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 .
Claim Status
Claims 28, 35-36, 41-45, 47-49, and 51-56 are pending.
Claims 41 and 51 are withdrawn.
Claims 28, 35-36, 42-45, 47-49, and 52-56 are under examination.
Withdrawn Claim Objections
The objection to claim 28 due to informalities as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 112(a)
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 28, 35-36, 42-45, 47-49, and 52-56 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.
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: methods of introducing a gene of interest (GOI) into the albumin locus comprising intravenously administering to a subject:
a gRNA comprising a spacer sequence from any one of SEQ ID NOs: 21, 22, 28 and 30, wherein the gRNA comprising the spacer sequence has cellular cleavage frequency of greater than about 40%.
This encompasses all possible subject types in vivo and requires the gRNA comprising the spacer sequence has cellular cleavage frequency of greater than about 40% in all possible in vivo subjects.
Direction or Guidance Presented
While contemplating gRNAs with cellular cleavage frequencies of greater than about 40% in a method including all possible in vivo subjects, Applicant provides limited guidance of cellular cleavage frequences only from in vitro data (pg. 108 Table 4) in HuH7 cells and HepG2 cells.
Furthermore, even for the in vitro data, only SEQ ID NO: 22 has a cleavage frequency which meets the claimed requirements of cellular cleavage frequency of greater than about 40% (Table 4 pg. 108). Importantly, this is in vitro data and guidance only, and data and guidance on the cellular cleavage frequencies of the claimed gRNAs is not provided for in vivo methods in subjects.
Present Working Examples
Cleavage Frequency data in vitro
Table, 4, pg. 108, discloses cleavage frequencies obtained for the claimed gRNA from in vitro data (pg. 108 Table 4) in HuH7 cells and HepG2 cells which are copied below for reference.
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(copied from Table 4: pg. 108).
Importantly, even for in vitro data, ONLY SEQ ID NO: 22 has a cellular cleavage frequency above 40% in both cell lines tested.
Working Examples
Relevant Working Examples 10-13 were summarized previously (see Non-Final rejection mailed on 12th, August, 2024 pg. 13-17).
Importantly, while the examples provide in vivo data, no numeric measurement of cleavage frequency of the claimed gRNA in in vivo embodiments is provided.
Absent Working Examples
As stated above, while in vitro cleavage data is provided, and the examples provide in vivo data, no measurement of cleavage frequency of the claimed gRNA in these in vivo embodiments.
State of the Art and Unpredictability in the Art
Thyme
Applicant is directed to the art of Thyme et al. (Nat Commun. 2016 Jun 10;7:11750.; henceforth “Thyme”). Thyme evidences that gRNA cleavage frequencies (performance) is not predictable in vivo. Specifically, Thyme evidences two mechanisms that contribute to poor gRNA performance: first, some gRNAs could be inherently poor at forming active Cas9–gRNA complexes, or second, they do form active complexes but their target sites could be refractory in vivo (pg. 2 col. 1 2nd para.) Thyme evidences by measuring both the in vitro cleavage and in vivo activity in zebrafish embryos, there are gRNAs that fail for both reasons which suggests that gRNAs that cleave well in vitro but not in vivo, are blocked by sequence-specific genomic factors and chromatin (pg. 2 col. 1 2nd para.; see also Figures 1 and 3).
Therefore, the state of the art evidences cleavage frequencies are not predictable between in vitro data and in vivo methods and therefore Applicant is not enabled for the claimed cleavage frequencies in an in vivo method while the Application only provides evidence of in vitro data.
Evidence of Unpredictability of the Specification
Applicant’s own specification evidences that cleavage frequencies, even for in vitro data, are not predictable. As stated above, Table, 4, pg. 108, discloses cleavage frequencies obtained for the claimed gRNA from in vitro data (pg. 108 Table 4) in HuH7 cells and HepG2 cells which are copied below for reference.
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(copied from Table 4: pg. 108).
For each of the claimed gRNAs, the cleavage frequencies vary drastically between cells lines (HuH7 cells which are human cells and HepG2 cells), which evidences that even for in vitro data cleavage frequences are not predictable from cell line to cell line of the same species type and same cell type.
Furthermore, Applicant’s specification evidences that , even for in vitro data, ONLY SEQ ID NO: 22 has a cellular cleavage frequency above 40% in both cell lines tested, and SEQ ID NO: 21 and 30 did not have an average cleavage frequency above 40% in either cell line tested.
Brooks Art
The prior art of Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth “Brooks”) also teaches what appears to be the same in vitro cleavage frequency data of the instant application (Brooks reference; Table 4; pg. 112). Therefore, Brooks also teaches that even for in vitro data, cleavage frequences are not predictable from cell line to cell line of the same species type and same cell type.
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Unpredictability of the Art and the Quantity of Experimentation Necessary
As the arts of Thyme as Brooks as well as the evidence of the instant specification demonstrate, the obstacles that hinder the use of the claimed method with the claimed cleavage frequencies in in vivo embodiments are not easy tasks to be done or solely routine experimentation to enable 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 method of the instant claimed invention.
Enablement – Conclusion
In conclusion, the claims lack enablement because the specification provides limited working examples of cleavage frequencies in vitro, while the state of the art as well as Applicant’s specification evidences that cleavage frequencies in vitro are not predictable and also do not predictably translate to in vivo methods. The art at the time of effective filing fail to provide specific guidance that supplement the 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 claims and this level of experimentation is undue.
Withdrawn Claim Rejections - 35 USC § 112
Improper Markush
The rejection of claim 57 on the basis that it contains an improper Markush grouping of alternatives as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
Claim Rejections - 35 USC § 112
Improper Markush
Claims 28, 35-36, 42-45, 47-49, and 52-56 remains rejected on the basis that it contains an improper Markush grouping of alternatives.
By nature of their ultimate dependency on claim 28, claims 35-36, 42-45, 47-49, and 52-56 are also rejected.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of FVIII protein, FIX protein, alpha-1-antitrypsin, FXIII protein, FVII protein, FX protein, Protein C, and serpin G1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The listed proteins are structurally distinct, have materially different functions, and are involved in or used to treat materially different diseases and physiologic processes.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Arguments
Applicant’s arguments, filed 8th, January, 2026 have been fully considered but are not found persuasive.
Applicant argues “According to MPEP 2117: "A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300,305 (CCPA 1980))"(pg. 6).
In response, as set forth above, A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. MPEP 2117 (I) specifically states that “A Markush grouping is proper if the members of a group share a single structural similarity and a common use.” Applicant’s citation refers to improper Markush groupings. If the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use, then the Markush group is not proper because the group does not share a “single structural similarity” and a common use if either one of these is not met.
Applicant argues “When claim 28 is considered on a case-by-case basis it is clear that the member of the group recited in claim 28 (i.e., FVIII protein, FIX protein, alpha-1-antitrypsin, FXIII protein, FVII protein, FX protein, Protein C, or serpin G 1) share a common use in the context of the claimed invention. The claimed invention is a method of introducing a gene of interest (001) into a specific locus. Thus, the specified genes in the group have a common use in that all of the listed genes can serve as a gene of interest. Furthermore, the listed genes are all genes associated with blood disorders and thus further share the common use of treatment of blood disorders when the claimed method is performed. This, the listed genes belong to an art recognized group of genes that are implicated in blood disorders. As a result, the grouping is permissible under the standards outlined in the MPEP” (pg. 6-7).
In response, the members do not share a “single structural similarity” and a common use as set forth above, which are the requirements of a Markush group. The members do not have a single structural similarity, and therefore the Markush Grouping is improper regardless of whether they share a common use.
Regarding common uses, merely being able to serve as a gene of interest is not sufficient to meet a common use. Regarding uses as blood disorders, the genes are used to treat structurally distinct blood disorders and therefore this is also not a common use.
Regarding Art-recognized classes, Applicant is directed to MPEP 2117 (II)(A) which states that Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved. For example, in the context of a claim covering a disposable diaper, a limitation "the fastener selected from the group consisting of a pressure sensitive adhesive and complementary release material, a complementary hook and loop structure, a snap, and a buckle" would likely be considered an art recognized class because a review of the prior art would establish that it was well known that each member could be substituted for each other with the expectation that the intended result (repositionable and refastenable) would occur. (see MPEP 2117 (II)(A)). In the instant case, the listed members do not belong to the same art recognized class because the intended result would not be the same. The result of expressing structurally and functionally distinct proteins would be physiologically distinct in a subject and is not the same intended result.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejection of claims 28, 35-36, 42-45, 49, and 52-56 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 57 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
New 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 28, 35-36, 42-45, 47-49, and 52-56 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 28 recites “greater than about,” with no corresponding special definition of “greater than about.” Thus, there is nothing in the specification, prosecution or prior art to provide any indication as to the claimed range, thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(b), III.A. Additionally, the phrase “greater than” creates a hard lower cutoff for the value, but the term “about” indicates there is a range for the stated value. Including both “greater than” and “about” makes it unclear whether or not the lower value is a hard cutoff for the range.
By nature of their ultimate dependency on claim 28, claims 35-36, 42-45, 47-49, and 52-56 are also rejected because they do not clarify the issue.
Claim 28 recites “the gRNA comprising the spacer sequence has cellular cleavage frequency of greater than about 40%” while claim 28 also recites the gRNA comprises a spacer sequence from any one of SEQ ID NOs: 21, 22, 28 and 30. However, the instant specification recites the following cleavage frequencies obtained from in vitro data (IVT gRNA in HuH7 and the synthetic gRNA in HepG2 cells (pg. 108) of:
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(copied from Table 4: pg. 108).
It is unclear how the gRNAs comprising SEQ ID NO: 21, 28 and 30 can have cleavage frequences of “greater than about 40%” when SEQ ID NO: 21, 28 and 30 appear to not have cleavage frequences above 40%.
Claims 47 recites “the target site.” However, claim 45, upon which claim 47 depends does not recite a “target site.” Therefore, there is improper antecedent basis for this term and it is unclear which target site is intended to be encompassed, and in what context.
Because claim 48 also recites “the target site,” but does not clarify the issue, claim 48 is also rejected.
Response to statement pursuant to 35 U.S.C. 102(b)(2)(C)
Applicant’s statement pursuant to 35 U.S.C. 102(b)(2)(C) is insufficient to overcome the rejection of claims 28, 35-36, 42-45, 47-49, and 52-57 under 35 U.S.C. 102(a)(2) as being anticipated by Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth th “Brooks”) for the following reasons:
1. The statement does not state that that the disclosure of the subject matter on which the rejection is based and the claimed invention were made by or on behalf of parties to a joint research agreement under AIA 35 U.S.C. 102(c).
Specifically, the statement recites the following:
“US 17 /286,276 (this application), which claims priority to U.S. Provisional Patent Application
Ser. No. 62/747,128, filed on Oct. 17, 2018, and the cited reference, Brooks WO2019079527,
corresponding to US 16/756,927, which claims priority to U.S. Provisional Patent
Application No. 62/573,633, filed Oct. 17, 2017, were, not later than the effective filing date
of the invention claimed in the above-captioned application, owned by, or were subject to an
obligation of assignment to, CRISPR Therapeutics AG as evidenced by the following
recorded assignments:
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This statement is insufficient because it only states that US 17 /286,276 and the cited brooks reference were “owned by, or were subject to an obligation of assignment to, CRISPR Therapeutics AG” and does not state that the disclosure of the subject matter on which the rejection is based and the claimed invention were made by or on behalf of parties to a joint research agreement under AIA 35 U.S.C. 102(c).
2. The statement does not indicate that the agreement was in effect on or before the effective filing date of the claimed invention, and that the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement.
3. The specification has not been amended to disclose the names of the parties to the joint research agreement, in accordance with 37 CFR 1.71(g). The originally filed specification also does not contain this required information.
4. A processing fee set in 37 CFR 1.17(i) does not appear to have been paid.
Applicant is directed to 37 CFR 1.17(g)(2) which states:
(2) An amendment under paragraph (g)(1) of this section must be accompanied by the processing fee set forth in § 1.17(i) if not filed within one of the following time periods:
(i) Within three months of the filing date of a national application;
(ii) Within three months of the date of entry of the national stage as set forth in § 1.491 in an international application;
(iii) Before the mailing of a first Office action on the merits; or
(iv) Before the mailing of a first Office action after the filing of a request for continued examination under § 1.114.
Applicant is directed to the requirements to invoke a joint research agreement, recited in MPEP 2156:
In order to invoke a joint research agreement to except a disclosure as prior art, the applicant (or the applicant's representative) must provide a statement that the disclosure of the subject matter on which the rejection is based and the claimed invention were made by or on behalf of parties to a joint research agreement under AIA 35 U.S.C. 102(c). The statement must also assert that the agreement was in effect on or before the effective filing date of the claimed invention, and that the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement. The statement should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c) ). The statement must be signed in accordance with 37 CFR 1.33(b). See MPEP § 717.02(a), subsection II. If the names of the parties to the joint research agreement are not already stated in the application, it is necessary to amend the application to include the names of the parties to the joint research agreement in accordance with 37 CFR 1.71(g). The amendment to include the names of the parties must be accompanied by a processing fee set in 37 CFR 1.17(i) unless it is filed within one of the time periods set forth in 37 CFR 1.17(g)(2). See MPEP § 717.02(b), subsection IV. An amendment limited to adding the names of the parties to the joint research agreement does not constitute new matter (see MPEP 2156).
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claim 57 under 35 U.S.C. 102(a)(2) as being anticipated by Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth “Brooks”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
Examiner’s Remark
Because the Joint Research Agreement was missing elements as discussed above, the rejection of claims 28, 35-36, 42-45, 47-49, and 52-57 remain rejected under 35 U.S.C. 102(a)(2) as being anticipated by Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth “Brooks”) is reapplied below.
It is noted that the prior art of by Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth “Brooks”) is as enabling as Applicant’s disclosure.
Maintained Claim Rejections - 35 USC § 102
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.
Claims 28, 35-36, 42-45, 47-49, and 52-56 remain rejected under 35 U.S.C. 102(a)(2) as being anticipated by Brooks (WO-2019/079527-A1; see IDS filed 26th, July, 2023; priority to U.S. Provisional Application 62/573,633 filed 17th, October, 2017; henceforth “Brooks”).
The applied reference has a common Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claim 28, Brooks discloses
A method of introducing a gene of interest (GOI) (“knocking in”; abstract) into the albumin locus (“the locus of albumin gene” abstract), the method comprising:
intravenously administering (“iv injection”) to a subject (mouse; Example 4 and primate; Example 5):
(a) a gRNA comprising a spacer sequence from SEQ ID NOs: 22(Brooks SEQ ID NO: 22, 49, 53, 66 and 70 comprise a spacer sequence from SEQ ID NO: 22)
(b) a nucleic acid encoding a Cas DNA endonuclease (“Cas9 mRNA”; Example 4 para. [0603]); and
(c) a donor template comprising a nucleic acid sequence encoding a gene of-
interest (GOI), wherein the GOI encodes FVIII protein (“FVIII-encoding gene” abstract; “donor DNA template”; Example 4),
wherein the gRNA, nucleic acid encoding the Cas DNA endonuclease (“The sequence specific gRNA mAlb_T1 and the Cas9 mRNA are delivered to the hepatocytes of the liver of the same mice by intravenous or RO injection”; para. [0603]), and donor template “The donor DNA template is delivered
in an AAV virus, preferably a AAV8 virus in the case of mice, which preferentially transduces the hepatocytes of the liver after intravenous injection” para. [0603]) are introduced into hepatocytes of the liver of the subject,
wherein the gRNA targets the Cas endonuclease to the albumin locus (“CRISPR-Cas9 nuclease targeted to albumin intron 1” para. [0603]) and
wherein the donor sequences is introduced into the target sequence in the genome and expressed from the albumin locus (“the delivered donor DNA is stably maintained in the nuclei of the hepatocytes” para. [0603]), and
wherein the GOI is expressed (“FVIII levels in the blood” para. [0610])) (See Examples 4-5, 9-13 and claims 22-48).
Regarding the limitation that “the Cas endonuclease cleaves a target sequence in the albumin locus” of claim 28, the gRNA disclosed by Brooks targets the albumin locus and the Cas9 mRNA is delivered to hepatocytes by IV injection and therefore the Cas9mRNA would inherently cleave the target sequence in the albumin locus.
Regarding claim 28, concerning the limitation that the gRNA comprising the spacer sequence has cellular cleavage frequency of greater than about 40%, Brooks discloses the structural requirements of the gRNA above and therefore the cellular cleavage frequency of greater than about 40% would be inherent to the gRNA disclosed by Brooks. Furthermore, Brooks discloses cleavage frequencies greater than 40% (pg. 111 line 35 and pg. 112 line 1 and Table 4). Brooks disclose gRNAs of T5 (SEQ ID NO: 22 of Brooks), which is encompassed by instant claims, had a cellular cleavage frequency of greater than 40% (Table 4).
Regarding claims 35-36, further to the discussion of claim 28 above, Brooks discloses the Cas DNA endonuclease is a type II Cas endonuclease (instant claim 35) which is Cas9 (instant claim 36) (Examples 4-5, 9-13).
Regarding claims 42-43, further to the discussion of claim 28 above, as stated above, Brooks discloses the nucleic acid encoding said DNA endonuclease is a ribonucleic acid (RNA) (instant claim 42) which is an mRNA (instant claim 43)(“ Cas9 mRNA” para. [0603]; Examples 4-5, 9-13).
Regarding claim 44, further to the discussion of claim 28 above, Brooks discloses the donor template is encoded by an AAV vector (“AAV virus, preferably a AAV8 virus” para. [0603]; Examples 4-5, 9-13).
Regarding claim 45, further to the discussion of claim 28 above, Brooks discloses the donor template comprises a donor cassette comprising the nucleic acid sequence encoding the GOI (AAV-donor template) and the donor cassette is flanked on one or both sides by homology arms that are homologous to the target site (“HDR homology arms” para. [0604]; Examples 4-5, 9-13).
Regarding claim 47, further to the discussion of claims 28 and 45 above, Since the gRNA of Brooks is designed for the target site, one of ordinary skill would have immediately envisioned the gRNA target site was for the disclosed gRNA that has 100% sequence identity to a spacer sequence of instant SEQ ID NO: 22.
Regarding claim 48, further to the discussion of claims 28, 45, and 47 above, as stated above, Brooks discloses the donor cassette is flanked by two homology arms, and Brooks discloses the transgene can be integrated by homology directed repair (“integration to occur via HDR” para. [0604]). Therefore, because homology directed repair requires the regions of homology are the reverse complement of the target site, Brooks discloses the gRNA target site of the donor template is the reverse complement of a gRNA target site in the cell genome for the gRNA.
Regarding claim 49, further to the discussion of claim 28 above, Brooks discloses the nucleic acid encoding the DNA endonuclease is formulated in a lipid nanoparticle (“mRNA delivered by a LNP” para. [0603]; Examples 4-5, 9-13).
Regarding claim 52, further to the discussion of claim 28 above, Brooks discloses the gRNA of (a) and the nucleic acid encoding the DNA endonuclease of (b) are provided to the cell more than 4 days after the donor template of (c) is provided to the cell (“Four days after the AAV was injected one cohort of mice (group 3) was injected with C12-200 based LNP encapsulating spCas9 mRNA and mAlbT1 gRNA (1 mg/kg of each) (Example 11 para. [0063]).
Regarding claim 53, further to the discussion of claim 28 above, Brooks discloses the gRNA of (a) and the DNA endonuclease or nucleic acid encoding the DNA endonuclease of (b) are provided to the cell at least 14 days after (c) is provided to the cell (“At 28 days after the AAV had been injected the mice in group 4 were dosed with C12-200 based LNP encapsulating spCas9 mRNA and mAlbT1 gRNA” para. [0633]; Example 11; claims 143-145).
Regarding claim 54, further to the discussion of claims 28 and 52 above, Brooks discloses one or more additional doses of the gRNA of (a) and the DNA endonuclease or nucleic acid encoding the DNA endonuclease of (b) are provided to the cell following the first dose of the gRNA of (a) and the DNA endonuclease or nucleic acid encoding the DNA endonuclease of (b) (“mice were re-dosed with C12-200 LNP encapsulated spCas9 mRNA and mALbT1 gRNA” Example 13; para. [0638]; claims 143-145)
Regarding claim 55, further to the discussion of claims 28, 52, and 54 above, as stated above, Brooks discloses additional doses of (a) and (b). Brooks discloses one or more additional doses of the gRNA of (a) and the DNA endonuclease or nucleic acid encoding the DNA endonuclease of (b) are provided to the cell following the first dose of the gRNA of (a) and the DNA endonuclease or nucleic acid encoding the DNA endonuclease of (b) until a target level of targeted integration of the nucleic acid sequence encoding the GOI and/or a target level of expression of the nucleic acid sequence encoding the GOI is achieved (claim 146).
Regarding claim 56, further to the discussion of claim 28 above, Brooks discloses the nucleic acid sequence encoding the GOI is expressed under the control of the endogenous albumin promoter (claim 47).
Regarding claim 57, further to the discussion of claim 28 above, as stated above, Brooks discloses expression in hepatocytes (See claim 28 rejection above and Examples 4-5, 9-13 of Brooks).
Accordingly, Brooks anticipates instant claims.
Response to Arguments
Applicant argues “the accompanying statement pursuant to 35 U.S.C. 102(b)(2)(C)” (pg. 7) overcomes the rejection. In response, the statement is not sufficient for the reasons stated above.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 28, 35-36, 42-45, 47-49, and 52-57 under 35 U.S.C. 103 as being unpatentable over Cowan et al. (WO-2017077386; henceforth “Cowan”) in view of Miller et al. (WO-2015089046-A1; henceforth “Miller”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments. Because Applicant’s amendment necessitated an enablement rejection above, the previously set forth combination of Cowan in view of Miller would also not be enabled for the claimed cleavage frequencies and cannot be applied.
The rejection of claim 57 under 35 U.S.C. 103 as being unpatentable over Cowan et al. (WO-2017077386; henceforth “Cowan”) in view of Miller et al. (WO-2015089046-A1; henceforth “Miller”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
Withdrawn Nonstatutory Double Patenting
Withdrawn Provisional Nonstatutory Double Patenting
Co-pending Application No. 18385310
The provisional rejection of claims 28, 35-36, 42-45, 47-49, and 52-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108 and 110 of copending application No. 18385310 (claims filed 15th, February, 2024) in view of Cowan et al. (WO-2017077386; henceforth “Cowan”) and Miller et al. (WO-2015089046-A1; henceforth “Miller”) s set forth in the previous office action is withdrawn in view of Applicant’s amendments. Because Applicant’s amendment necessitated an enablement rejection above, the previously set forth combination of in view of Cowan and Miller would also not be enabled for the claimed cleavage frequencies and cannot be applied.
The provisional rejection of claim 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108 and 110 of copending application No. 18385310 (claims filed 15th, February, 2024) in view of Cowan et al. (WO-2017077386; henceforth “Cowan”) and Miller et al. (WO-2015089046-A1; henceforth “Miller”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
Examiner’s Remark
As set forth above, the present claims are rejected under 35 U.S.C. 112(a) because they are not enabled. Because the claims are not enabled, they can’t be made obvious because obviousness requires a reasonable expectation of success. Applicant is advised that amendments of the claims to an enabled claim set may necessitate new rejections under 35 U.S.C. 103 and/or Double Patenting.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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