DETAILED CORRESPONDENCE
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 17, 2025 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6, 14, 18-30, 34, 36, 37, 41-43, and 45-50 are pending in the application.
Applicant's amendment to the claims, filed December 17, 2025, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant's remarks filed December 17, 2025 in response to the final rejection filed September 24, 2025 are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Restriction/Election
In response to requirements for restriction/election filed September 7, 2022 and August 26, 2024, applicant elected without traverse the following subject matter in the replies filed November 7, 2022 and October 25, 2024:
Group I, claims 1-6, 14, 18-24, 27-30, 34, 36, 37, 41-43, and 45, drawn to the technical feature of an engineered, non-naturally occurring system suitable for modifying post-translational modification sites on a protein encoded by a target RNA, a cell, and a non-human animal or plant;
Species A) a catalytically inactive (dead) Cas13 protein and a nucleotide deaminase protein;
Species 1) the ADAR protein or catalytic domain thereof comprises a mutation in amino acid L332 of an hADAR2-D amino acid sequence of the corresponding mutation in a homologous ADAR protein;
Species BB) the target sequence comprises one or more codons with a cytidine;
Species AAA) the nucleotide deaminase is an adenosine deaminase or catalytic domain thereof;
Species BBBB) the Cas13 protein is Cas13b; and
Species BBBBB) a single guide molecule is used to target the at least two or at least three phosphorylation sites of the same protein.
Claims 25, 26, and 46-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claims 4 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are being examined on the merits with claims 1, 2, 5, 6, 14, 18, and 22 are being examined only to the extent the claims read on the elected subject matter set forth above.
Claim Objections
Claim 5 is objected to in the recitation of “the hADAR2 protein” in lines 1 and 6 and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “the nucleotide deaminase.”
Claim 6 is objected to in the recitation of “a hADAR2 catalytic domain thereof” in line 2 and “hADAR2 protein” in line 3 and in the interest of improving claim form, it is suggested that the noted phrases be amended to recite “a catalytic domain of the nucleotide deaminase protein” and “nucleotide deaminase protein,” respectively.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 under 35 U.S.C. 112(b) as being indefinite in the recitation of “a K350I mutation, or a corresponding mutation in a homolog or ortholog of the hADAR2 protein or catalytic domain” is withdrawn in view of the instant amendment to claim 1 to delete the phrase “or a corresponding mutation in a homolog or ortholog of the hADAR2 protein or catalytic domain.”
The rejection of claim 6 under 35 U.S.C. 112(b) as being indefinite and confusing in the recitation of “wherein (a) is a hADAR2 catalytic domain thereof” is maintained for the reasons of record.
RESPONSE TO REMARKS: Applicant argues the rejection does not apply to the amended claims.
Applicant’s argument is not found persuasive because it remains unclear as to the item “(a)” that is being referenced by the claim. It is suggested that applicant clarify the meaning of the noted phrase. In the interest of advancing prosecution, the applicant may consider amending the phrase “ wherein (a) is a hADAR2 catalytic domain thereof” to recite “(a) is a catalytic domain of the nucleotide deaminase protein.”
Claim Rejections - 35 USC § 112(a)
Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are newly rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims 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 at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims”. See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Claim 1 has been amended to recite (in relevant part) “wherein the nucleotide deaminase protein or catalytic domain thereof has at least 98% sequence identity to a human adenosine deaminase acting on RNA 2 (hADAR2) protein or catalytic domain thereof comprising a K350I mutation.” According to applicant’s remarks at p. 12:
Regarding the claim amendment directed to "at least 98% sequence identity to [hADAR2]," support can be found in paragraphs [0328]-[0388], which disclose more than 14 sequence variants (mutations) of hADAR2. Accordingly, the Specification describes hADAR2 variants having at least 98% sequence identity when these mutations are taken into account.
However, applicant’s noted remarks fail to show support for the newly added limitation “wherein the nucleotide deaminase protein or catalytic domain thereof has at least 98% sequence identity to a human adenosine deaminase acting on RNA 2 (hADAR2) protein or catalytic domain thereof comprising a K350I mutation.” First, it is unclear from the applicant’s remarks as to how the “more than 14 sequence variants (mutations) of hADAR2” provide descriptive support for the limitation at issue. Second, the disclosed mutations of hADAR2 at paragraphs [0328]-[0388] of the specification specify both a specific amino acid position and a specific amino acid substitution at that position and fail to provide descriptive support for any mutation(s) at any position(s) within the recited "at least 98% sequence identity” limitation. Applicant is invited to show support for the claim 1 limitation “wherein the nucleotide deaminase protein or catalytic domain thereof has at least 98% sequence identity to a human adenosine deaminase acting on RNA 2 (hADAR2) protein or catalytic domain thereof comprising a K350I mutation.” In the absence of descriptive support, the newly added limitation introduces new matter into the claims.
Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention. This rejection has been modified from its previous version to address the instant amendment to the claims.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to MPEP 2163.II.A.3.(a).ii), [s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
As amended, the claims recite a genus of nucleotide deaminase proteins or catalytic domains thereof having at least 98% sequence identity to a human adenosine deaminase acting on RNA 2 (hADAR2) protein or catalytic domain thereof comprising a K350I mutation.
The recitation of “comprising a K350I mutation” in part (b) of claim 1 is interpreted as referring to the catalytic domain of the hADAR2 protein (not to the nucleotide deaminase protein or catalytic domain thereof). In view of the recitation of the open-ended “comprising” in the phrase “catalytic domain thereof comprising a K350I mutation,” other than requiring an isoleucine at position 350 of a catalytic domain of hADAR2, the remaining sequence of the catalytic domain of hADAR2 is unlimited. As such, the sequences of the genus of nucleotide deaminase proteins and catalytic domains thereof which have at least 98% identity to the catalytic domain of hADAR2 are also unlimited and are considered to be widely variant.
In this case, the amino acid K350 of hADAR2-D is completely conserved (see Table 1, p. 9 of Supplementary Text and Figures, obtained from https://www.nature.com/articles/nsmb.3203#Sec21, 2016, 14 pages; cited on Form PTO-892 filed August 26, 2024) and the specification discloses only a single tolerable amino acid substitution at K350 of hADAR2-D, i.e., a K350I mutation, which is one mutation among a combination of mutations that confers cytidine deaminase activity to hADAR2.
The specification discloses the following representative species of the genus of recited ADAR proteins or catalytic domains thereof: a polypeptide having cytidine deaminase activity and comprising the amino acid sequence of human ADAR2 deaminase domain with the exception of E488Q, V351G, S486A, T375S, S370C, P462A, N597I, L332I, I398V, and K350I mutations. Other than these mutations of hADAR2, neither the specification nor the prior art of record discloses any other mutations of a hADAR2-D, much less corresponding mutations in a homolog or ortholog of the hADAR2 protein or catalytic domain.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on Form PTO-892 filed June 4, 2025) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on Form PTO-892 filed June 4, 2025), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
The level of knowledge and skill in the art does not allow one of skill to structurally envisage or recognize those structures of the genus of nucleotide deaminase proteins or catalytic domains thereof. In view of the high level of unpredictability in the art of amino acid mutation, and because the specification discloses the actual reduction to practice of only a single representative species among a genus that is widely variant, the single disclosed representative species is insufficient to describe the genus.
One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
RESPONSE TO REMARKS: In summary, applicant argues the rejection is moot in view of the instant amendment to claim 1 to recite “at least 98% sequence identity to” a hADAR2 protein or catalytic domain thereof comprising a K350I mutation.
Applicant’s arguments are not found persuasive. By applicant’s amendment, the recitation of “comprising a K350I mutation” is no longer a required feature of the “nucleotide deaminase protein or catalytic domain thereof.” Rather, the recitation of “comprising a K350I mutation” is interpreted as referring to the catalytic domain of the hADAR2 protein. As explained in detail above, the sequences of the genus of nucleotide deaminase proteins and catalytic domains thereof which have at least 98% identity to the catalytic domain of hADAR2 comprising a K350I mutation are unlimited and are considered to be widely variant and for the reasons set forth above, the specification fails to adequately describe the claimed invention.
Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a polypeptide having cytidine deaminase activity and comprising the amino acid sequence of human ADAR2 deaminase domain with the exception of E488Q, V351G, S486A, T375S, S370C, P462A, N597I, L332I, I398V, and K350I mutations, does not reasonably provide enablement for all nucleotide deaminase proteins and catalytic domains thereof as broadly encompassed by the claims. 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/or use the invention commensurate in scope with these claims. This rejection has been modified from its previous version to address the instant amendment to the claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The nature of the invention: The nature of the invention is the directed evolution of an ADAR2 adenosine deaminase to acquire cytidine deaminase activity.
The breadth of the claims: As amended, the claims recite a nucleotide deaminase protein or catalytic domain thereof having at least 98% sequence identity to a human adenosine deaminase acting on RNA 2 (hADAR2) protein or catalytic domain thereof comprising a K350I mutation.
The recitation of “comprising a K350I mutation” in part (b) of claim 1 is interpreted as referring to the catalytic domain of the hADAR2 protein (not to the nucleotide deaminase protein or catalytic domain thereof). In view of the recitation of the open-ended “comprising” in the phrase “catalytic domain thereof comprising a K350I mutation,” other than requiring an isoleucine at position 350 of the catalytic domain of hADAR2, the remaining sequence of the catalytic domain of hADAR2 is unlimited. As such, the sequence of the nucleotide deaminase protein or catalytic domain thereof which has 98% identity to the catalytic domain of hADAR2 is also unlimited.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.”
The amino acid K350 of hADAR2-D is completely conserved (see Table 1, p. 9 of Supplementary Text and Figures, obtained from https://www.nature.com/articles/nsmb.3203#Sec21, 2016, 14 pages; cited on Form PTO-892 filed on August 26, 2024) and the specification discloses only a single tolerable amino acid substitution at K350 of hADAR2-D, i.e., a K350I mutation, which is one mutation among a combination of mutations that confers cytidine deaminase activity to hADAR2.
The sequence of the nucleotide deaminase protein or catalytic domain thereof is unlimited. The reference of Singh (supra) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top).
The unpredictability associated with amino acid mutation is exemplified by the reference of Zhang (supra), which discloses that even a mutation that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
As such, one of skill in the art would recognize a high level of unpredictability that all proteins as encompassed by the claims would have acquired or maintained the desired activity/utility.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working example of the recited nucleotide deaminase protein or catalytic domain thereof: a polypeptide having cytidine deaminase activity and comprising the amino acid sequence of human ADAR2 deaminase domain with the exception of E488Q, V351G, S486A, T375S, S370C, P462A, N597I, L332I, I398V, and K350I mutations. Other than this working example, the specification fails to disclose other mutations of to a nucleotide deaminase or catalytic domain thereof that maintain or confer the cytidine deaminase activity.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: While methods of modifying the amino acid sequence of a polypeptide were known at the time of the invention, it was not routine in the art to make a vast and essentially unlimited scope of nucleotide deaminase proteins as recited by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
RESPONSE TO REMARKS: In summary, applicant argues the rejection does not apply to the amended claims in view of the instant amendment to claim 1 to recite “at least 98% sequence identity to” a hADAR2 protein or catalytic domain thereof comprising a K350I mutation.
Applicant’s arguments are not found persuasive. By applicant’s amendment, the recitation of “comprising a K350I mutation” is no longer a required feature of the “nucleotide deaminase protein or catalytic domain thereof.” Rather, the recitation of “comprising a K350I mutation” is interpreted as referring to the catalytic domain of the hADAR2 protein. As explained in detail above, the sequence of the nucleotide deaminase protein and catalytic domain thereof which have at least 98% identity to the catalytic domain of hADAR2 comprising a K350I mutation are unlimited and for the reasons set forth above, the specification fails to enable the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
Claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 are newly rejected under 35 U.S.C. 103 as being unpatentable over Yeo et al. (US 2018/0334685 A1, with priority to May 10, 2017; cited on Form PTO-892 filed September 7, 2022; hereafter “Yeo”) in view of
Zhang et al. (Sci. China Life Sci. 59:8, 2016, 3 pages; cited on Form PTO-892 filed September 7, 2022; hereafter “Zhang”) and
Radivojac et al. (Bioinformatics 24:241-247, 2008; cited on Form PTO-892 filed September 7, 2022; hereafter “Radivojac”).
This rejection is necessitated by applicant’s amendment to claim 1.
According to the instant specification at paragraph [0164]), “C2c2 is now known as Cas13a. It will be understood that the term ‘C2c2’ herein is used interchangeably with ‘Cas13a’”. In the interest of avoiding confusion, only the term “Cas13a” is used in the rejection set forth below.
The recitation of “comprising a K350I mutation” in part (b) of claim 1 is interpreted as referring to the catalytic domain of the hADAR2 protein (not to the nucleotide deaminase protein or catalytic domain thereof). In view of the recitation of the open-ended “comprising” in the phrase “catalytic domain thereof comprising a K350I mutation,” other than requiring an isoleucine at position 350 of a catalytic domain of hADAR2, the remaining sequence of the catalytic domain of hADAR2 is unlimited. As such, the sequence of the nucleotide deaminase protein or catalytic domain thereof which has at least 98% identity to the catalytic domain of hADAR2 is also unlimited.
Regarding claims 1, 5, 6, 24, 27-30, 41-43, and 45, the reference of Yeo discloses a CRISPR/Cas RNA editing fusion protein comprising a nuclease-dead Cas fused to a catalytically active deaminase domain of ADAR and a guide RNA comprising a short extension sequence of homology to the target RNA comprising a mismatch for a target adenosine for adenosine to inosine RNA editing of the target sequence (paragraph [0008] and claim 32), which inosine is ultimately read by translational and splicing machinery as guanosine (paragraph [0117]). Yeo discloses editing RNAs in living cells that cause cancer (paragraph [0028]) and discloses the subject is a human, mouse, or rat (paragraph [0097]).
Regarding claim 2, Yeo discloses the guide RNA forms an A-C mismatch with a target RNA (paragraph [0066]).
Regarding claims 22 and 37, Yeo discloses the guide RNA comprises one or more modified nucleotides (paragraph [0121]).
Regarding claim 23, Yeo discloses the dCas comprises a nuclear localization signal (NLS) linked to the C-terminus of the dCas (paragraphs [0030] and [0183]).
Regarding claim 45, the recitation of “for use in therapy, wherein the therapy is a cell therapy” is interpreted as an intended use limitation (see MPEP 2111.02) and does not structurally and/or functionally limit the cell of claim 41.
The differences between Yeo and the claimed invention are:
1) Yeo does not disclose a catalytically inactive (dead) Cas13 protein as recited in claims 1, 5, 6, 14, and 21; and
2) Yeo does not disclose a guide molecule that is complementary to a target sequence encoding an amino acid phosphorylation site of a protein as recited in claims 1, 22, and 30.
Regarding difference 1), Zhang teaches that progress in converting the CRISPR/Cas9 system into a sequence-specific RNA-manipulating platform has been limited (p. 854, column 1, middle) and teaches ribonuclease-dead Cas13a as an alternative programmable sequence-specific RNA-binding platform (p. 855, column 2, bottom). Zhang teaches the application of Leptotrichia shahii dCas13a in editing of a mRNA using a fusion of a dCas13a-cytidine deaminase (p. 856, column 1, top).
Regarding claims 1, 5, and 6, given a broadest reasonable interpretation, the recitation of “the nucleotide deaminase protein or catalytic domain thereof has at least 98% identity” to a hADAR2 protein or catalytic domain thereof comprising a K350I mutation and additional mutations recited in claims 5 and 6 encompasses Zhang’s dCas13a.
Regarding claim 21, given a broadest reasonable interpretation, the recitation of “wherein said Cas13 is a C-terminally truncated Cas13b functional variant of the corresponding wild type Cas13, wherein said C-terminally truncated Cas13b is encoded by nt 1-984 of Prevotella sp. P5-125 Cas13b or the corresponding nt of a Cas13b orthologue or homologue” is interpreted as encompassing Zhang’s dCas13a.
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Yeo and Zhang to modify Yeo to use dCas13a in place of dCas9. One would have been motivated to do this because Zhang teaches that progress in converting the CRISPR/Cas9 system into a sequence-specific RNA-manipulating platform has been limited and teaches dCas13a as an alternative programmable sequence-specific RNA-binding platform and suggests its application in RNA editing by fusion with a deaminase. One would have had a reasonable expectation of success to modify Yeo to use dCas13a in place of dCas9 because of Zhang’s express teaching to use dCas13a as a programmable sequence-specific RNA-binding platform and its application in RNA editing by fusion with a deaminase.
Regarding difference 2), the reference of Radivojac teaches phosphorylation of amino acid residues serine, threonine, and tyrosine is common in cancer-associated proteins and changes in phosphorylation signaling can be due to disruption and deregulation of kinase and phosphatase function due to amino acid substitutions of kinases and phosphatases that results in changes in target phosphorylation (p. i241, column 2, middle). Radivojac teaches there is evidence that disruptions of phosphorylation are associated with cancer (p. i241, column 2, bottom) and that cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation when compared to control datasets (p. i241, Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Yeo and Radivojac to design the guide RNA of Yeo to modify a codon encoding a cancer-related phosphorylation site. One would have been motivated to and would have had a reasonable expectation to do this because Yeo discloses editing RNAs that cause cancer and Radivojac teaches cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation.
Therefore, the claimed invention would have been obvious to one of ordinary skill in the art before the effective filing date.
In the interest of clarity, it is noted that the instant rejection is directed in-part to the non-elected species of Cas13a. The non-elected species has yet to be searched and examined on the merits as the cited prior art was already of record in the application file.
Claim 3 is newly rejected under 35 U.S.C. 103 as being unpatentable over Yeo in view of Zhang and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 above, and further in view of Kouranova et al. (Human Gene Therapy 27:464-475, 2016; cited on Form PTO-892 filed January 25, 2023; hereafter “Kouranova”).
The relevant teachings of Yeo, Zhang, and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 are set forth above.
The combination of Yeo, Zhang, and Radivojac does not teach or suggest a particle delivery system comprising a ribonucleoprotein complex as recited in claim 3.
The reference of Kouranova teaches that the components of CRISPR can be delivered into cells as a precomplexed ribonucleoprotein particle (p. 465, column 2, top). Kouranova teaches a method for RNP complex formation (p. 466, column 1, middle). Kouranova teaches benefits to delivering CRISPR components by RNP including fewer off-target modifications (p. 465, column 1, top) and RNP is the only format that is reliably active in cells (p. 474, column 2). According to Kouranova, the RNPs are the most convenient and efficient delivery method for cultured cell lines (p. 464, Abstract). Kouranova teaches delivery of the RNP into cells by cationic lipid transfection or via a nanoparticle (p. 12, paragraph bridging columns 1-2).
In view of the teachings of Kouranova, it would have been obvious to one of ordinary skill in the art before the effective filing date to further modify Yeo to deliver a RNP by cationic lipid transfection or via a nanoparticle. One would have been motivated to and would have had a reasonable expectation of success to do this because Kouranova taught the benefits of RNP delivery and taught RNP delivery by cationic lipid transfection or via a nanoparticle. Therefore, the claimed invention would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 18-20 are newly rejected under 35 U.S.C. 103 as being unpatentable over Yeo in view of Zhang and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 above, and further in view of Abudayyeh et al. (Science 353:6299, 2016, 23 pages; cited on the IDS filed April 28, 2020; hereafter “Abudayyeh”).
As an initial matter, it is noted that the term “about” in claim 19 (and any other claim) is interpreted in light of the instant specification (paragraph [0163]) as meaning +/−10% or less of a recited value.
The relevant teachings of Yeo, Zhang, and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 are set forth above. The combination of Yeo, Zhang, and Radivojac does not teach or suggest the limitations of claims 18-20.
Regarding claim 18, Abudayyeh teaches that Leptotrichia shahii C2c2 comprises two HEPN domains (p. 2, bottom) and that alanine substitution of the catalytic residues R597 and R1278 of the HEPN domain converted C2c2 into an inactive programmable RNA-binding protein (dC2c2) (paragraph bridging pp. 5-6; p. 9, top). R597 and R1278 of Leptotrichia shahii C2c2 HEPN domain are considered to correspond to R474 and R1046 of Leptotrichia wadei C2c2 HEPN domain.
In view of the further teachings of Abudayyeh, it would have been obvious to one of ordinary skill in the art before the effective filing date for a dC2c2 comprising alanine substitutions of the HEPN domain catalytic residues R597 and R1278. One would have been motivated to and would have had a reasonable expectation of success for a dC2c2 comprising alanine substitutions of the HEPN domain catalytic residues R597 and R1278 because Abudayyeh taught that alanine substitution of any of the four predicted HEPN domain catalytic residues converted C2c2 into dC2c2.
Regarding claims 19 and 20, Yeo further discloses the guide RNA forms an A-C mismatch with a target RNA (paragraph [0066]). Abudayyeh teaches that C2c2 is guided by a single crRNA (p. 1, Abstract) with a spacer of at least 22 nucleotides that is complementary to the target ssRNA and a double repeat longer than 24 nucleotides (p. 6, bottom). Abudayyeh teaches that C2c2 is tolerant to single mismatches across the spacer (p. 7, top).
In view of the further teachings of Abudayyeh, it would have been obvious to one of ordinary skill in the art before the effective filing date for a guide RNA comprising a non-pairing cytosine with the 5’ end of the guide sequence being 20-30 nucleotides. One would have been motivated to and would have had a reasonable expectation of success for a guide RNA comprising a non-pairing cytosine with the 5’ end of the guide sequence being 20-30 nucleotides because Yeo disclosed a guide RNA that forms an A-C mismatch with a target RNA and Abudayyeh taught C2c2 is guided by a single crRNA with a spacer of at least 22 nucleotides that is complementary to the target ssRNA and a double repeat longer than 24 nucleotides and C2c2 is tolerant to single mismatches across the spacer.
Therefore, the claimed invention would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 34 is newly rejected under 35 U.S.C. 103 as being unpatentable over Yeo in view of Zhang and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 above, and further in view of Gao et al. (Biochem. Biophys. Res. Comm. 264:860-864, 1999; cited on Form PTO-892 filed January 25, 2023; hereafter “Gao”) and Carr et al. (Cell Reports 16:2618-2629, 2016; cited on Form PTO-892 filed January 25, 2023; hereafter “Carr”).
The relevant teachings of Yeo, Zhang, and Radivojac as applied to claims 1, 2, 5, 6, 14, 21-24, 27-30, 37, 41-43, and 45 are set forth above. The combination of Yeo, Zhang, and Radivojac does not teach or suggest a p53 wild-type lymphoma.
Regarding claim 34, Gao teaches that tumors with MDM2 amplification or overexpression typically contain the wild-type p53 and that loss of p53 function in tumors has been associated with drug resistance and poor prognosis (p. 860, column 2). Carr teaches that ATM phosphorylation of Mdm2-S394 is required for robust p53 activation (p. 2618, Abstract) and that failure to induce a robust p53 response translates to increased spontaneous lymphomagenesis (p. 2619, column 1). Carr teaches that Mdm-S394A mice are resistant to IR-induced lymphomagenesis (p. 2622, column 2) and that inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies (p. 2618, Abstract).
In view of the further teachings of Gao and Carr, it would have been obvious to one of ordinary skill in the art before the effective filing date to further modify the guide RNA of Yeo to be designed to substitute the codon encoding S394 of Mdm with A. One would have been motivated to and would have had a reasonable expectation of success to do this because Yeo teaches editing RNAs in living cells that cause cancer and Carr teaches that Mdm-S394A mice are resistant to IR-induced lymphomagenesis and teaches inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies.
Therefore, the claimed invention would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim Rejections - 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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 14, and 18-24 of co-pending application no. 16/756,139 (reference application) in view of Yeo et al. (US 2018/0334685 A1, with priority to May 10, 2017; cited on Form PTO-892 filed September 7, 2022: hereafter “Yeo”) and Radivojac et al. (Bioinformatics 24:241-247, 2008; cited on Form PTO-892 filed September 7, 2022; hereafter “Radivojac”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of the reference application recite an engineered, non-naturally occurring system suitable for modifying post-translational modification sites on a protein encoded by a target RNA, comprising:
(a) a catalytically inactive (dead) Cas13 protein, or a nucleotide sequence encoding said dead Cas13 protein;
(b) an adenosine deaminase acting on RNA (ADAR) protein or catalytic domain thereof comprising cytidine deaminase activity, a mutation of E488Q, and one or more mutations selected from L332I and K350I of an hADAR2- D amino acid sequence, or one or more corresponding mutations in a homologous ADAR protein;
(c) a guide molecule comprising a guide sequence designed to have a degree of complementarity with a target sequence in the target RNA at one or more codons that comprises an adenosine or cytosine and encodes an amino acid that is post-translationally modified;
wherein said adenosine deaminase protein or catalytic domain thereof is covalently or non- covalently linked to said dead Cas13 protein or said guide molecule, or is adapted to link thereto when contacted with the dead Cas13 protein or said guide molecule, and
wherein the post-translational modification sites are not phosphorylation sites.
The claims of the reference application do not recite the instant claim 1 limitation of the codon encodes an amino acid that is post-translationally modified by phosphorylation.
Yeo teaches editing RNAs in living cells that cause cancer (paragraph [0028)]). Radivojac teaches phosphorylation of amino acid residues serine, threonine, and tyrosine is common in cancer-associated proteins and changes in phosphorylation signaling can be due to disruption and deregulation of kinase and phosphatase function due to amino acid substitutions of kinases and phosphatases that results in changes in target phosphorylation (p. i241, column 2, middle). Radivojac teaches there is evidence that disruptions of phosphorylation are associated with cancer (p. i241, column 2, bottom) and that cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation when compared to control datasets (p. i241, Abstract).
Regarding claim 37, Yeo teaches the guide RNA comprises one or more modified nucleotides (paragraph [0121)).
In view of the teachings of Yeo and Radivojac, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the system of the claims of the reference application for the guide sequence to be designed to modify one or more codons encoding a cancer-related phosphorylation site or sites. One would have been motivated to and would have had a reasonable expectation to do this because Yeo discloses editing RNAs that cause cancer and Radivojac teaches cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation.
Therefore, claims of this application are unpatentable over claims of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 6, 14, 19-24, 27-30, 37, 41-43, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17 of co-pending application no. 17/264,340 (reference application) in view of Yeo and Radivojac. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 17 of the reference application recites an engineered, non-naturally occurring system for modifying nucleotides in a target nucleic acid, comprising:
a) a dead CRISPR-Cas or CRISPR-Cas nickase protein, or a nucleotide sequence encoding said dead CRISPR-Cas or CRISPR-Cas nickase protein, optionally wherein the CRISPR-Cas or CRISPR-Cas nickase protein is Cas9, Casl2, Cas13, Cas 14, CasX, or CasY, optionally wherein the dead CRISPR-Cas or CRISPR-Cas nickase protein is Casl3b, Casl3b-tl, Casl3b-t2, or Casl3b-t3, optionally wherein the dead CRISPR-Cas protein is less than 1000 amino acids, less than 950, less than 900, less than 850, less than 800, less, or than 750 amino acids in size;
b) a guide molecule comprising a guide sequence that hybridizes to a target sequence and designed to form a complex with the dead CRISPR-Cas or CRISPR-Cas nickase protein; and
c) the engineered protein of claim 1, or a nucleotide sequence encoding said engineered protein; and
claim 1 of the reference application recites an engineered protein having cytidine deaminase activity and comprising the amino acid sequence having at least 97% sequence identity to a hADAR2 protein wherein said hADAR2 consists of E488Q and D619G mutations and one or more of the mutations selected from the group consisting of: V351G, S486A, T375S, S370C, P462A, N5971, L332I, 1398V, K350I, M383L, S661T, S582T, V440I, S495N, and K418E, wherein the amino acid numbering of the mutation positions corresponds to the amino acid sequence of the hADAR2 protein.
The claims of the reference application do not recite the instant claim 1 limitation that the sequence of the guide molecule is designed to have a degree of complementarity with a target sequence in the target RNA at one or more codons that comprises an adenosine or cytosine and encodes an amino acid that is post-translationally modified.
Yeo teaches a CRISPR/Cas RNA editing fusion protein comprising a nuclease-dead Cas fused to a catalytically active deaminase domain of ADAR and a guide RNA comprising a short extension sequence of homology to the target RNA comprising a mismatch for a target adenosine for adenosine to inosine RNA editing of the target sequence (paragraph [0008] and claim 32), which inosine is ultimately read by translational and splicing machinery as guanosine (paragraph [0117]). Yeo discloses editing RNAs in living cells that cause cancer (paragraph [0028]) and discloses the subject is a human, mouse, or rat (paragraph [0097]).
Yeo discloses the guide RNA forms an A-C mismatch with a target RNA (paragraph [0066]).
Yeo discloses the guide RNA comprises one or more modified nucleotides (paragraph [0121]).
Yeo discloses the dCas comprises a nuclear localization signal (NLS) linked to the C-terminus of the dCas (paragraphs [0030] and [0183]).
The recitation of “for use…” in claims 27, 28, and 45 is interpreted as an intended use limitation (see MPEP 2111.02).
Radivojac teaches phosphorylation of amino acid residues serine, threonine, and tyrosine is common in cancer-associated proteins and changes in phosphorylation signaling can be due to disruption and deregulation of kinase and phosphatase function due to amino acid substitutions of kinases and phosphatases that results in changes in target phosphorylation (p. i241, column 2, middle). Radivojac teaches there is evidence that disruptions of phosphorylation are associated with cancer (p. i241, column 2, bottom) and that cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation when compared to control datasets (p. i241, Abstract).
In view of the teachings of Yeo and Radivojac, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the system of the claims of the reference application for the guide sequence to be designed to modify one or more codons encoding a cancer-related phosphorylation site or sites. One would have been motivated to and would have had a reasonable expectation to do this because Yeo discloses editing RNAs that cause cancer and Radivojac teaches cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation.
Therefore, claims of this application are unpatentable over claims of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17 of co-pending application no. 17/264,340 (reference application) in view of Yeo and Radivojac as applied to claims 1, 2, 5, 6, 14, 19-24, 27-30, 37, 41-43, and 45 above, and further in view of Kouranova et al. (Human Gene Therapy 27:464-475, 2016; cited on Form PTO-892 filed January 25, 2023; hereafter “Kouranova’). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of the reference application do not recite the limitations of claim 3 of this application.
Regarding claim 3 of this application, the reference of Kouranova teaches that the components of CRISPR can be delivered into cells as a precomplexed ribonucleoprotein particle (p. 465, column 2, top). Kouranova teaches a method for RNP complex formation (p. 466, column 1, middle). Kouranova teaches benefits to delivering CRISPR components by RNP including fewer off-target modifications (p. 465, column 1, top) and RNP is the only format that is reliably active in cells (p. 474, column 2). According to Kouranova, the RNPs are the most convenient and efficient delivery method for cultured cell lines (p. 464, Abstract). Kouranova teaches delivery of the RNP into cells by cationic lipid transfection or via a nanoparticle (p. 12, paragraph bridging columns 1-2).
In view of the teachings of Kouranova, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the claims of the reference application to deliver a RNP by cationic lipid transfection or via a nanoparticle. One would have been motivated to and would have had a reasonable expectation of success to do this because Kouranova taught the benefits of RNP delivery and taught RNP delivery by cationic lipid transfection or via a nanoparticle.
Therefore, claims of this application are unpatentable over claims of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17 of co-pending application no. 17/264,340 in view of Yeo and Radivojac as applied to claims 1, 2, 5, 6, 14, 19-24, 27-30, 37, 41-43, and 45 above, and further in view of Abudayyeh et al. (Science 353:6299, 2016, 23 pages; cited on the IDS filed on April 28, 2020; hereafter "Abudayyeh").
The claims of the reference application do not recite the limitations of claim 18 of this application.
Regarding claim 18, Abudayyeh teaches that Leptotrichia shahii C2c2 (C2c2 is otherwise known in the prior art as Cas13a) comprises two HEPN domains (p. 2, bottom) and that alanine substitution of the catalytic residues R597 and R1278 of the HEPN domain converted C2c2 into an inactive programmable RNA-binding protein (dC2c2) (paragraph bridging pp. 5-6; p. 9, top). R597 and R1278 of Leptotrichia shahii C2c2 HEPN domain are considered to correspond to R474 and R1046 of Leptotrichia wadei C2c2 HEPN domain.
In view of the teachings of Abudayyeh, it would have been obvious to one of ordinary skill in the art before the effective filing date for a Leptotrichia shahii dCas13a comprising alanine substitutions of the HEPN domain catalytic residues R597 and R1278. One would have been motivated to and would have had a reasonable expectation of success for a Leptotrichia shahii dCas13a comprising alanine substitutions of the HEPN domain catalytic residues R597 and R1278 because the claims of the reference application recite a dead Cas13a and Abudayyeh taught that alanine substitution of any of the four predicted HEPN domain catalytic residues converted Leptotrichia shahii Cas13a into dCas13a.
Therefore, claims of this application are unpatentable over claims of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 34 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17 of co-pending application no. 17/264,340 in view of Yeo and Radivojac as applied to claims 1, 2, 5, 6, 14, 19-24, 27-30, 37, 41-43, and 45 above, and further in view of Gao et al. (Biochem. Biophys. Res. Comm. 264:860-864, 1999; cited on Form PTO-892 filed January 25, 2023; hereafter “Gao”) and Carr et al. (Cell Reports 16:2618-2629, 2016; cited on Form PTO- 892 filed January 25, 2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of the reference application do not recite the limitations of claim 34 of this application.
Regarding claim 34 of this application, Gao teaches that tumors with MDM2 amplification or overexpression typically contain the wild-type p53 and that loss of p53 function in tumors has been associated with drug resistance and poor prognosis (p. 860, column 2). Carr teaches that ATM phosphorylation of Mdm2-S394 is required for robust p53 activation (p. 2618, Abstract) and that failure to induce a robust p53 response translates to increased spontaneous lymphomagenesis (p. 2619, column 1). Carr teaches that Mdm-S394A mice are resistant to IR-induced lymphomagenesis (p. 2622, column 2) and that inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies (p. 2618, Abstract).
In view of the teachings of Gao and Carr, it would have been obvious to one of ordinary skill in the art before the effective filing date for the guide RNA of the claims of the reference application to be designed to substitute the codon encoding S394 of Mdm with A. One would have been motivated to and would have had a reasonable expectation of success to do this because Yeo teaches editing RNAs in living cells that cause cancer and Carr teaches that Mdm-S394A mice are resistant to IR-induced lymphomagenesis and teaches inhibiting Mdm2-S394 phosphorylation during radiation exposure or chemotherapy would ameliorate bone marrow failure and prevent the development of secondary hematological malignancies.
Therefore, claims of this application are unpatentable over claims of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
RESPONSE TO REMARKS: Applicant argues the provisional rejections include the same references cited above under 35 U.S.C. § 103(a); the applications cited in the rejection have the same or a later effective filing date; and where a provisional non-statutory obviousness-type double patenting (ODP) rejection is the only remaining rejection in an application having an earlier or the same effective filing date, the provisional ODP rejection should be withdrawn.
Applicant’s arguments are not found persuasive. The provisional rejections are not the only rejections remaining in the instant application. Moreover, the instant application and at least the 16/756,139 application have the same effective filing date and according to MPEP 804.I.B.1.(b).(ii), “[i]f both the application under examination and the reference application have the same patent term filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome.”
Conclusion
Status of the claims:
Claims 1-6, 14, 18-30, 34, 36, 37, 41-43, and 45-50 are pending in the application.
Claims 4, 25, 26, 36, and 46-50 are withdrawn from consideration.
Claims 1-3, 5, 6, 14, 18-24, 27-30, 34, 37, 41-43, and 45 are rejected.
No claim is in condition for allowance.
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