DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/12/2025 has been entered.
Applicant’s arguments filed on November 12, 2025 have been received and entered. Claims 1-6, 19, 23 and 24 have been canceled, while claim 28 is newly added. The objection to claims 25 and 26 are hereby withdrawn. Claims 7-18, 20-22, 25-27 and 28 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-2, 7-13, 15-21 (group I) in the reply filed on November 23, 2020 was acknowledged. Applicant’s election of AAV9 as species for single AAV serotype was also acknowledged. However, upon further consideration, election of species requirement between different species of AAV were withdrawn and all the non-elected species were rejoined with the elected invention.
Claim 14 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 23, 2020.
Priority
This application is a divisional of US application no 15/687,196 filed on 08/25/2017 that is a Continuation of PCT/US2016/019783 filed 02/26/2016, which claims priority from a US provisional application 62/126,271 filed on 02/27/2015.
Claims 7-18, 20-22, 25-27 and 28 are under consideration.
Allowable Subject Matter
The following claims 15, 16 and 21 are drafted by the examiner and considered to distinguish patentably over the art of record in this application, claims 15 and 21 are presented to applicant for consideration:
--A polynucleotide comprising a synthetic nucleotide sequence encoding a human fukutin-related protein (FKRP) operably linked to a muscle specific promoter and/or enhancer element, wherein the synthetic nucleotide sequence has at least 90% sequence identity to SEQ ID NO:1, and wherein the GC content of the synthetic nucleotide sequence encoding the FKRP is reduced by about 5% to about 10% relative to the GC content of SEQ ID NO:2, wherein the polynucleotide has increased expression in mammalian cells as compared to identical native FKRP encoded by SEQ ID NO: 2--.
--a method of increasing glycosylation of alpha-dystroglycan (a- DG) in a skeletal muscle cell of a subject in need thereof, said method comprising intravenously administering an effective amount of adeno-associated virus comprising a synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific, wherein the synthetic nucleotide sequence consist of SEQ ID NO:1, wherein the FKRP is expressed in skeletal muscle or cardiac muscle of said subject and thereby producing human FKRP and increase glycosylation of a-DG in same cell of the subject in need thereof.--
--A method of delivering a nucleic acid to a subject, comprising intravenously administering to the subject an effective amount of an adeno-associated (AAV) vector comprising a polynucleotide comprising a synthetic nucleotide sequence encoding a human fukutin-related protein (FKRP) operably linked to a muscle specific promoter and/or enhancer element, wherein the synthetic nucleotide sequence has at least 90% sequence identity to SEQ ID NO:1, and wherein the GC content of the synthetic nucleotide sequence encoding the FKRP is reduced by about 5% to about 10% relative to the GC content of SEQ ID NO:2, wherein said subject exhibits increased expression of FKRP in cells of said subject as compared to identical native FKRP encoded by SEQ ID NO: 2.--
Maintained & new -Claim Rejections - 35 USC § 112 -new matter
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 7-18, 20-22, 25-26 and 27 remain rejected and claim 28 is newly 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instant case, the recitation of limitation “..has a GC content that is reduced by at least relative to the GC content of SEQ ID NO:2” (claims 21-22) and has a GC content that is reduced by at least 5% relative to the GC content of SEQ ID NO:2 (claim 25) and has a GC content that is reduced by 12% relative to the GC content of SEQ ID NO:2 (claim 28), are considered new matter.
Applicants have previously pointed to paragraph 77 of the published specification for the specific support of the claimed amendment. However, upon further review of the instant specification, examiner could not find support for the limitation having a GC content that is reduced by at least 4.95% or at least 5% relative to the GC content of SEQ ID NO:2” (claims 21-22 and 25). There is no explicit or implicit support for a codon optimized FKRP sequence that has a GC content that is reduced by at least 5% relative to the GC content of SEQ ID NO:2. In fact, contrary to applicants' assertions, paragraph 77 of the published application directly supports to a sequence, wherein the GC content is reduced by about 5% to about 10% compared to the GC content of SEQ ID NO:2 (e.g., 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, or any range or value therein). Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of the synthetic nucleotide sequence has a GC content that is reduced by at least 4.5% or at least 5% or 12% relative to the GC content of SEQ ID NO:2, as claimed. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for a FKRP sequence that has GC content that is reduced by at least 4.95% or at least 5% or reduced by 12% relative to the GC content of SEQ ID NO: 2 as recited in claims 21, 22 25 and 28 of the instant application (emphasis added). Claims 7-18, 20, 24, 26 and 27 are included in the rejection because they directly or indirectly depend from the rejected base claims. This is a new matter rejection.
Response to arguments
Applicants traverse the rejection arguing that the instant application provides implicit support throughout, for example, it exemplifies the use of a FKRP coding sequence that has a GC content that is reduced by at least 4.95% and at least 5%.” (emphasis added). Applicants’ arguments have been considered, but are not found fully persuasive.
As stated in previous office action, instant rejection pertains to new matter rejection that is applied in order to prevent applicant from adding information that goes beyond the subject matter originally filed. See In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 323, 326 (CCPA 1981); see also MPEP §§ 2163.06 through 2163.07. As such the rejection is not directed to the breadth of the claims. While there is no in haec verba requirement, the claim limitations must be supported in the specification through express, implicit, or inherent disclosure.
As stated in previous office action, instant specification explicitly supports to a FKRP sequence, wherein the GC content is reduced by about 5% to about 10% compared to the GC content of SEQ ID NO:2 (e.g., 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, or any range or value therein) (see para. 77 of the published application) (emphasis added). This portion of the specification explicitly provide support wherein the GC content is reduced by: (i) about 5%, (ii) about 10% or (iii) any value in between about 5% to about 10% including one exemplified in the instant application (SEQ ID NO: 1)..
Applicant fails to point explicit or implicit support for a codon optimized FKRP sequence that has a GC content that is reduced by at least 4.5% or at least 5% or reduced by 12% relative to the GC content of SEQ ID NO:2. The claims 21-22 and 25 as such do not limit upper boundary of reduction of GC content relative to the GC content of SEQ ID NO:2. MPEP 2163.05 states “ The failure to meet the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, commonly arises when the claims are changed after filing to either broaden or narrow the breadth of the claim limitations, or to alter a numerical range limitation or to use claim language which is not synonymous with the terminology used in the original disclosure. In the decision in In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976), the ranges described in the original specification included a range of "25%- 60%" and specific examples of "36%" and "50%." A corresponding new claim limitation to "at least 35%" did not meet the description requirement because the phrase "at least" had no upper limit and caused the claim to read literally on embodiments outside the "25% to 60%" range. In the instant case, the claims as amended do not limit the upper percentage of reduced GC content relative to the GC content of SEQ NO: 2. Absent evidence to the contrary or applicant pointing for any explicit and/or implicit support in the specification, instant rejection is maintained for the reasons of record.
Examiner’s note: A telephone call was made on December 3, 2025 to applicant’s representative Dr. Schwartzman to suggest amendments as indicated above in the beginning of this office action to put the instant application in conditions of allowance. However, Applicant’s representative indicated that inventors don't want to make any amendments at this point of time. Applicant’s representative reiterated the support for the claimed limitations at paragraph 77 of the published application. No agreement was reached.
Maintained & New -Claim Rejections - 35 USC § 112- scope of enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15, 18, 20, 26 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
a method of increasing glycosylation of alpha-dystroglycan (a- DG) in a skeletal muscle cell of a subject in need thereof, said method comprising intravenously administering an effective amount adeno-associated virus comprising a synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific, wherein the synthetic nucleotide sequence is set forth in SEQ ID NO:1, wherein the FKRP is expressed in skeletal muscle or cardiac muscle of said subject and thereby produces human FKRP and increase glycosylation of a-DG, wherein the AAV is selected from the group consisting of AAV6–11
does not reasonably provide enablement for a method of treating or increasing glycosylation of alpha-dystroglycan (a- DG) in a skeletal muscle cell of a subject in need thereof with any FKRP related muscular dystrophy by intravenously delivering an effective amount of a polynucleotide comprising a synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP), wherein the synthetic nucleotide sequence has at least 85.5% or 89.1% identity to SEQ ID NO:1, and has a GC content that is reduced by at least 5% 4 or 4.95% respectively relative to the GC content of SEQ ID NO:2 or using any other serotype of AAV injected intravenously to increase glycosylation of alpha-dystroglycan (a- DG) in a skeletal muscle cell of the subject. 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.
To the extent that Applicants’ arguments are pertinent to the standing rejection of claims 15, 18, 26 and claims dependent therefrom, they are addressed as follows:
Applicant disagree with the rejection arguing that Examiner cites and relies on publications that contradict each other. For example, the Examiner cites to Mauro for the teaching that a "serious problem is that the scientific basis of codon optimization in mammals does not support that codon usage is rate limiting for protein expression. et al. (Front. Bioeng. Biotech. 12:1371596: 1-18, 1 (2024)). Applicant argues that Paremskaia teaches "codon optimization is [SIC] routine technique." See Action, page 11 and Office Action dated 7/25/24, at p.10, line 13-15, and at p. 10, line 21-22, respectively. Importantly, however, the overarching issue with respect to the rejection is that the Examiner's focus is on codon optimization, which involves many factors, and the instant claims are directed to GC content. None of the cited prior art recognizes that reducing GC content increases FKRP gene expression, as taught in the instant application, and as such it is inapplicable. Applicant assert that Paremskaia actually supports enablement of the claims insofar as reducing GC content impacts reduction in CpG motifs, as it teaches deletion of CpG motifs decreases immunogenicity and is effective in gene therapy. See Paremskaia, page 9-10 and Fig. 2. The Examiner, while raising various alleged concerns and possible pitfalls with respect to the far broader field of codon optimization, fails to provide specific information as to how the level of experimentation proposed by the Applicants, when specifically applied to reduced GC content, qualifies as undue. The application demonstrates the use of an FKRP mutant mouse model system for use of the FKRP gene recited in the instant claims in restoring functional glycosylation in muscle tissue (e.g., through immunofluorescence of recipient tissue) and further for producing functional improvement (e.g., via treadmill tests) in the recipient. The application further defines a treatment or a therapeutically effective amount as providing some alleviation, mitigation, or decrease in at least one clinical symptom, and notes it need not be completely curative, as long as some benefit is provided. See e.g., Application, paragraphs [0037] and [0040]. The skilled artisan is able to verify the activity of the AAV vector recited in the instant claims as therapeutically effective for treatment using the model system and the guidance provided in the application without undue experimentation. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant’s argument that claims do not recite a method of treating any condition, it is noted that active method step of independent claims 15, 18 and 26 are the same and directed to intravenously delivering to a subject an effective amount of any adeno-associated (AAV) vector comprising the polynucleotide of the invention to a subject with an FKRP related muscular dystrophy (claim 15) or treating FKRP related muscular dystrophy in a subject in need thereof (claim 18, 26). The term “subject in need thereof” in the context of treatment or therapy is a subject known to have, or suspected of having or being at risk of having, a disease or disorder (e.g., dystroglycanopathy), and that is likely to benefit from the treatment or therapy, i.e., is in need thereof (see page 17 of the instant specification). In view of foregoing, it is apparent that the sole purpose of increasing glycosylation of alpha-dystroglycan (a- DG) in muscle tissue of a subject with an FKRP related muscular dystrophy is to treat FKRP related muscular dystrophy (see specification page 17). Therefore, claim 15 along with claims 18 and 26 are interpreted and analyzed for a method intended for treating FKRP related muscular dystrophy in a subject.
In response to applicant’s argument that AAV genomes generated are routinely verified prior to administration, it is relevant to note that claims 16-17 directed to a method of delivering a genus of nucleic acid to a cell or a subject is fully enabled as they are directed to a method of delivering a genus of nucleic acid without any requirement for expressing FKRP in any specific cell or tissue.
. However, as stated above, the specification does not enable for a method of increasing glycosylation of alpha-dystroglycan (a- DG) in muscle tissue of a subject with an FKRP related muscular dystrophy or treating a subject with any FKRP related muscular dystrophy by intravenously delivering to said subject an effective amount of any other adeno-associated (AAV) vector comprising a genus of synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP), wherein the synthetic nucleotide sequence has at least 85.5% or 89.1% identity to SEQ ID NO:1, and has a GC content that is reduced by at least 5% 4 or 4 .95% respectively relative to the GC content of SEQ ID NO:2 as broadly embraced by the breadth of the claims.
The claims embrace intravenously delivering to a subject an effective amount of any adeno-associated (AAV) vector. The specification discloses AAV includes he AAV vector selected from the group consisting of AAV type 1, AAV type 2, AAV type 3a, AAV type 3B, AAV type 4, AAV type 5, AAV type 6, AAV type 7, AAV type 8, AAV type 9, AAV type 10, AAV type 11, avian AAV, bovine AAV, canine AAV, equine AAV, and ovine AAV (see page 14 of the specification). Further, the claims read on intravenously administering a genus of synthetic nucleotide sequence variant of a codon optimized SEQ ID NO: 1 encoding FKRP .
The guidance provided in the specification is limited to intravenous delivery of AAV9-CK7 promoter-codon optimized human FKRP-mir122 target sites (AAV9 CK7) and MCK enhancer-Syn100 promoter-codon-optimized human FKRP gene-mir122 target sites (AAV9enMCK) to FKRP mutant mice with P448l mutation. It is emphasized that instant specification exemplified intravenous delivery of AAV9 comprising codon optimized human FKRP gene of SEQ ID NO:1 that is capable of restoring functional glycosylation in muscle tissue of a subject in need thereof.
The state of prior art importantly describes, a single intravenous delivery of AAV-6, -8, and -9 results in whole-body muscle transduction in rodents and large mammals (see Gregorevic et al Nat. Med., 10 (2004), 828-834, Wang et al Nat. Biotechnol., 23 (2005), 321-328 and Yue et al Mol. Ther.16 (2008),1944-1952). However, the art teaches AAV5, which is the phylogenetically most distant from other serotypes, transduces liver but failed to effectively transduce muscle and heart (Walkey et al Molecular Therapy, 2025, 33, 3, 1282-1299). This is further supported Xu (Mol Ther 2013 (10):1832-40, art of record) who teaches among the AAV serotypes, AAV9 has higher tropism to cardiac muscle, thus could be the choice for treating FKRP-related cardiomyopathy (see page 1833, col. 1, para. 2). In view of foregoing disclosure, one of skill in the art would conclude that an intravenous injection of genus of AAV of different serotype would not be enabling transducing skeletal muscle and/or heart cells to make and use the invention. A showing that enough of a codon optimized variant of FKRP nucleic acid is expressed in the target cell (skeletal muscle or heart cells), enough nucleic acid is incorporated into the target cells, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough protein is produced and enhanced FKRP expression have an effect on the target cells and such effect is enough of an effect for a long enough period of time resulting in treating FKRP-related cardiomyopathy in a predictable animal model. There is no evidence on record or any nexus between an intravenous injection of different serotype AAV that would effectively target and transduce skeletal muscle and heart to over express FKRP in FKRP related muscular dystrophy in a subject. An artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
In response to applicant’s argument that none of the cited prior art including Paremskaia recognizes that reducing GC content increases FKRP gene expression and as such it is inapplicable, it should be noted that claimed method encompasses a genus of DNA sequences of all the synthetic nucleotide sequence that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and has a GC content that is reduced by at least 5% or 4.95% relative to the GC content of SEQ ID NO:2, showing contemplated biological activity.
The guidance provided in the specification is limited to a codon optimized sequence as set forth in SEQ ID NO: 1 (GC content=63.46) that has a GC content reduced by about ~7.1% relative to wild type FKRN as set forth in SEQ ID NO: 2 (GC content=70.56%) (see example 1) (emphasis added). Thus, the breadth of the claims encompasses a genus of synthetic nucleotide sequence that is a variant of codon optimized sequence of SEQ ID NO: 1 (at least 85.5% or 89.1% identical to SEQ ID NO: 1) and has a GC content that is reduced by at least 5% or 4.95% relative to the GC content of SEQ ID NO:2, showing contemplated biological activity. The claims as amended do not disclose the upper limit of reduced GC content relative to the GC content of SEQ NO: 2 and therefore encompass reduction of most if not all the GC content relative to wild type as long as it is at least 85.5% or 89.1% identical to SEQ ID NO: 1.
It is in this context, Examiner cited Mauro (Trends in Molecular Medicine, 2014, 20(11), 604-613) who teaches “codon optimization is often suggested as a primary consideration for generating high-expressing constructs suitable for gene therapy …., it is evident, however, that mRNAs contain numerous layers of information that overlap the amino acid code and that this complexity can be disrupted by codon optimization. … there are potentially serious consequences associated with using codon optimization, particularly for nucleic acid therapeutics. In the absence of analysis; these potential problems include: (i) disrupting the normal patterns of cognate and wobble tRNA usage, affecting protein structure and function; (ii) producing novel peptides with unknown biological activities; and (iii) altering post-transcriptional modifications that may modify protein ensembles” (see page .611, col. 1, para. 1).
In response to applicant’ argument that Paremskaia supports enablement of the claims insofar as reducing GC content impacts reduction in CpG motifs thereby decreases immunogenicity, it is noted that claimed method uses genus of synthetic nucleic acid that is not limited to only reducing the GC content, rather claims read on use of variants of codon optimized sequence that are at least 85.5% or 89.5% identical to an optimized sequence of SEQ ID NO: 1 and complete reduction or reducing most of GC content from the coding sequence that is likely to result in a non-functional gene resulting in minimal or no expression. This is because an extremely low GC content could trigger the formation of a repressive chromatic structure thereby silencing the gene (see summary Barahimipour et al Plant J. 2015 November ; 84(4): 704–717). Further, art teaches that secondary structures in mRNA, which are often stabilized by GC content also influence mRNA fate (see Zhang et al BMC Genomics 2011, 12:90, 1-11). The claimed variant that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% or at least % (reduction of most if not all the GC content) relative to the GC content of SEQ ID NO:2 would likely significantly alter the stability of the secondary structure. The cited art of record teaches requirement for experimental verification of properties such as mRNA stability and protein expression levels are necessary before further experimentation can be conducted (see page 11, col. 2, para. 1). Further, the codon optimization of the target sequence could also result in reduced mRNA stability in solution, which would impair its functionality thereby making it necessary to confirm the stability of the structure of the optimized variant of the nucleic acid (see page 11, col. 2, last para. to page 12, col. 1, para. 1).
There is no evidence on the record of a relationship between the structures of the codon optimized DNA molecules as set forth in SEQ ID NO: 1 that would provide any reliable information about the structure of other variant that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% or at least 5 % (reduction of most if not all the GC content) relative to the GC content of SEQ ID NO:2 encompassed by the claimed genus. The specification does not teach any other variant of codon optimized sequence that is at least 85.5% or 89.5% identical to an optimized sequence (SEQ ID NO: 1) and has GC content that is reduced by at least 5% relative to the GC content relative to SEQ ID NO: 2 that would also show contemplated biological activity under in vitro or in vivo condition (restoration of functional glycosylation of a-DG in muscle tissue) other than SEQ ID NO: 1. As such, the Artisan of skill could not predict that Applicant enabled any species, except for the SEQ ID NO: 1 that could be used to express FKRP protein in vivo for restoration of functional glycosylation of a-DG for therapeutic purposes. One of skill in the art would have to perform undue experimentation to identify variant that could be altered to increase expression and maintain protein structure, and codons that are limiting for translation in cardiac cell or any other muscle cells type for restoration of functional glycosylation of a-DG intended to treat FKRP related muscular dystrophy in a subject in need thereof as embraced by the breadth of the claim, without reasonable expectation of success.
Maintained-Claim Rejections - 35 USC § 112
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 7-18, 20-22, 25-26 and 27 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass a genus of synthetic nucleotide sequence that has at least 85.5% (claim 25) or 89.1% (claim 21) identity to a codon optimized FKRP sequence as set forth in SEQ ID NO:1 and has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2 showing contemplated biological activity (increased expression in mammalian cells as compared to an otherwise identical native polynucleotide encoding FKRP). Thus, claims encompass synthetic nucleotide sequence that are variant of a codon optimized sequence of FKRP as set forth in SEQ ID NO: and has a GC content that is reduced by at least 4.95% or 5% relative to the GC content of SEQ ID NO:2.
Claim 22 embraces a genus of synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP), wherein the synthetic nucleotide sequence has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2. In the instant case, independent claims 21-22 and 25 encompass synthetic nucleotide sequence that do not have an upper limit for the percentage reduction in GC content relative to the GC content of SEQ NO: 2.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The genus of DNA sequences of all the synthetic nucleotide sequence that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2, encompassed within the genus of optimized synthetic FKRP gene sequence showing contemplated biological activity have not been disclosed.
The guidance provided in the specification is limited to a codon optimized sequence as set forth in SEQ ID NO: 1 (GC content=63.46) that has a GC content reduced by about ~7.1% relative to wild type FKRN as set forth in SEQ ID NO: 2 (GC content=70.56%) (see example 1). The specification prophetically contemplates various variants of the optimized synthetic polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1; and/or a nucleotide sequence having at least 85.5 or 90% identity to SEQ ID NO: 1; and/or a synthetic polynucleotide comprising a nucleotide sequence encoding FKRP, wherein the GC content is reduced by about 5% to about 10% compared to the GC content of SEQ ID NO:2 (specification page 2, lines 30-34, page 10, lines 14-16, table 2 and example ). It is unclear from the specification whether any of the plurality of variant that are 85.5 or 89.1% identical to SEQ ID NO: 1 that has a GC content that is reduced by at least 4.95% or 5% relative to the GC content of SEQ ID NO:2 have any functional activity. The specification has not disclosed the sequences of any of the variant that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2 other than SEQ ID NO: 1 showing contemplated biological activity as embraced by the claims.
It is known in prior art that, due to the degeneracy of the genetic code, sequences sharing relatively low levels of identity code for the same protein. Due to the degeneracy of the genetic code, an extraordinarily large number of nucleotide sequences may encode the optimized FKRP. While codon optimization was a known technique at the time of filing of the instant application, there are myriad techniques, websites, algorithms, and services for doing so, including making manual changes to the sequence. Thus, it is unclear how the specific engineered sequence of SEQ ID NO: 1, or a sequence sharing at least 85.5 or 89.1% identity to SEQ ID NO: 1 that has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2 would have been predictably show biological activity from the other numerous sequences available. Paremskaia teaches codon optimization is routine technique. However, Paremskaia raise a number of issues including incomplete synonymy of substitutions that carries the potential to disrupt natural posttranscriptional modification sites or, alternatively, give rise to novel sites, leading to critical alterations in the final protein’s structure, properties, and functions. Furthermore, overlooking the existence of alternative translation initiation sites can lead to the unintended production of new proteins, adding another layer of complexity to the process (see page 3, col. 1, para. 3, Paremskaia et al Front. Bioeng. Biotechnology. 12:1371596, 2024, 1-18, Godfried Sieetal , 2012, FEBS Lett. 586, 2313–2317.and Matsuda et al 2010, PLoS One 5, e15057 and Mauro (Trends in Molecular Medicine, 2014, 20(11), 604-613, page 611, col. 1). The art further teaches requirement for experimental verification of properties such as mRNA stability and protein expression levels are necessary before further experimentation can be conducted (see page 11, col. 2, para. 1). It is also disclosed that codon optimization of the target sequence could also result in reduced mRNA stability in solution, which would impair its functionality thereby making it necessary to confirm the stability of the structure of the optimized variant of the nucleic acid (see page 11, col. 2, last para. to page 12, col. 1, para. 1). There is no evidence on the record of a relationship between the structures of the codon optimized DNA molecules as set forth in SEQ ID NO: 1 that would provide any reliable information about the structure of variant optimized FKRP sequence within the claimed genus. One of skill in the art would have to determine codon usage in the variants as embraced by the breadth of the claims that could be altered to increase expression and maintain protein structure, and codons that are limiting for translation in cardiac cell or any other cells type as embraced by the breadth of the claim. In the instant case, specification provides guidance of only one species of a codon optimized sequence as set forth in SEQ ID NO: 1 showing contemplated biological effect. The specification is silent on disclosing any other species of synthetic sequence as embraced by the breadth of the claims.
. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
The specification fails to describe what DNA molecules fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed synthetic nucleotide sequence that has at least 85.5% (claim 25) or 89.1% (claim 21) identity to a codon optimized FKRP sequence as set forth in SEQ ID NO:1 and has a GC content that is reduced by at least 4.95% or 5% relative to the GC content of SEQ ID NO:2 showing contemplated biological activity, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 UsPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF'S were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, Applicant was not in possession of the genus of synthetic nucleotide sequence that has at least 85.5% (claim 25) or 89.1% (claim 21) identity to a codon optimized FKRP sequence as set forth in SEQ ID NO:1 and/or has a GC content that is reduced by at least 4.95% or 5% relative to the GC content of SEQ ID NO:2 showing contemplated biological activity as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention."
Response to arguments
Applicant disagree with the rejection arguing that due to the absence of appropriate evidence or reasoning to the contrary, the Examiner has failed to meet the initial burden of proof required in this rejection. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it should be noted that instant rejection pertains to claims that encompass:
a genus of synthetic nucleotide sequence that has at least 85.5% (claim 25) or 89.1% (claim 21) sequence identity to a codon optimized FKRP sequence as set forth in SEQ ID NO:1 and has a GC content that is reduced by at least 5% or at least 4.95% relative to the GC content of SEQ ID NO:2 showing contemplated biological activity (increased expression in mammalian cells as compared to an otherwise identical native polynucleotide encoding FKRP). Claim 22 embraces a genus of synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP), wherein the synthetic nucleotide sequence has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2.
The instant rejection is not to lack of teaching in identifying critical element or motif of the AAV vector as previously argued by the applicant.
In the instant case, it is emphasized that independent claims 21-22, 25 encompasses a genus of variant synthetic nucleotide sequence that does not have an upper limit for the percentage reduction in GC content relative to the GC content of SEQ NO: 2 and therefore BRI of the claims encompasses synthetic nucleotide variant sequence that has at least 85.5% (claim 25) or 89.1% (claim 21) sequence identity to a codon optimized FKRP sequence as set forth in SEQ ID NO:1 that lacks all or most of the GC content ( reduced by at least 5% or at least 4.95%) (emphasis added) relative to the GC content of SEQ ID NO:2 (wild type FKRP).
The guidance provided in the specification is limited to a codon optimized human FKRP sequence as set forth in SEQ ID NO: 1 (GC content= ~63.5) that has a GC content reduced by about ~7.1% relative to wild type FKRN sequence as set forth in SEQ ID NO: 2 (GC content=70.56%) (see example 1).
The specification prophetically contemplates various variants of the optimized synthetic polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1; and/or a nucleotide sequence having at least 85.5 or 90% identity to SEQ ID NO: 1; and/or a synthetic polynucleotide comprising a nucleotide sequence encoding FKRP, wherein the GC content is reduced by about 5% to about 10% compared to the GC content of SEQ ID NO:2 (specification page 2, lines 30-34, page 10, lines 14-16, table 2 and example ) and has increased expression in mammalian cells as compared to an otherwise identical native polynucleotide encoding FKRP.
MPEP2163 states “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor 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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
It is emphasized that instant specification is completely silent on any variant that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% or at least 5% (lacks all or most of the GC content ) relative to the GC content of SEQ ID NO:2 other than SEQ ID NO: 1 showing contemplated biological activity as embraced by the breadth of the claims. In fact, instant specification does not even contemplate a variant sequence that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% or at least 5% with out limiting the upper limit of reduced GC content. Therefore, Applicant was not in possession of the genus the genus of synthetic nucleotide sequence showing contemplated biological activity as encompassed by the claims.
In the instant case, previous office action, in part relying on the teaching of Mauro (Trends in Molecular Medicine, 2014, 20(11), 604-613) and Paremskaia stated that GC content and gene expression is complex and highly dependent on the specific organism and the location of the GC-rich sequence within the gene.
It should be noted that complete removal or reducing most of GC content from the coding sequence would likely results in non-functional gene resulting in minimal or no expression as low extremely low GC content could trigger the formation of a repressive chromatic structure thereby silencing the gene (see summary Barahimipour et al Plant J. 2015 November ; 84(4): 704–717). Further, art teaches that secondary structures in mRNA, which are often stabilized by GC content that influences mRNA fate (see Zhang et al BMC Genomics 2011, 12:90, 1-11). The claimed variant that is at least 85.5% or 89.1% identical to SEQ ID NO: 1 and having a GC content that is reduced by at least 4.95% or at least 5% (reduction of most if not all the GC content) relative to the GC content of SEQ ID NO:2 would likely significantly alter the stability of the secondary structure. The cited art of record r teaches requirement for experimental verification of properties such as mRNA stability and protein expression levels are necessary before further experimentation can be conducted (see page 11, col. 2, para. 1). Further, the codon optimization of the target sequence could also result in reduced mRNA stability in solution, which would impair its functionality thereby making it necessary to confirm the stability of the structure of the optimized variant of the nucleic acid (see page 11, col. 2, last para. to page 12, col. 1, para. 1).
The instant specification neither provide any guidance with respect to the extent codon usage specify the protein conformation nor does it provide any information on whether codon usage that is altered to increase expression maintains the protein structure. Further, the specification fails to provide any information on which codons are limiting for translation in different cell types as broadly embraced by the breadth of the claim. The specification lacks the testing and/or provide any guidance with respect to possible effects on the include testing the possible effects of codon optimization, which may include mass spectrometry analysis of cryptic peptide expression from constructs intended for in vivo nucleic acid therapies as suggested in Mauro.
It is emphasized that instant specification fails to disclose the structural diversity of the claimed genus, either through the disclosure of sufficient species of variant of the optimized sequence that are representative of the full variety or scope of the genus, or by the establishment of a reasonable structure-function correlation with respect to substitutions that carries the potential to disrupt natural posttranscriptional modification sites or, alternatively, give rise to novel sites, leading to critical alterations in the final protein. The specification does not teach any other variant of codon optimized human sequence other than SEQ ID NO: 1 or at least 90% sequence identity to SEQ ID NO:1, and wherein the GC content of the synthetic nucleotide sequence encoding the FKRP is reduced by about 5% to about 10% relative to the GC content of SEQ ID NO:2 showing contemplated biological activity under in vitro or in vivo condition (intended for restoration of functional glycosylation of a-DG in muscle tissue).
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of genus of synthetic nucleotide sequence as embraced by the breadth of the claim for contemplated biological activity.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 21, 7-11, 13, 16-17 were rejected under 35 U.S.C. 103 as being unpatentable over Qiao et al (Molecular Therapy, 2014, 22, 11, 1890-1899 art of record) as evidenced by Vannoy (Human Gene Therapy, 2014, 25, 187-196), Genbank accession no (AJ314847.1, 07.10.2008, art of record), Liu (USPGPUB 20110081708, dated 4/7/11) as evidenced by Akhtar et al (Pak. J. Pharm. Sci., Vol.26, No.6, November 2013,.1181-1188) and Bancel et al (US20140010861, dated 6/9/2014, EFD/3/9/13 or WO/2013/151663, art of record). Applicant’s argument that there is no motivation modify the wild type FKRP coding sequence to obtain a sequence that has at least 89.1% identity to SEQ ID NO:1 and also has a GC content that is reduced by at least 4.95% or reduced by 12% relative to the GC content of SEQ ID NO: 2 is found persuasive. It is noted that claims are drawn to finite and more limiting engineered codon optimized sequence that has at least about 90% identity to SEQ ID NO:1. The breadth of claims embraces a finite number of solutions and one of ordinary skill in the art would have not predictably selected out of the sequences available within the finite number of synthetic nucleotide sequence that has at least 89.1% identity to SEQ ID NO:1 and also has a GC content that is reduced by at least 4.95% or reduced by 12% relative to the GC content of SEQ ID NO: 2. Therefore, previous rejection of claims 21, 7-11, 13, 16-17 are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 7, 12 were rejected under 35 U.S.C. 103 as being unpatentable over Qiao et al (Molecular Therapy, 2014, 22, 11, 1890-1899 art of record) as evidenced by (Genbank accession no (AJ314847.1, 07.10.2008, art of record), Liu (USPGPUB 20110081708, dated 4/7/11) as evidenced by Akhtar et al (Pak. J. Pharm. Sci., Vol.26, No.6, November 2013,.1181-1188) and Bancel et al (US20140010861, dated 6/9/2014, EFD/3/9/13 or WO/2013/151663, art of record) as applied to claim 21 above, and Xu et al (Molecular Ther. 2013, 21, 10, 1832-1840, IDS) and Qiao et al (Gene Ther. 2011; 18(4): 403–410, IDS). The rejection is withdrawn for the reasons discussed above.
Maintained -Claim Rejections - 35 USC § 103-in modified form
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Qiao et al (Molecular Therapy, 2014, 22, 11, 1890-1899 art of record) as evidenced by Vannoy (Human Gene Therapy, 2014, 25, 187-196, IDS), Genbank accession no (AJ314847.1, 07.10.2008, art of record) and Liu (USPGPUB 20110081708, dated 4/7/11) as evidenced by Akhtar et al (Pak. J. Pharm. Sci., Vol.26, No.6, November 2013,.1181-1188).
Claim 22 is directed to a polynucleotide comprising a genus of synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific, wherein the synthetic nucleotide sequence has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2, and has increased expression in mammalian cells as compared to an otherwise identical native polynucleotide encoding FKRP.
Qiao teaches a vector comprising a synthetic codon-optimized polynucleotide for expression in mammalian cells, encoding a codon optimized human fukutin-related protein (FKRP) that is operably linked to a muscle specific syn100 promoter (see page 1897, col. 1, para. 2). Vannoy provide evidence of using human FKRP cDNA that is codon optimized and synthesized for high expression in mammalian cells (see page 188, col. 2, para. 3). It is relevant to note that wild type human fukutin-related protein (FKRP) and its nucleotide sequence has 100% identity to SEQ ID NO: 2 as evident from the accession number (see sequence search report). In view of foregoing, it is apparent that Qiao teaches a human FKRP cDNA that is codon optimized to obtain a synthetic codon-optimized polynucleotide for a higher expression in mammalian cells. A review of SEQ ID NO: 2 shows GC content of a wild type FKRP is about 70.6%. It is further disclosed that codon optimizes FKRP sequence shows higher expression. While Qiao teaches a codon optimized human FKRP sequence but differ from claimed invention by not explicitly disclosing that the synthetic sequence has a GC content that is reduced by at least 4.95% relative to the GC content of the wild type FKRP (SEQ ID NO: 2).
Before the effective filing date of instant application, Liu teaches method for boosting the recombinant expression of genes in mammalian cells by using codon optimized gene in host cells. Liu teaches a general method takes into account of multiple factors affecting protein expression including codon usage, tRNA usage, GC-content, ribosome binding sequences, promoter, 5'-UTR, ORF and 3'-UTR sequences of the genes to improve and optimize the gene sequences to boost the protein expression of the genes in bacteria, yeast, insect and mammalian cells (see abstract). Liu teaches ideal range for GC percentage is a gene is approximately 30-70%. It is disclosed that high GC-content will make mRNAs to form strong stem-loop secondary structures. It will also cause problems for PCR amplification and gene cloning (see abstract and para. 46) This is further evident from the teaching of Akhtar who reported that GC content should be between 30-70% in any gene to be highly expressed (see page 1183, col. 1, para. 1). Akhtar discloses comparison of GC value between wild type and synthetic gene that shows reduction of GC content. Akhtar emphasizes that the ideal percentage range of GC content is in-between 30% to 70% and any peak outside of this range will negatively affect transcriptional and translational efficiency (see page 1186, col. 1, para. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the wild type human FKRP sequence as disclosed in accession number that is optimized by Qiao using method known in prior art and reduce the GC content of human FKRP within the ideal range as suggested in Liu and Akhtar, with reasonable expectation of success, before the effective filing date of instant application, to improve the gene expression. Although the specific nucleotide sequence of the codon optimized human FKRP sequence used in Qiao is not disclosed, however, codon optimization of coding sequence to match codon frequencies in target and host organisms to improve gene expression was known in prior art. Liu and Akhtar provide motivation to keep range of GC content in between 30-70% in a resulting codon optimized synthetic sequence (see above) It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): With regards to determining experimental parameters, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)). Absent evidence of any unexpected or superior result for genus of synthetic FKRP codon optimized sequence embraced by the breadth of claim, it would have been obvious, to one of ordinary skill to modify the wild type FKRP sequence by reducing the GC content such that it falls in between 30-70%. Furthermore, KSR has already stated that motivation need not be specific, and only in the case of an infinite number of variants, it is only a specific variant non-obvious. Given that one of ordinary skill in the art was well aware of the results of codon optimization of FKRP with GC content in between 30-70%, the requirements and known proprietary methods and software for codon optimization, and was already able to make sequence with reduced GC content for other gene in a coding sequence as in Akhtar. Absent evidence to an unexpected superior result with any specific variant of synthetic FKRP sequence, it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human FKRP using method disclosed in prior art by reducing the GC content of wild type FKRP sequence (70.6%) to a GC content in between 30-70% for the synthetic codon optimized FKRP to improve the expression in host cells, with reasonable expectation of success. One who would practice the invention would have had reasonable expectation of success because codon optimization was already known in the art to work in an obvious manner to produce higher expression in mammalian cells in increasing glycosylation of alpha-dystroglycan as in Qiao (fig, 2, 4), Vannoy. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith,--USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 22 and 25 remain rejected under 35 U.S.C. 103 as being unpatentable over Qiao et al (Molecular Therapy, 2014, 22, 11, 1890-1899 art of record) as evidenced by Vannoy (Human Gene Therapy, 2014, 25, 187-196), Genbank accession no (AJ314847.1, 07.10.2008, art of record), Liu (USPGPUB 20110081708, dated 4/7/11) as evidenced by Akhtar et al (Pak. J. Pharm. Sci., Vol.26, No.6, November 2013,.1181-1188) and Bancel et al (US20140010861, dated 6/9/2014, EFD/3/9/13 or WO/2013/151663, art of record).
Claims are also directed to a polynucleotide comprising a synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific or muscle preferred, wherein the synthetic nucleotide sequence has a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2. Claims are also directed to an AAV viral vector comprising a polynucleotide comprising a synthetic nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific, wherein the synthetic nucleotide sequence has at least 85.5% identity to SEQ ID NO:1, and has a GC content that is reduced by at least 5% relative to the GC content of SEQ ID NO:2.
With respect to claims 22, 25, Qiao teaches a vector comprising a synthetic codon-optimized polynucleotide for expression in mammalian cells, encoding a codon optimized human fukutin-related protein (FKRP) that is operably linked to a muscle specific syn100 promoter (see page 1897, col. 1, para. 2). Vannoy provide evidence of using human FKRP cDNA that is codon optimized and synthesized for high expression in mammalian cells (see page 188, col. 2, para. 3). It is relevant to note that wild type human fukutin-related protein (FKRP) and its nucleotide sequence that has 100% identity to SEQ ID NO: 2 was known as evident from the accession number (see sequence search report). In view of foregoing, it is apparent that Qiao teaches a human FKRP cDNA that is codon optimized to obtain a synthetic codon-optimized polynucleotide for a higher expression in mammalian cells. A review of SEQ ID NO: 2 shows GC content of a wild type FKRP is about 70.6%. It is further disclosed that codon optimizes FKRP sequence shows higher expression.
Qiao teaches a codon optimized nucleotide sequence encoding human FKRP that is operably linked to muscle specific promoter but differs from claimed invention by not explicitly disclosing that nucleotide has at least 85.5% sequence identity to SEQ ID NO: 1 and has a GC content that is reduced at least 4.95% or at least 5% the GC content of SEQ ID NO:2 (wild type human FKRP) (limitation of claims 22 and 25).
Before the effective filing date of instant application, Liu teaches a method for boosting the recombinant expression of genes in mammalian cells by using codon optimized gene in host cells. Liu teaches a general method takes into account of multiple factors affecting protein expression including codon usage, tRNA usage, GC-content, ribosome binding sequences, promoter, 5'-UTR, ORF and 3'-UTR sequences of the genes to improve and optimize the gene sequences to boost the protein expression of the genes in bacteria, yeast, insect and mammalian cells (see abstract). Liu teaches ideal range for GC percentage is a gene is approximately 30-70%. It is disclosed that high GC-content will make mRNAs to form strong stem-loop secondary structures. It will also cause problems for PCR amplification and gene cloning. This is further evident from the teaching of Akhtar who reported that GC content should be between 30-70% in any gene to be highly expressed (see page 1183, col. 1, para. 1). Akhtar discloses comparison of GC value between wild type and synthetic gene that shows reduction of GC content. Akhtar emphasizes that any peak outside of this range (30-70% if GC content) will negatively affect transcriptional and translational efficiency (see page 1186, col. 1, para. 1). The combination of reference differs from claimed invention by not disclosing a codon optimized sequence encoding FKRP that has at least 85.5 sequence identity to SEQ ID NO: 1.
Bancel teaches codon optimized nucleotide sequence encoding human FKRP as set forth in SEQ ID NO 82176 that has about 90% sequence identity to SEQ ID NO: 1 and has about 1.8% reduced GC content as compared to GC content relative SEQ ID NO: 2. (Bancel Table 6). Bancel teaches that codon optimization methods are known in the art to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons insert or delete restriction sites, modify ribosome binding sites and mRNA degradation sites, to adjust translational rates to allow the various domains of the protein to fold properly, or to reduce or eliminate problem secondary structures within the mRNA. Bancel discloses codon optimization tools, algorithms and services including services from GeneArt (Life Technologies) as disclosed in Qiao (see page 1897, col. 2, para. 2) and/or proprietary methods (see para. 189) that are known in the art.
Therefore, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of prior art to modify the composition of Qiao by codon optimizing the coding sequence of wild type human fukutin-related protein (FKRP) as disclosed in accession number using method known in prior art by reducing the GC content as disclosed and suggested in Liu, Akhtar and Bancel, with reasonable expectation of success, before the effective filing date of instant application, to improve the gene expression. Although the specific nucleotide sequence of the codon optimized human FKRP sequence used in Qiao is not disclosed, however, prior art of Qiao explicitly reported codon optimization of coding sequence to match codon frequencies in target and host organisms to improve FKRP expression in cardiac cells. Further, Bancel discloses a codon optimized sequence that falls within the scope of a sequence that is at least about 85.5% identical to SEQ ID NO: 1 that has reduced GC content (~1.8%) relative to GC content in SEQ ID NO: 2. It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): With regards to determining experimental parameters, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
Absent evidence of any unexpected or superior result for genus of FKRP coding sequence embraced by the breadth of claims reciting at least 85.5% of SEQ ID NO: 1 and having at least 5% reduced GC content relative to SEQ ID 2, it would appear that Applicant's contribution to the art is simply to claim a genus of codon optimized sequence that would be specifically obvious, to or one of ordinary skill in the art before the effective filing date of the invention, particularly since prior art recognized that GC content should be between 30-70% in any gene to be highly expressed (See Akhtar and Liu) and delivery of other codon optimized polynucleotide encoding human fukutin-related protein (FKRP) as disclosed in Qiao resulted in improved expression of FKRP. Furthermore, KSR has already stated that motivation need not be specific, and only in the case of an infinite number of variants, it is a specific variant non-obvious. Given that one of ordinary skill in the art was well aware of the results of codon optimization of FKRP, the requirements and known proprietary methods and software for codon optimization, and was already able to make sequence with reduced GC content in a coding sequence that has about 90% sequence identity to SEQ ID NO: 1 as in Bancel. Absent evidence to an unexpected superior result with any specific variant of FKRP, it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human FKRP by reducing GC contusing method disclosed in Liu, Akhtar and Bancel (see para. 189) to improve the expression of FKRP in host cells, with reasonable expectation of success. One who would practice the invention would have had reasonable expectation of success because codon optimization of human FKRP was already known in the art to work in an obvious manner to produce higher expression in mammalian cells in increasing glycosylation of alpha-dystroglycan as in Qiao (fig, 2, 4). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith,--USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicant re-iterates in part prior arguments. The Examiner's response to prior arguments is found in prior Office Actions.
To the extent that Applicants’ arguments are pertinent to the standing rejection of claims 22 and 25, they are addressed as follows:
A: Applicants disagree with the rejection and maintain that (a) some of the cited references are inappropriate due to inapplicable subject matter and (b) there is no reasonable expectation of success . Applicant continue to argue that Qiao 2014 and Vannoy merely disclose codon optimized FKRP and are both silent with respect to GC content. There is nothing in Qiao 2014 or Vannoy to suggest a reduction in GC content of huFKRP to increase gene expression in mammalian cells. Akhtar is inappropriate because the instant claims are specific for mammalian expression. The Examiner further puts forth a strained interpretation of Liu alleging a 0.6% difference with respect to the GC content of SEQ ID NO: 2 and the range given in Liu of preferred optimization "around 30-70%" is relevant, and further interpreting Fath's disclosure of an end result of percent GC (all of which resulted from having the natural GC content increased) as motivating, because it happens to be less than the GC content of SEQ ID NO: 2. These are unreasonable positions and interpretations that are only made possible through the benefit of hindsight gained from the instant application. Applicants re-iterate the argument in part relying on teaching of Kudla and Kim from the prior submission (see exhibit D, filed on June 3, 2021). The ordinarily skilled artisan, informed by Kudla, Kim, and Fath, would have no motivation or reasonable expectation of success in reducing the overall GC content of FKRP coding sequences to increase gene expression, from the Liu disclosure, since the GC content already falls within the acceptable range taught by Liu, and since they would reasonably expect further reduction of the GC content would decrease gene expression in mammalian cells in vivo. Applicants’ arguments have been considered, but are not found fully persuasive.
In response, as an initial matter, it should be noted that claim 22 is not limited to any finite or specific engineered codon optimized sequence. The breadth of the claim encompasses a polynucleotide comprising a synthetic nucleotide sequence having a GC content that is reduced by at least 4.95% relative to the GC content of SEQ ID NO:2. The claims as written encompasses polynucleotide comprising a synthetic nucleotide sequence having GC content that is mostly reduced if not all GC content is removed relative to the GC content of SEQ ID NO:2. The prior art of Qiao 2014 and Vannoy disclose the importance of using codon optimized human FKRP, however, both are silent with respect to GC content.
Examiner reiterate and emphasizes that codon optimization was routine in prior art that typically included increase in overall GC content for genes that are not GC rich (emphasis added) or to maintain an overall GC content between 44-60% (emphasis added). The cited art of record as summarized by Liu explicitly discloses factors affecting protein expression including codon usage, tRNA usage, GC-content, ribosome binding sequences, promoter, 5'-UTR, ORF and 3'-UTR sequences of the genes to improve and optimize the gene sequences to boost the protein expression of the genes in any cell including bacteria, yeast, insect or mammalian cells (see abstract). Liu teaches an ideal range for GC % is approximately 30-70%. Liu teaches the high GC-content of the target sequence is preferably mutated using codon degeneracy to be around 50-60%. Liu reported GC % of gene that is optimized to around 50-60% (see para. 46). These assertions are further supported by Akhtar who reported that GC content should be between 30-70% in any gene to be highly expressed (see page 1183, col. 1, para. 1). Akhtar discloses comparison of GC value between wild type and synthetic gene that shows 5% reduction of GC content in bacterial cells. Akhtar like Lin emphasizes that the ideal percentage range of GC content is in-between 30% to 70% and any peak outside of this range will negatively affect transcriptional and translational efficiency (see page 1186, col. 1, para. 1).
In view of foregoing, it is apparent that contrary to applicant’s argument that there is no motivation to decrease GC content, Liu and . Akhtar both provide explicit motivation to optimize the of coding sequences of a gene to be around 50-67% (see para. 46).
In response to applicant’s argument that Akhtar disclosure is specific for increasing expression in E. coli and not in mammalian cells, it should be noted that Applicants have further engaged in selective reading of the teachings of Akhtar et al. to formulate the grounds for teaching away. It should be noted that the ultimate goal of optimizing the GC content of a wild type gene is to be around 30-70%. Akhtar like Liu teaches GC content should be between 30 to 70% for any gene (see page 1183, col. 1, para. 2 in Akhtar and para. 46 of Liu). These assertions are further supported by Fath (cited as evidence without relying on the rejection ) who clearly show that the optimal GC content of the optimized gene for almost all the 50-wildtype gene tested in HEK293T cells is between 60-66% (emphasis added). It should be noted that Fath discloses testing five representative gene constructs in CHOK1, or insect-Sf9 cells that are widely used for recombinant protein production, in comparison to HEK293T cells (Fig. 2). Fath teaches that the impact of gene optimization was comparable in all three systems: Theses studies show that optimizing genes for expression in one cell type may be equally suitable for testing for improving expression in cells of other species (eg. insect). In the instant case, Akhtar like Fath shows use of multiparameter algorithm to optimize genes for expression in one cell type that should be suitable for testing expression in other cell type. It is emphasized that codons of the natural genes (wildtype FKRP, IFN-g or any other wildtype gene) are routinely replaced by the codons used frequently by different species (bacteria, human, rodent etc) without change in the protein sequence. Liu teaches improving and optimizing the gene sequences by optimizing the GC content of a wild type gene is to be around 30-70%. to boost the protein expression of the genes in bacteria, yeast, insect and mammalian cells (Liu abstract and para. 46).
As stated before, claim 22 is not limited to any finite or specific engineered codon optimized sequence. The breadth of claims embraces a large number of unidentified, unpredictable solutions and one of ordinary skill in the art would have predictably selected out of the innumerable sequences available within the genus. Furthermore, Examiner in part relying on that KSR stated “only in the case of an infinite number of variants, it is a specific set of variant non-obvious.” That is not the case here (emphasis added). The claims are not limited to any particularly effective set of variants amongst a large number of possibilities. It is noted that obviousness does not require absolute predictability of success; for obviousness under 35 U.S.C. § 103, all that is required is a reasonable expectation of success. See In re O’Farrell, 7 USPQ2d 1673 (CAFC 1988). Given that one of ordinary skill in the art was well aware of the results of codon optimization of FKRP and requirement of GC content in between 50-60% in mammalian or bacterial host (see Liu and Akhtar), the requirements and known proprietary methods and software for codon optimization (such as one disclosed in Qiao, Vannoy), and was already able to make sequence with reduced GC content for other gene in a coding sequence as in Akhtar and Bancel as suggested in Liu. Absent evidence to an unexpected superior result with any specific variant of synthetic FKRP sequence, it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human FKRP using method disclosed in prior art by optimizing the GC content of wild type FKRP sequence (70.6%) to a GC content in between 50-67 % for the synthetic codon optimized FKRP as suggested in Liu and Akhtar and test the expression in host cells using method disclosed in Qiao/Vannoy, with reasonable expectation of success.
In response to applicant’s previous submission in part relying on Kudla and Kim to assert that one would expect that increasing GC content would increase gene expression in mammalian cells, and that decreasing GC content would decrease gene expression, it is noted that Kudla reported increasing GC content of wild type coding sequence of GFP (GC:32), BPV1 L1 (GC:36) HIV gaga-pol (35) and HIV gag (38) to an optimized sequence with higher GC content of 67% increases gene expression again suggesting that the optimal range of GC content for an optimized sequence varies anywhere from 50-67%. (emphasis added) as suggested in Liu. Previously, Examiner took a position that codon optimization is routine and typically include increase in GC content of for a gene that are not GC rich or to maintain a GC content between 44-60%. It is this context, Fath ( PloS One, 2011, e17596, 1-14, cited as evidence without relying on rejection, see non-final of 7/25/2024) was cited as evidence that compared the expression of 50 wild type and optimized human gene sequence, wherein GC content of wild type gene (ranging from 44%-60%) is increased to GC content in between 60- 67% (see table 1, Fath, PloS One, 2011, e17596, 1-14). In fact, both Kulda and Fath references show GC content of most of the optimized gene sequence varies anywhere from 50-67%.
In view of foregoing, it is clear that the optimal range of GC content for an optimized sequence varies anywhere from 50-67%. It would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human FKRP using method disclosed in prior art by optimizing the GC content of wild type FKRP sequence (70.6%) to a GC content in between 50-67% for the synthetic codon optimized FKRP as suggested in Liu and Akhtar and test the expression in host cells using method disclosed in Qiao/Vannoy, with reasonable expectation of success.
B. Applicant disagree with the rejection arguing examiner couples the previous rejection with Bancel's disclosure of a mere 1.8% reduced GC content in an untested huFKRP coding sequence, to establish motivation and a reasonable expectation of success at making the instant invention, to one of ordinary skill in the art. This is not reasonable. Bancel discloses SEQ ID NO: 82171, which has 1.8% reduced GC content of the huFKRP gene, as one in a list of thousands of seemingly unrelated sequences. Bancel further fails to demonstrate SEQ ID NO: 82171 exhibits any expression let alone increased expression in mammalian cells. Further, the term "biasing GC content" is disclosed in Bancel only once, amid numerous other possible sequence modifications, without specific indication of the direction of such bias (e.g., increasing or decreasing GC). See Bancel, paragraph [0189]. Since the understanding in the art at the time, discussed further below, was that increasing GC content leads to increased gene expression in mammalian cells, the ordinarily skilled artisan would assume that such biasing refers to increasing GC content. In light of this, the ordinarily skilled artisan is left uninformed as to how, or even if, the Bancel sequences have improved expression, and certainly would not be motivated by the possibly inconsequential 1.8% reduction in GC content of one of thousands of sequences presented in Bancel to further reduce GC content of huFKRP in the hopes of increasing expression, nor would they reasonably expect success in such an endeavor. Applicants’ arguments have been considered, but are not found fully persuasive.
As an initial matter, applicant’s argument pertaining to claims 21, 28 and claims dependent therefrom are drawn to a polynucleotide comprising a synthetic nucleotide sequence that has at least 89.1% identity to SEQ ID NO:1, and has a GC content that is reduced by at least 4.95% or reduced by 12% relative to the GC content of SEQ ID NO: 2 is found persuasive as they are drawn to finite and more limiting engineered codon optimized sequence. The breadth of claims embraces a finite number of solutions and one of ordinary skill in the art would have not predictably selected out of the sequences available within the finite number of synthetic nucleotide sequence that has at least 89.1% identity to SEQ ID NO:1 and also has a GC content that is reduced by at least 4.95% or by 12% relative to the GC content of SEQ ID NO: 2. Applicant’s argument that there is no motivation modify the wild type FKRP coding sequence to obtain a sequence that has at least 89.1% identity to SEQ ID NO:1 and also has a GC content that is reduced by at least 4.95% or by 12% relative to the GC content of SEQ ID NO: 2 is found persuasive, therefore, previous rejection of claims 21, 7-11, 13, 16-17 are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
To the applicant’s argument pertains to claims 22 and 25, they are addressed as follows:
Applicant re-iterates and rely on prior arguments on the teaching of Liu and Akhtar that are substantially the same as discussed in preceding section. The arguments are substantially the same as foregoing response.
In response to applicant’s argument that Bancel discloses SEQ ID NO: 82171, which has 1.8% reduced GC content of the huFKRP gene, as one in a list of thousands of seemingly unrelated sequences, it is emphasized that Bancel may have codon optimized many other unrelated sequences. However, this does not negate the fact that Banccel reported SEQ ID NO: 82171 that has about 90% sequence identity to SEQ ID NO: 1 and has 1.8% reduced GC content of the huFKRP gene relative to SEQ ID NO: 2.
In response to applicant’s argument that there is no motivation and reasonable expectation of success in reducing the GC content for the huoFKRP sequences based on the teaching of Bancel, it is reiterated that the rejection in part relies on the teaching of prior art that suggest that the ideal percentage range of GC content ranges from 30% to 70% (emphasis added). Any peaks out-side of this range is known to adversely affect transcriptional and translational efficiency (Akhtar and Liu, both art of record). In the instant case, overall GC content of a wild type FKRP gene is calculated to be ~70.56%., which is outside range of 30-70%. Qiao and Vannoy that were published in 2014 (both of record) show availability of codon optimization tool (GeneArt) to generate numerous codon optimized sequence that are synthesized for high expression in mammalian cells. In the instant case, both the references disclose that human FKRP polynucleotide sequence is codon optimized, however, the exact sequence of the codon-optimized polynucleotide sequences are not disclosed. In the instant case, Qiao /Vannoy both explicitly teaches the use of human FKRP DNA is codon optimized and synthesized for high expression in mammalian cells (see page 188, col. 2, para. 3) (emphasis added). MPEP 2143.02 states “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018)”. To the extent, prior art teaches means to codon optimize the human FKRP coding sequence using software known in art to increase gene expression in a mammalian host, it would be obvious for one of ordinary skill in the art to try optimizing the GC content of wildtype FKRP from 70.6% to a GC content ranging from 50-67% as suggested in prior art of Liu and Akhtar for optimal expression in a host cell, with reasonable expectation of success. Akhtar exemplified and provided evidence of GC content adjustment showing reduction of at least 5% of GC content in synthetic optimized IFN-l gene as compared to GC content in wild type gene (see figure 3 and table 1) to improve expression in bacteria. To the extent, prior art teaches ways to codon optimize the same human FKRP coding sequence using software known in art to increase gene expression in a mammalian host, it is applicable to the rejection. In the instant case, claims are not limited to any finite or specific engineered codon optimized sequence. The breadth of claims embraces a large number of unidentified, unpredictable solutions and one of ordinary skill in the art would have predictably selected out of the innumerable sequences available within the genus. As stated in previous office action, Examiner in part relying on that KSR stated “only in the case of an infinite number of variants, it 1s a specific set of variant non-obvious.” That is not the case here (emphasis added). The claims are not limited to any particularly effective set of variants amongst a large number of possibilities. Given that one of ordinary skill in the art was well aware of the results of codon optimization of FKRP with GC content in between 50-70% (see Liu and Akhtar), the requirements and known proprietary methods and software for codon optimization such as one disclosed in Qiao, Vannoy and Bancel (GenArt). and was already able to make sequence with reduced GC content for other gene in a coding sequence as in Akhtar and Bancel. Absent evidence to an unexpected superior result with any specific variant of synthetic FKRP sequence, it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human FKRP using method disclosed in prior art by optimizing the GC content of wild type FKRP sequence (70.6%) to a sequence having GC content ranging between 50- 70% and select a synthetic codon optimized FKRP from the genus of sequence that exhibits improved expression of FKRP using the method/assay disclosed in Qiao /Vannoy in a host/cell, with reasonable expectation of success.
On pages 15-16 of the applicant’s argument, Applicant re-iterates prior arguments on the teaching of Bancel, Kim and Kulda of the arguments that are substantially the same as discussed above and in previous office action mailed on 08/24/2023. The arguments are substantially the same as those addressed on pages 15-17 of the prior office actions mailed on 08/24/2023 and incorporated herein.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments on record are not compelling and do not overcome the rejection of record.
Examiner’s note: Applicant’s representative is requested to contact Examiner to resolve the pending issues to put instant application in condition for allowance.
Maintained -Double Patenting
Claims 7-18, 20-22, 24-26 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10350305 in view of Qiao et al (Molecular Therapy, 2014, 22, 11, 1890-1899).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass polynucleotide comprising a nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific or muscle preferred. As such, the ‘305 claims represent a species of the instant broader product claims. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Additionally, method as claimed in the instant application encompass delivery of a polynucleotide sequence claimed in ‘305. Regarding claims’305 differ from claimed invention by not disclosing intravenously delivering AAV encoding human EKRP having at least 90% sequence identity to SEQ ID NO: 1 that has at least 5% reduced GC content relative to SEQ ID NO: 2. Qiao et al cure deficiency by teaching a method of increasing glycosylation or delivering a subject in need thereof or treating dystroglycanopathy, said method comprising delivering a therapeutic effective amount of AAV9-human codon optimized FKRP to a subject in need thereof (see page 1895, figure 2 and 4). Therefore, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of prior art to modify the method of Qiao by using polynucleotide encoding codon optimized human fukutin-related protein (FKRP) as disclosed in in ‘309, with reasonable expectation of success, before the effective filing date of instant application. Further, the method as claimed encompass the nucleic specifically claimed in ‘305.
Response to argument
Applicant request reconsideration of the rejection in view of arguments against the teaching of Qiao. Applicants’ arguments have been considered, but are not found fully persuasive.
In response, in the instant case, the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass polynucleotide comprising a nucleotide sequence which encodes a human fukutin-related protein (FKRP) operably linked to a promoter and/or enhancer element that is muscle specific or muscle preferred. As such, the ‘305 claims represent a species of the instant broader product claim directed to synthetic nucleotide sequence has at least 85.1% 89.1% identity to SEQ ID NO:1, and has a GC content that is reduced by at least 4.95% or 5% relative to the GC content of SEQ ID NO:2. It is well established that a species of a claimed invention renders the genus obvious. Therefore, instant broader claims are anticipated by the synthetic nucleotide of claims of ‘305. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Therefore, rejection is maintained for the reasons of record.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. (i) Afzal-Javan (J Microbiol. 2013 October; 6(8): e7371, 1-7) teaches CAI of 1.0 is considered ideal while a CAI of > 0.8 is rated as good for expression in the desired expression organism. The lower the number, the higher the chance that desired gene will be expressed poorly. The ideal percentage range of GC content is ranged from 30% to 70%. Any peaks out-side of this range will adversely affect transcriptional and translational efficiency.
(2) Exhibit A- Novopro codon optimization tool between Seq ID NO: 2 vs SEQ ID NO: 1, 2024, page 1-3. The data shows that codon optimized FKRP shows at least 5% reduced GC content relative to SEQ ID NO: 2.
(3) Exhibit B Vector Builder codon optimization, 2024, page 1 teaches codon optimized FKRP shows at least 5% reduced GC content relative to SEQ ID NO: 2.
(4) Fath, PloS One, 2011, e17596, 1-14.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632