas component, highly throughput delivery method, and potential off‐target impact (abstract). Zhang teaches the off‐target effect is one of the major concerns for CRISPR/Cas9 gene therapy, more research should be focused on limiting this impact by designing high specific gRNAs and using high specificity of Cas enzymes. Modifying the CRISPR/Cas9 delivery method not only targets a specific tissue/cell but also potentially limits the off‐target impact (abstract).
Thus the art before the effective filing date of the claimed invention teaches methods of administering gene editing components to a cell were highly unpredictable, with challenges of a lack a specificity, adverse immune responses with the nucleases and cleavage agents, as well as questionable translatability of rat in vivo results to other mammal for specific results, such as therapeutic effects or providing a predictable amount of such a composition to get the intended result. Further, the post-filing arts of Zhang and Mattes described above demonstrate that these unpredictability and hurdles to in vivo embodiment persist from the prior time of effective filing and post-filing.
Unpredictability of the Art and the Quantity of Experimentation
As the arts of Mattes and Zhang demonstrate, the obstacles that hinder the use of the claimed method in in vivo embodiments are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant broadly claimed invention.
Scope of Enablement - Conclusion
In conclusion, the breadth of the claims lacks enablement because the specification provides limited working examples in vitro and the specification provides no guidance and no working examples of the claimed method in vivo. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot predictably be performed. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.
Claim Interpretation
Claims 42 - 47 recite, method for genetically modifying a cell, method for improving targeting efficiency of a nucleic acid cutting entity for genetic modification of a cell, method for reducing off-target integration of a donor DNA during genetic modification of a cell, method for enhancing delivery of a donor DNA to a cell for genetic modification of the cell, method for reducing degradation of a donor DNA for genetic modification of a cell, method for genetically modifying a cell, and method for genetically modifying a cell, respectively.
These recitations are preamble recitations. MPEP 2111.02 (II) states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"); Kropa v. Robie, 187 F.2d at 152, 88 USPQ2d at 480-81 (preamble is not a limitation where claim is directed to a product and the preamble merely recites a property inherent in an old product defined by the remainder of the claim); STX LLC. v. Brine, 211 F.3d 588, 591, 54 USPQ2d 1347, 1350 (Fed. Cir. 2000) (holding that the preamble phrase "which provides improved playing and handling characteristics" in a claim drawn to a head for a lacrosse stick was not a claim limitation).
Therefore, the recitations are not considered a limitation and are of no significance to claim construction.
Claims 42 - 47 recite in last two lines, under conditions that allow for genetically modifying the cell at a predetermined locus.
Here, no structural feature is present in the disclosure that spells out what the conditions are. Therefore, the clause recited is not considered a limitation and is of no significance to claim construction.
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) 42-49 are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Cemák (US 2020/0407754 A1 published Dec. 31, 2020, supported by its provisional application 62/866,317, filed on Jun 25, 2019).
Cemák discloses methods for genome editing and improving CRISPR/Cas-mediated genome editing and teach that to do so, the cell must be contacted with a composition comprising an HDR-enhancer (see, e.g., title and abstract). HDR-enhancer is also an HDR promoting agent, and comprises: an SSAP, an exonuclease, and an SSB. Cemák teach these components are required for methods of modification of the target editing site of the eukaryotic cell genome and increasing efficiency of HDR-mediated genome editing (claim 1, table B), increasing HDR precision (reducing off-target integration) ([0284] and Table 4A), transient expression of HDR promoting agents (enhancing delivery of a donor DNA) ([0081] onwards), and improving functionality of polynucleotides by including additional nucleotide sequences into polynucleotides to provide useful functionality by complexing with a non-nucleic acid element (reducing degradation) ([0083]); where the method comprises the step of providing genome editing molecules comprising (i) at least one sequence-specific endonuclease which cleaves a DNA sequence in the target editing site; and (ii) a donor template DNA molecule having homology to the target editing site; template nucleic acids for correcting mutation having homology arms, and the above mentioned HDR promoting agents such as SSB [0006].
Regarding claims 42 – 47, Cemák discloses a method for genetically modifying a cell and improving targeting efficiency, the method comprising introducing into the cell: (i) a donor template (donor DNA molecule);(ii) SSB (a single stranded DNA binding protein) or nucleic acid encoding SSB; and (iii) at least one sequence-specific endonuclease which cleaves a DNA sequence in the target editing site or at least one polynucleotide encoding the sequence-specific endonuclease (at least one nucleic acid cutting entity or nucleic acid encoding the at least one nucleic acid cutting entity) (see, e.g., [0245]; nucleic acid that encodes… SSB [0169]).
Regarding claims 48 and 49, Cemák discloses many examples of nucleases and specifically, Cas nuclease (nucleic acid cutting entity) (e.g. [0100]; see Fig. 1, [0017], and Examples starting on pg. 48 for Cas).
Thus the claimed invention is clearly anticipated by Cemák.
Relevant Prior Art Not relied Upon
The following art is made note of and not currently relied on, but is relevant to applicants invention. Cotta-Ramusino (US Patent Application Publication 2018/0298392 A1, published on October 18, 2018, filed on November 9, 2015) discloses methods for improving CRISPR/Cas-mediated genome editing and that to increase the likelihood that the break is repaired by HDR, the cell can be contacted with an HDR-enhancer (see, e.g., title and abstract). Cotta-Ramusino discloses a method for increasing HDR-mediated genome editing where the method comprises the step of providing genome editing molecules comprising (i) at least one sequence-specific endonuclease which cleaves a DNA sequence in the target editing site (contacting the cell with a gRNA that targets a target position and a Cas9 molecule, see, e.g., [1231]); and (ii) a donor template DNA molecule having homology to the target editing site (a template nucleic acid, see, e.g., [1231]; template nucleic acids for correcting mutation… homology arms, see e.g. [1216]). Cotta-Ramusino further discloses providing HDR promoting agents (an HDR-enhancer, see, e.g., [1231]) to a eukaryotic cell (see [0089]) to a eukaryotic cell (see e.g. [1474]). Cotta-Ramusino discloses HDR-enhancer molecules that are up-regulators of SSA and include the protein RAD52 (see, e.g., [0045]). Cotta-Ramusino discloses exonucleases which can at least partially convert a double stranded DNA substrate to a single stranded DNA product (EXO1, see, e.g., [1334]). Cotta-Ramusino discloses single stranded DNA binding proteins (RPA1, RPA2, and RPA3, see, e.g., [1334]) and that RPA proteins prevent repeat sequences from inappropriate annealing (see [1321]). Cotta-Ramusino discloses methods involving stimulating or overexpressing one or more components of an HDR pathway (see, e.g., [1334]). Cotta-Ramusino discloses that HDR enhancing molecules, e.g. an HDR-enhancing gRNA, enhances HDR as compared to what would occur in absence of the HDR-enhancing molecule (see, e.g., [0292-0293]).
Cotta-Ramusino does not disclose SSB as an efficient single stranded DNA binding protein in the process of genome editing.
The closest prior art disclosing preferred embodiments is applied above.
Conclusion
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635