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 .
DETAILED ACTION
Claim status
Claims 73-93 are pending
Claims 73-93 are under examination
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/16/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Allowable subject matter
Claims 76, 77, 78 and 81 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Specifically, the prior art does not teach nor suggest a functional CRISPR Cas polypeptide or encoding polynucleotide of SEQ ID NO:1 with at least one of the claimed amino acid substitutions selected from K58W, I80R, T84R, K105R, N193K, C202R, S209F, G210R, A218R, A218K, D220R, E225R, E225K, D237A, C246R, N286K, M298L, A306K, Y315M, E335A, E335Q, Q360R, D418A, D418N.
Claim Rejections - 35 USC § 112(a)
(Written Description)
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 73-93 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claims 73, 91, and 93 encompass a genus of AAV compositions and their methods of use to modify a target gene comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, while the specification discloses a limited number of such engineered polypeptides that are functional in a method of use.
Dependent claims 74-76 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein there is a certain type of target sequence and is in a human cell.
Dependent claims 77 and 79 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a Type V Cas, that is under a certain length.
Dependent claims 78, 82 and 84 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 98% identical to a part of SEQ ID NO:1, and 95% similar to SEQ ID NO:1, respectively.
Dependent claims 80 and 81 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a non-conserved or conserved mutations.
Dependent claims 83 encompasses a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide further comprises a type of guide sequence.
Dependent claims 85-87 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a fusion protein.
Dependent claims 88 and 89 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the AAV vector is a scAAV, and AAV3, AAV8, or AAV9.
Dependent claim 90 encompasses a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide further comprises a NLS.
Dependent claims 92 encompasses a genus of methods for modifying a target gene in the liver or muscle.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
ACTUAL REDUCTION TO PRACTICE
In regard to instant composition claims encompassing a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, the specification discloses a limited number of such engineered polypeptides that are functional.
Specifically, Applicant has described the following arginine mutations in CasM.265466 (the nuclease encoded by SEQ ID NO:1) that are capable of strengthening interactions with target DNA including I80R, T84R, K105R, C202R, G210R, A218R, E225R, C246R, Q360R (p. 252, Example 29, Figs. 24 & 25).
Moreover, Applicant has described the following mutations in CasM.265466 that are capable of maintaining cleavage functioning K58W, N193K, S209F, A218K, D220R, E225K, N286K, M298L, A306K, Y315M (p. 258, Example 41, Table 44 and Fig. 37).
Furthermore, Applicant has described the following mutations in CasM.265466 that are capable of inhibiting cleavage including D237A, E335A, E335Q, D418A, D418N (p. 266, Example 44, Fig.39), as well as causing a several fold decrease in binding affinity of the Cas466 to a DNA substrate (p. 267, Example 45, Fig. 46).
Thus, Applicant’s specification describes the following positions in CasM.265466 (as shown in SEQ ID NO:1, below):
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In regard to instant methods claims encompasses a genus of methods for modifying a cell comprising a pharmaceutical composition of an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, the specification discloses a limited number of such engineered polypeptides that are functional and disclose the in vitro modification of several cell types (e.g., Hepa1, HSC, iPS, NK cells) of several target genes (e.g., Pcks9, HBB, B2M, TRAC, CIITA, MLH, GAK, APOB, VEGF) with varying efficiencies depending on the nature of the conditions and spacer used. However, as stated supra, these methods were either conducted with the wild-type CasM.265466 or a very specific substitutions that still retained nuclease activity (e.g., specific arginine substitutions as outlined above in Fig.25).
Furthermore the fact that Applicant’s specification demonstrates that each and every potential mutation must be empirically tested and that there was no manner for one of ordinary skill to have reduced to practice the claimed compositions and method without undue experimentations. For example, not only do Applicant’s functional measurements indicate that substitutions in neighboring amino acids can have drastically different effects on activity, but even the same amino acid such as E335A versus E335Q can have nearly a 7-fold difference in binding to a DNA substrate (see Fig. 46, 25 mP versus 175 mP, respectively).
Accordingly, Applicant did not demonstrate the full genus of AAV compositions nor methods of use to modify a target gene comprising an engineered polypeptide that is at least 90% or 95% similar to SEQ ID NO:1, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention (e.g., rational approach to making such substitutions) that are sufficiently detailed to show that Applicant was in possession of the claimed genus of compositions comprising an engineered polypeptide that is at least 90 or 95% similar to SEQ ID NO:1.
DISCLOSURE OF STRUCTURE
The Applicant has provided a limited genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1. Certainly, with the help of computer and recombinant expression system, a skilled artisan could make genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1. However, the prior art is silent with respect to engineered polypeptide that is at least 90% similar to SEQ ID NO:1. Furthermore, neither the specification nor the art indicate a relationship between the structure of the claimed genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1 and the ability to make and use a functional engineered protein.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, SEQ ID NO:1 nor a sequence 90% similar to SEQ ID NO: 1 was NOT known in the prior art.
The breadth of the claims encompass a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, yet the present specification provides no guidance nor description which modification would result in a functional engineered protein, therefore the skilled artisan would not know what rational approach to take to make the genus of engineered proteins with any predictable outcome on function. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of engineered proteins.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making and using the claimed invention is not well established. Although the making of engineered Cas9 type II CRISPR proteins was known in the state of the art, one of skill in the art would neither expect nor predict an appropriate functioning CasM according to the claimed genus of engineered proteins.
The following describes the state of the art with respect to SEQ ID NO:1.
In regard to the CasM type of CRISPR, the prior art of Carter et al (US 10,889,808, patented 1/12/2021, see IDS filed 2/16/2024) teaches CRISR Cas enzymes derived from Eubacterium and Ruminococccus bacteria that are termed “CasM” enzymes, yet possess no significant similarity to the CasM 265466 enzyme of SEQ ID NO:1.
Furthermore, the prior art of Thomas et al. (US 2023/0227857, CON of PCT/US2021/021259 filed 3/06/2021, see IDS filed 2/16/2024) teaches novel CRISPR Cas enzymes from uncultivated microorganisms and teaches the CRISPR Cas enzyme of SEQ ID NO:526, which is about 63% identical to instant SEQ ID NO:1 (see SCORE search 4/03/2026, rapm.file). Thus, the closest prior art provides no guidance as to which substitution could be made in SEQ ID NO:1 and still make and use a functioning Cas enzyme.
Finally, Bhattacharya et al. (ACS Omega, 2023, 8:1817-1837, see IDS filed 2/16/2024) reviews mutations that can be made in Cas enzymes and still retain function. Specifically, Bhattacharaya teaches functional Cas enzymes can be either enzymatically functional in regard to their nuclease activity, or non-enzymatically function in regard to their ability to bind guide RNA and target a gene of interest. In both cases, binding the guide RNA and the target DNA are prerequisites for a functional Cas enzyme. Specifically, Bhattacharaya teaches that recognition of the guide RNA by Cas occurs through many regions such as the PAM motif, the repeat-antirepeat duplex, and the other stem loops of the guide RNA (p.1823, Section 4.2). Bhattacharaya explains that the formation of the Cas complex involves both specific and non-specific interactions, complex conformational changes, and requires trace ions such as Mg2+, and even modern computer aided modeling techniques have limitations for predicting the amino acids involved in these complex interactions (p. 1827, Section 5). Thus, even if an amino acid position is identified to be modified, the nature of the substitution (i.e., ionic charge) would unpredictably affect function. Finally, Bhattacharaya evidences predicting the amino acids involved in these functions “demand(s) comparative in-depth structure-based mechanistic studies of various Cas9 proteins” (p. 1832, 1st para.).
However, Applicant’s disclosure has provided no such structural information.
Moreover, Applicant’s disclosure admits the state of the art for generating a genus of compositions comprising a functional engineered polypeptide that is at least 90% similar to SEQ ID NO:1 was not well established. The disclosure demonstrates that many of the mutations in SEQ ID NO:1 entirely loose nuclease function (Fig. 37 of Applicant’s disclosure) or even mutations at the same amino acid position can have dramatic differences in substrate binding (Fig. 46 of Applicant’s disclosure). Thus, the making and using of a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1 was not well established
Applicant has claimed a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, yet the specification has discloses a limited number of species, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention (e.g., structural studies through crystallography or molecular modeling) that are sufficiently detailed to show that Applicant was in possession of the claimed a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1. Furthermore, the state of the art indicated that making the claimed genus of engineered polypeptides is not well established with the claimed function in nuclease activity, much less guide RNA binding, and would require undue experimentation, and one of skill in the art would neither expect nor predict a functional CasM enzyme according to the claimed a genus of AAV compositions and methods of use comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1. Specifically, there is limited description of the structure-function relationship between the claimed genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1 and their ability to produce a functional CasM enzyme, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1.
Claim Rejections - 35 USC § 112(a)
(Scope of Enablement)
Claims 73-93 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 making and using an AAV vector comprising a functional CRISPR Cas polypeptide or encoding polynucleotide of SEQ ID NO:1 with at least one of the following amino acid substitutions selected from K58W, I80R, T84R, K105R, N193K, C202R, S209F, G210R, A218R, A218K, D220R, E225R, E225K, D237A, C246R, N286K, M298L, A306K, Y315M, E335A, E335Q, Q360R, D418A, D418N, does not reasonably provide enablement for any substitution in SEQ ID NO:1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of AAV compositions and their methods of use to modify a target gene comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1. As discussed supra, the specification fails to describe the genus of engineered polynucleotides and would require undue experimentation to discover these engineered polynucleotides.
Independent claims 73, 91, and 93 encompass a genus of AAV compositions and their methods of use comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, while the specification discloses a limited number of such engineered polypeptides that are functional in a method of use.
Dependent claims 74-76 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein there is a certain type of target sequence and is in a human cell.
Dependent claims 77 and 79 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a Type V Cas, that is under a certain length.
Dependent claims 78, 82 and 84 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 98% identical to a part of SEQ ID NO:1, and 95% similar to SEQ ID NO:1, respectively.
Dependent claims 80 and 81 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a non-conserved or conserved mutations.
Dependent claims 83 encompasses a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide further comprises a type of guide sequence.
Dependent claims 85-87 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide is a fusion protein.
Dependent claims 88 and 89 encompass a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the AAV vector is a scAAV, and AAV3, AAV8, or AAV9.
Dependent claim 90 encompasses a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, wherein the polypeptide further comprises a NLS.
Dependent claims 92 encompasses a genus of methods for modifying a target gene in the liver or muscle.
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.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
ACTUAL REDUCTION TO PRACTICE
In regard to instant composition claims encompassing a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, the specification discloses a limited number of such engineered polypeptides that are functional.
Specifically, Applicant has described the following arginine mutations in CasM.265466 (the nuclease encoded by SEQ ID NO:1) that are capable of strengthening interactions with target DNA including I80R, T84R, K105R, C202R, G210R, A218R, E225R, C246R, Q360R (p. 252, Example 29, Figs. 24 & 25).
Moreover, Applicant has described the following mutations in CasM.265466 that are capable of maintaining cleavage functioning K58W, N193K, S209F, A218K, D220R, E225K, N286K, M298L, A306K, Y315M (p. 258, Example 41, Table 44 and Fig. 37).
Furthermore, Applicant has described the following mutations in CasM.265466 that are capable of inhibiting cleavage including D237A, E335A, E335Q, D418A, D418N (p. 266, Example 44, Fig.39), as well as causing a several fold decrease in binding affinity of the Cas466 to a DNA substrate (p. 267, Example 45, Fig. 46).
Thus, Applicant’s specification describes the following positions in CasM.265466 (as shown in SEQ ID NO:1, below):
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In regard to instant methods claims encompasses a genus of methods for modifying a cell comprising a pharmaceutical composition of an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, the specification discloses a limited number of such engineered polypeptides that are functional and disclose the in vitro modification of several cell types (e.g., Hepa1, HSC, iPS, NK cells) of several target genes (e.g., Pcks9, HBB, B2M, TRAC, CIITA, MLH, GAK, APOB, VEGF) with varying efficiencies depending on the nature of the conditions and spacer used. However, as stated supra, these methods were either conducted with the wild-type CasM.265466 or a very specific substitutions that still retained nuclease activity (e.g., specific arginine substitutions as outlined above in Fig.25).
Furthermore the fact that Applicant’s specification demonstrates that each and every potential mutation must be empirically tested and that there was no manner for one of ordinary skill to have reduced to practice the claimed compositions and method without undue experimentations. For example, not only do Applicant’s functional measurements indicate that substitutions in neighboring amino acids can have drastically different effects on activity, but even the same amino acid such as E335A versus E335Q can have nearly a 7-fold difference in binding to a DNA substrate (see Fig. 46, 25 mP versus 175 mP, respectively).
Accordingly, Applicant did not demonstrate the full genus of AAV compositions nor methods of use to modify a target gene comprising an engineered polypeptide that is at least 90% or 95% similar to SEQ ID NO:1, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention (e.g., rational approach to making such substitutions) that are sufficiently detailed to show that Applicant was in possession of the claimed genus of compositions comprising an engineered polypeptide that is at least 90 or 95% similar to SEQ ID NO:1.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making and using the claimed invention is not well established. Although the making of engineered Cas9 type II CRISPR proteins was known in the state of the art, one of skill in the art would neither expect nor predict an appropriate functioning CasM according to the claimed genus of engineered proteins.
The following describes the state of the art with respect to SEQ ID NO:1.
In regard to the CasM type of CRISPR, the prior art of Carter et al (US 10,889,808, patented 1/12/2021, see IDS filed 2/16/2024) teaches CRISR Cas enzymes derived from Eubacterium and Ruminococccus bacteria that are termed “CasM” enzymes, yet possess no significant similarity to the CasM 265466 enzyme of SEQ ID NO:1.
Furthermore, the prior art of Thomas et al. (US 2023/0227857, CON of PCT/US2021/021259 filed 3/06/2021, see IDS filed 2/16/2024) teaches novel CRISPR Cas enzymes from uncultivated microorganisms and teaches the CRISPR Cas enzyme of SEQ ID NO:526, which is about 63% identical to instant SEQ ID NO:1 (see SCORE search 4/03/2026, rapm.file). Thus, the closest prior art provides no guidance as to which substitution could be made in SEQ ID NO:1 and still make and use a functioning Cas enzyme.
Finally, Bhattacharya et al. (ACS Omega, 2023, 8:1817-1837, see IDS filed 2/16/2024) reviews mutations that can be made in Cas enzymes and still retain function. Specifically, Bhattacharaya teaches functional Cas enzymes can be either enzymatically functional in regard to their nuclease activity, or non-enzymatically function in regard to their ability to bind guide RNA and target a gene of interest. In both cases, binding the guide RNA and the target DNA are prerequisites for a functional Cas enzyme. Specifically, Bhattacharaya teaches that recognition of the guide RNA by Cas occurs through many regions such as the PAM motif, the repeat-antirepeat duplex, and the other stem loops of the guide RNA (p.1823, Section 4.2). Bhattacharaya explains that the formation of the Cas complex involves both specific and non-specific interactions, complex conformational changes, and requires trace ions such as Mg2+, and even modern computer aided modeling techniques have limitations for predicting the amino acids involved in these complex interactions (p. 1827, Section 5). Thus, even if an amino acid position is identified to be modified, the nature of the substitution (i.e., ionic charge) would unpredictably affect function. Finally, Bhattacharaya evidences predicting the amino acids involved in these functions “demand(s) comparative in-depth structure-based mechanistic studies of various Cas9 proteins” (p. 1832, 1st para.).
However, Applicant’s disclosure has provided no such structural information.
Moreover, Applicant’s disclosure admits the state of the art for generating a genus of compositions comprising a functional engineered polypeptide that is at least 90% similar to SEQ ID NO:1 was not well established. The disclosure demonstrates that many of the mutations in SEQ ID NO:1 entirely loose nuclease function (Fig. 37 of Applicant’s disclosure) or even mutations at the same amino acid position can have dramatic differences in substrate binding (Fig. 46 of Applicant’s disclosure). Thus, the making and using of a genus of compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1 was not well established
Since the prior art at the effective filing date of the present application did not provide guidance for making and using of a genus of AAV compositions comprising an engineered polypeptide that is at least 90% similar to SEQ ID NO:1, it is incumbent upon the instant specification to do so. 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, first paragraph 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 make and use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to making and using a functional Cas enzyme, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to make and use the claimed invention.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is require to make and use the invention beyond the scope of claimed amino acid substitutions in SEQ ID NO:1 selected from K58W, I80R, T84R, K105R, N193K, C202R, S209F, G210R, A218R, A218K, D220R, E225R, E225K, D237A, C246R, N286K, M298L, A306K, Y315M, E335A, E335Q, Q360R, D418A, D418N.
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 74-75, 82 and 91-93 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 74 recites the limitation that the gene is from “Table 8”, while Claim 74 limits the gene to a human cell. A claim may be rendered indefinite by reference to a figure or table (see MPEP 2173.05(s)). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Claim 82 recites the limitation that the amino acid sequence is at least 98% identical to 300 consecutive "nucleotides" of SEQ ID NO: 1. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO: 1 is an amino acid sequence.
Claims 91-93 recites the limitation of modifying “a target gene” as per claim 91, and mutating “a gene” as per claim 93. There is insufficient antecedent basis for this limitation in the claim because the compositions of Claim 73 is silent to a “gene”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
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.
Claim 79 is 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.
Specifically, claim 79 draws to a polypeptide that is less than 500 amino acids, which does NOT narrow the scope of claim 73 wherein the polypeptide is at least 90% similar to the 448 amino acid sequence of SEQ ID NO: 1. Specifically, a 10% difference in similarity would only allow an additional 44.8 amino acids to be added to the 448 amino acids of SEQ ID NO: 1, thereby producing a polypeptide of at most 492 amino acids. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 73-87, and 91 are rejected on the grounds of nonstatutory double patenting over claims 1-10, and 13-29 of U.S. Patent No. 12,077,775 (Deloughery et al., Patented 9/03/2024).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the AAV composition comprising the Cas nuclease at least 95% identical to SEQ ID NO:1 with a specific set of mutations and methods of use for treating a disease of cited patent anticipates the AAV composition and methods of use of instant application. It is clear that all the elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims are much more specific with respect to sequence of SEQ ID NO:1. Thus the invention of said claims of the cited patent are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by over cited patent claims, said claims are not patentably distinct.
Claims 88-90, and 92-93 are rejected on the grounds of nonstatutory double patenting over claims 1-10, and 13-29 of U.S. Patent No. 12,077,775 (Deloughery et al., Patented 9/03/2024), in view of Zhang et al. (US 10,946,108, filed 12/16/2016, patented 3/16/2021).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the AAV composition comprising the Cas nuclease at least 95% identical to SEQ ID NO:1 with a specific set of mutations and methods of use for treating a disease of cited patent makes obvious the AAV composition and methods of use of instant application. It is clear that all the elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the instant claims are more specific with respect to 1) a NLS, 2) a self-complementary AAV, and 3) the AAV serotype and tropism for liver targets.
Nevertheless, Zhang et al, teaches AAV compositions and methods of use for modifying a target cell (see Claims 1-49 of Zhang). Specifically, Zhang teaches the Cas nuclease is fused to a NLS (col 10 7th, para.), the Cas nuclease is in a AAV8 vector (col 59, 2nd para.), and refers to the use of self-complementary viral vectors (col 307 #2).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to make and use the CasM as claimed by cited patent, and further claim an NLS, an scAAV, and/or claim an AAV8 vector as taught by Zhang with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Zhang because the NLS allows a non-mammalian Cas to efficiently enter the nucleus of a mammalian cell, the scAAV was well-known to skip second strand synthesis for quicker expression, and the AAV8 vector was taught to exhibit tropism of liver cells, thereby allowing the treatment of liver diseases.
Since the instant application claims are obvious over cited patent claims in view of Zhang et al., said claims are not patentably distinct.
Claims 73-86, 88, and 91-92 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 95-112 of copending Application No. 19/410,151. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV compositions and methods of use of the composition comprising a modified RDDP-CasM.265466 of Table of cited application anticipates the composition and methods of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the Cas being a fusion protein.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-86, 88, and 91-92 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-3, 5-6, 8-10, 14, 22-25, 35-38 of copending Application No. 19/230,223. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV compositions and methods of use of the composition comprising a modified SEQ ID NO:428 of cited application anticipates the composition and methods of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the gene target as DUX4.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-88, and 91 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 11, 20-23, 26-32 of copending Application No. 19/044,826. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV compositions and methods of use of the composition comprising a modified RDDP-CasM.265466 of Table of cited application anticipates the compositions and methods of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the Cas being a fusion protein.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-86, and 91 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 107-124 of copending Application No. 18/966,406. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV methods of use of the composition comprising a modified SEQ ID NO:3 of cited application makes obvious the composition and methods of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the gene target as RAS.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-87, and 91-92 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-1, 8-11, 1618, 39-47 of copending Application No. 18/919,415. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV compositions and methods of use of the composition comprising a modified SEQ ID NO:1 of cited application anticipates the compositions and methods of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the gene target as DMD.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-87, and 91 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 60-76 of copending Application No. 18/653,793. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the AAV compositions and methods of use of the composition comprising a modified SEQ ID NO:1 of Table 1 of cited application anticipates the composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims are more specific to the gene target in a HSC.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Claims 73-86, 88, and 91 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 116-118, 120-127, 129-142 of copending Application No. 17/935,042. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the compositions and methods of use of the composition comprising a modified SEQ ID NO:1 of cited application anticipates the composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims. The difference between the cited application claims and the instant claims lies in the fact that cited application claims recite a % identity of less than 100, while instant claims recite at least one substitution.
Since the instant application claims are anticipated over cited application claims, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
Prosecution Insights