DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-5, 14-17, 35-36, 39-41, 45-47, 51, and 54-62 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the instant application is entitled is 11/12/2021.
Information Disclosure Statement
Receipt of an information disclosure statement on 02/21/2025 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
Figure 1A is disclosed to depict various designed hSGSH constructs (page 4, lines 1-4). However, the grayscale legend is difficult to interpret. It would be remedial to present the legend such that one of ordinary skill in the art may easily interpret the components represented therein.
Figure 2C is disclosed to depict schematic representation of further engineering the mature SGSH coding sequence for use in BiP signal sequence- and vIGF2 peptide-comprising constructs (page 4, lines 13-14). However, the grayscale legend is difficult to interpret. It would be remedial to present the legend such that one of ordinary skill in the art may easily interpret the components represented therein.
Figures 3A-4B all depict graphs of SGSH enzyme activity (page 4, lines 15-22), with PBS as a control. The provided legends do not depict a difference between the “1e11” group and the “PBS” control group. For ease of clarification, it would be remedial to present the legend such that each and every depicted group may be distinguished from one another, for example as in Figure 5B.
Figures 6A-6D are disclosed to depict SGSH expression in various parts of the brain (page 4, lines 28-33). However, the graphs depicted therein list G1-G3 on the x axis, with no clarification either in the drawings themselves or in the associated brief description. It would be remedial to ensure that each group is clearly labeled such that one of ordinary skill in the art may easily interpret the components represented therein.
Figure 7A is disclosed to depict SGSH expression in the liver (page 5, lines 1-3). However, the graph depicted therein lists V1-V3 on the x axis, with no clarification either in the drawing itself or in the associated brief description. It would be remedial to ensure that each group is clearly labeled such that one of ordinary skill in the art may easily interpret the components represented therein.
Figures 14A-14B are disclosed to depict levels of total GM3 in mouse brain (page 6, lines 19-21). However, the graphs depicted therein include circle and square data points that are either dark or light gray, with no clarification as to the significance of these differences either in the drawings themselves or in the associated brief descriptions. It would be remedial to present a legend such that each group is clearly labeled in order for one of ordinary skill in the art to easily interpret the components represented therein.
Figures 17A-17C are disclosed to depict levels of total GM3 in mouse brain (page 7, lines 3-6). However, the graphs depicted therein include circle and square data points that are various grayscale shades, with no clarification as to the significance of these differences either in the drawings themselves or in the associated brief descriptions. It would be remedial to present a legend such that each group is clearly labeled in order for one of ordinary skill in the art to easily interpret the components represented therein.
Figures 18A-18D are disclosed to depict SGSH activity in treated brain tissue (page 7, lines 7-19). However, the graphs depicted therein include data points of different shapes (i.e. circle, square, and triangle), with no clarification as to the significance of these differences either in the drawings themselves or in the associated brief descriptions. It would be remedial to present a legend such that each group is clearly labeled in order for one of ordinary skill in the art to easily interpret the components represented therein.
Figures 19A-19C are disclosed to depict SGSH activity in treated spinal cord sections (page 7, lines 20-29). However, the graphs depicted therein include data points of different shapes (i.e. circle, square, and triangle), with no clarification as to the significance of these differences either in the drawings themselves or in the associated brief descriptions. It would be remedial to present a legend such that each group is clearly labeled in order for one of ordinary skill in the art to easily interpret the components represented therein.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 4, 5, 14, 16, 17, 45, 47, 51, 54-56, and 55-60 are objected to because of the following informalities:
Claim 1 recites “wherein the mature hSGSH coding has the nucleic acid sequence” at line 7, which is improper. It would be remedial to amend the instant claim to recite, for example, “wherein the mature hSGSH coding sequence has the nucleic acid sequence” (bolded emphasis added). Furthermore, claim 1 recites “an AAV 3’ITR” at lines 3-4, which lacks a space properly separating “3’” and “ITR.” It would be remedial to amend the instant claim to include a proper space separating “3’” and “ITR.”
Claim 4 recites “the rAAV according to claim 1, wherein the mature hSGSH coding sequence has the nucleic acid sequence of sequence of SEQ ID NO: 16…” (bolded emphasis added). This recitation appears to incorporate a simple typographical error meant to recite “the rAAV according to claim 1, wherein the mature hSGSH coding sequence has the nucleic acid sequence of SEQ ID NO: 16…” (bolded emphasis added). It would be remedial to amend the instant claim language such that this typographical error is corrected. Furthermore, instant claim 4 recites “the mature hSGSH coding sequence has the nucleic acid sequence of…SEQ ID NO: 16 or a nucleic acid which is 85% identical to SEQ ID NO: 16” (bolded emphasis added). Such claim language is inconsistent with the recitation of instant claim 1, which recites “a nucleic acid sequence which is…at least 85% identical to SEQ ID NO: 16” (bolded emphasis added). It is considered that the recitation of 85% identity reflects a simple typographical error in language meant to mirror that of instant claim 1, which recites at least 85% identity. It would be remedial to correct this typographical error, as appropriate.
Claim 5 recites “a native signal sequence having nucleic acid sequence of SEQ ID NO: 31” at lines 1-2, which lacks a proper article preceding “nucleic acid sequence.” It would be remedial to amend the instant claim to recite, for example, “a native signal sequence having the nucleic acid sequence of SEQ ID NO: 31” (bolded emphasis added).
Claim 14 recites “the regulatory sequences comprise a CMV IE enhancer, a chicken-beta actin (CB) promoter, and a chicken beta actin intron.” While not strictly improper, this recitation is nonetheless internally inconsistent, as chicken-beta actin species are recited as both “chicken-beta actin” and “chicken beta actin.” For purposes of internal consistency, it would be remedial to recite either “chicken-beta actin” or “chicken beta actin,” but not both.
Claim 16 also recites “chicken beta actin intron,” which is not internally consistent, as set forth above regarding instant claim 14. For purposes of internal consistency, it would be remedial to recite either “chicken-beta actin” or “chicken beta actin,” but not both. Furthermore, instant claim 16 lacks a conjunction such as “and” or “or” properly separating “chicken beta actin-intron” and “rabbit globin polyadenylation sequence.” It would be remedial to amend the instant claim to include a conjunction properly separating the recited species.
Claim 17 recites the acronym “WPRE” in line 2, which is an acronym that is not properly defined prior to its recitation. Based on the instant specification, WPRE refers to a woodchuck hepatitis virus posttranscriptional regulatory element (page 24, lines 2-3). It would be remedial to first define the acronym, for example by reciting “woodchuck hepatitis virus posttranscriptional regulatory element (WPRE).”
With regard to claim 45, which recites a pharmaceutical composition comprising a rAAV according to claim 1 in a formulation buffer” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. While “rAAV” is spelled such that it recites a consonant letter “r,” the pronunciation of the “r” in “rAAV” nonetheless begins with a vowel sound. It would be remedial to update the instant claim language to be grammatically proper.
Claim 47 recites “the pharmaceutical composition…is administrable at a dose 1 x 109 GC per gram of brain mass” at lines 1-2, which omits the preposition “of” preceding “dose.” It would be remedial to amend the instant claim to comport with standard grammatical and/or linguistic conventions by reciting “of” preceding “dose” (i.e. “the pharmaceutical composition…is administrable at a dose of 1 x 109 GC per gram of brain mass”).
Claim 51 recites “the engineered hSGSG gene” at line 4, which appears to be a simple typographical error meant to recite “the engineered hSGSH gene.” It would be remedial to amend the instant claim such that it recites “the engineered hSGSH gene” (bolded emphasis added). The Examiner notes that instant claims 54-56 depend from instant claim 51 and do not resolve the basis of the objection of record. Accordingly, they inherit the objection thereof.
Claim 55 includes grammatical errors, such as the recitation of “an AAV capsid coding sequences” (bolded emphasis added), which is improper, as “an” is a singular article, while “sequences” are pluralized. It would be remedial to amend the instant claim such that it is grammatically proper, for example by reciting “AAV capsid coding sequences” without a preceding “an.”
With regard to claim 56, which recites “a AAVhu68 and AAV4h91” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. It would be remedial to update the instant claim language to be grammatically proper, for example by reciting “an.”
With regard to claim 57, which recites “a AAV capsid protein” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. It would be remedial to update the instant claim language to be grammatically proper, for example by reciting “an.” With further regard to claim 57, the recitation of “an rAAV production system useful for producing the rAAV according to any of claims 1…” (bolded emphasis added) is improper, as claim 1 should be referred to in the singular. It would be remedial to amend the instant claim such that claim 1 is referred to in the singular, for example by reciting “an rAAV production system useful for producing the rAAV according to claim 1…” (bolded emphasis added).
With regard to claim 58, which recites “a AAVhu68 and AAV4h91” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. It would be remedial to update the instant claim language to be grammatically proper, for example by reciting “an.”
Claim 59 recites “the vector genome is selected from SEQ ID NO: 10 and 13” at line 2, which is improper. It would be remedial to amend the instant claim such that it is grammatically proper, for example by reciting “the vector genome is selected from SEQ ID NOs: 10 and 13” (bolded emphasis added).
Claim 60 recites “a method of treating a human subject diagnosed with MPS IIIA” at line 1, which includes an acronym that is not properly defined prior to its recitation. Based on the instant specification, MPS IIIA refers to mucopolysaccharidosis type IIIA (page 1, line 5). It would be remedial to first define the acronym, for example by reciting “a method of treating a human subject diagnosed with Mucopolysaccharidosis type IIIA (MPS IIIA).” Furthermore, the penultimate line of instant claim 60 recites “according to claim 1in” (bolded emphasis added), which omits a proper space separating “claim 1” and “in.” It would be remedial to amend the instant claim such that it includes a proper space separating “claim 1” and “in.”
The suggestions set forth above by the Examiner are merely examples and are not intended to be limiting.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) - Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 5, 14-17, 39-41, 45-47, 57, 58, and 60 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.
Claim 1, from which all other claims directly or indirectly depend, is drawn to a set of mature hSGSH coding sequences, wherein said coding sequences comprise a nucleic acid sequence at least 85% identical to instant SEQ ID NO: 16, which is 1452 nucleotides in length. The rejected claims thus comprise a set of hSGSH coding sequences that encompass a large number of variable residues-specifically up to 217 nucleotides. Claims 4, 5, 14-17, 39-41, 45-47, 57, 58, or 60 all inherit this large number of variable residues. Claim 4 explicitly requires at least 85% sequence identity, as in instant claim 1.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes mature coding sequences of hSGSH, including SEQ ID NO: 16 and SEQ ID NO: 22, both of which encode mature hSGSH (page 2, lines 5-12; page 14, lines 3-5). Notably instant SEQ ID NO: 22 is disclosed to encode SEQ ID NO: 23, which comprises stabilizing amino acid residue changes and/or substitutions at A482Y and E488V (i.e. not the native sequence) (page 12, line 31-page 13, line 3; page 14, lines 3-5). Alternatively, instant SEQ ID NO: 24 is also disclosed to encode hSGSH (page 33, lines 28-32), as are instant SEQ ID NOs: 20 and 26 (page 34, lines 1-8). No description is provided of a suite of nucleic acid sequences encoding mature hSGSH, wherein said suite encompasses all possible variant sequences that share at least 85% identity with instant SEQ ID NO: 16 and encode functional, mature hSGSH, as required by instant claim 1. As shown in the multiple sequence alignment of the Appendix, SEQ ID NOs: 16, 20, 22, 24, and 26 all share at least 99% identity to each other.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of SEQ ID NOs: 16, 20, 22, 24, and 26, all of which share at least 99% identity to each other, and all of which encode functional hSGSH. Based on the instant specification, at the time of filing, Applicant had possession of nucleic acid sequences encoding the amino acid sequence of SEQ ID NO: 23 (i.e. functional hSGSH). The results are not necessarily predictive of a suite of nucleic acid sequences, wherein said suite encompasses all possible variant sequences that share at least 85% identity with instant SEQ ID NO: 16 and must encode functional, mature hSGSH, as required by instant claim 1. Thus, it is impossible for one to extrapolate from the few examples described herein those nucleic acid sequences that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of nucleic acid sequences that share at least 85% identity to instant SEQ ID NO: 16 and still encode functional, mature hSGSH. As is known to those of ordinary skill in the art, amino acid sequences of protein products are determined by the corresponding nucleic acid sequence (reviewed in Crick, 1970). Therefore, any variation in the nucleic acid sequence must necessarily result in variation of the corresponding amino acid sequence translated from the same. This variation may be synonymous or non-synonymous, wherein non-synonymous substitutions are tolerated at a lower rate than synonymous substitutions. However, even synonymous substitutions have been found to impact the biological properties of the encoded protein (reviewed in Hunt et al., 2014: see especially Figure 1). Furthermore, the instant claim set does not limit the claimed sequence variation to synonymous substitutions and therefore necessarily encompasses both synonymous and non-synonymous substitutions, both of which would be expected to impact the biological properties of the encoded protein, as reviewed in Hunt et al., 2014
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 4, 5, 14-17, 39-41, 45-47, 57, 58, and 60.
Claim Rejections - 35 USC § 112(a) - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 60 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Instant claim 60 is drawn to a method of treating a human subject diagnosed with mucopolysaccharidosis type IIIA (MPS IIIA), and/or improving gait or mobility, reducing tremors, reducing spasms, improving posture, or reducing the progression of vision loss in a subject in need thereof, comprising administering to the subject a suspension of an rAAV comprising an AAV capsid and a vector genome, wherein the vector genome comprises an expression cassette encoding for a functional human N-sulfoglycosamine sulfohydrolase (hSGSH) in a formulation buffer at a specified dosage.
Breadth of the claims: The claims broadly encompass the treatment of human subjects diagnosed with MPS IIIA by administering a suspension of an rAAV comprising an AAV capsid and a vector genome, wherein the vector genome comprises an expression cassette encoding for a functional human N-sulfoglycosamine sulfohydrolase (hSGSH) in a formulation buffer at a specified dosage. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: While the specification envisions methods of treating human subjects diagnosed with MPS IIIA (page 55, lines 6-7), the working examples are drawn to treatment of mice and non-human primates (Examples 1-3), not of humans. As set forth below, while AAV therapeutics are promising in mouse models of MPS IIIA, these therapies have yet to be realized in human subjects. Regarding the non-human primate studies set forth in the instant specification, these studies are drawn to pharmacology (SGSH expression levels), toxicology, and histopathology (page 74, lines 12-14). While these studies demonstrate that the instantly claimed system shows expression on par or better with the lead engineered-WPRE candidate, they do not disclose any therapeutic outcome that may be translated into human therapeutics (page 78, lines 13-15).
Predictability and state of the art: Gray et al., 2019 (hereinafter Gray) discloses an improved AAV vector for neurological correction of the mouse model of mucopolysaccharidosis IIIA (abstract). This is consistent with the disclosure of Sawamoto et al., 2018 (hereinafter Sawamoto), which discloses successful trials utilizing rAAV vectors to treat MPS IIIA mice (see section 2.4.3. MPS IIIA and IIIB). While Gray is silent as to the translation of the therapies taught therein to human patients, Sawamoto discloses that the selection of a viral vector to deliver genetic material to the human body involves several logistical issues, including the limited number of viral vectors available for therapeutic use, the possibility of eliciting an immune response, the probability of pre-existing immunity against the viral vector increasing with patient age, concern for genotoxicity, appropriate administration method for CNS gene therapy, and the price and commercialization of the approved therapies (see section 4. Unmet challenge of viral vectors). While some shortcomings may be overcome through the use of different or hybrid vectors, per Sawamoto, in vivo AAV-mediated gene delivery is still under development as it moves forward to clinical trials (page 65, column 2, paragraphs 2 and 3). Therefore, AAV-mediated gene therapy for purposes of treating MPS IIIA is an underdeveloped and unpredictable topic in the current state of the art. Ths instant application is silent as to any proposals to overcome any of these known hurdles to in vivo AAV gene therapy, and as of the time of filing, such in vivo gene therapy was not yet realized in human MPS IIIA patients.
Amount of experimentation necessary: The quantity of experimentation needed to carry out the full scope of the claimed method is large. One could not rely solely upon the guidance provided in the instant disclosure and/or prior art, especially in view of the safety and delivery concerns set forth above (see Sawamoto). One would be required to address and overcome at least each and every consideration noted above in applying AAV therapy to MPS IIIA human patients in vivo to ensure both the safety and efficacy of the claimed treatment, which has not yet been achieved in the field despite a large amount of effort from the research community, underscoring the large amount of experimentation (with no guarantee or reasonable expectation of success) required to produce an AAV gene therapy system suitable for treating human MPS IIIA patients in vivo.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claim 60 is not considered to be enabled by the instant disclosure.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 56 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 has been amended to recite “the rAAV according to claim 1, wherein the mature hSGSH coding sequence is 99% identical to SEQ ID NO:,” which omits the sequence identifier number “16.” This omission renders the metes and bounds of the instantly claimed invention unclear and indefinite, as it is not clear from the claim language what sequences would infringe upon the scope of protection sought by the instant claim language. It would be remedial to amend the instant claim such that it includes the sequence identifier number “16,” thereby clearly establishing the metes and bounds of protection sought. For purposes of examination and in the interest of compact prosuection, the Examiner has interpreted instant clai m2 to recite “the rAAV according to claim 1, wherein the mature hSGSH coding sequence is 99% identical to SEQ ID NO: 16” (bolded emphasis added).
Claim 56 recites the limitation "the AAV capsid" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 56 depends from claim 54, which itself requires the nucleic acid molecule according to claim 51. While claim 51 does recite “an adeno-associated virus (AAV) capsid” at lines 1-2, this capsid is a component of the claimed rAAV-not of the claimed nucleic acid molecule. Accordingly, claim 56 lacks antecedent basis for the term “the AAV capsid.” It would be remedial to amend the instant claims such that there is sufficient antecedent basis for each and every claim term, for example by reciting “an AAV capsid” prior to reciting “the AAV capsid” or by reciting “an AAV capsid.”
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 5, 15, 16, 45, 46, and 57 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS).
With regard to claim 1, which recites “a recombinant adeno-associated virus (rAAV) comprising an adeno-associated virus (AAV) capsid and a vector genome, wherein the vector genome comprises an AAV 5’ inverted terminal repeat (ITR), an expression cassette, and an AAV 3’ ITR, wherein the expression cassette comprises an engineered nucleic acid sequence encoding for a functional human N-sulfoglycosamine sulfohydrolase (hSGSH), wherein the hSGSH coding sequence comprises a signal peptide sequence and a mature hSGSH coding sequence,l wherein the mature hSGSH coding [sequence] has the nucleic acid sequence of SEQ ID NO: 16 or a nucleic acid sequence which is (a) at least 85% identical to SEQ ID NO: 16…wherein the hSGSH coding sequence is operably linked to regulatory control sequences which direct expression of the hSGSH in a cell,” Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix), meeting the instant limitation of at least 85% identity to instant SEQ ID NO: 16. Miller further discloses that this transgene is delivered as part of an rAAV vector comprising an AAV capsid, two ITRs, and a vector genome (paragraphs [0077], [0079], [0092], [0097], and [00123]). Furthermore, control of the transgene is disclosed to be imparted by regulatory elements within the AAV vector, which may also include a signal peptide (paragraph [00117]).
With regard to claim 4, which recites “the mature hSGSH coding sequence [of the rAAV according to claim 1] has the nucleic acid sequence of SEQ ID NO: 16 or a nucleic acid sequence which is [at least-(see section Claim Objections)] 85% identical to SEQ ID NO: 16,” as set forth above, Miller discloses SEQ ID NOs: 100 and 101, which encode codon optimized hSGSH (Table 4) and are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix).
With regard to claim 5, which recites “the signal peptide sequence [of the rAAV according to claim 1] is a native signal sequence having [the] nucleic acid sequence of SEQ ID NO: 31 or a sequence at least about 95% identical thereto which encodes SEQ ID NO: 32,” as shown in the alignments of the Appendix, SEQ ID NOs: 100 and 101 comprise 85.2% identity to instant SEQ ID NO: 31. The Examiner notes that the instant claim language of “at least about 95% identical thereto” has been interpreted in light of the definition in the specification. Per the instant specification, the term “about” refers to a variant of + 10% from the reference integer and values therebetween (page 63, lines 32-33). Therefore, the recitation of “at least about 95%” is not indefinite but does embrace values ranging from 85%-100% sequence identity.
With regard to claim 15, which recites “the regulatory control sequences [of the rAAV according to claim 1] further comprise one or more of a Kozak sequence, an intron, an enhancer, a TATA signal and a polyA sequence,” as set forth above, Miller anticipates the rAAV of instant claim 1. Miller further discloses that the rAAV taught therein comprises a chicken beta actin intron (paragraph [00200]).
With regard to claim 16, which recites “the regulatory control sequences [of the rAAV according to claim 15] comprise one or more of a chicken beta actin intron, [and] a rabbit globin polyadenylation sequence,” as set forth above, Miller further discloses that the rAAV taught therein comprises a chicken beta actin intron (paragraph [00200]).
With regard to claim 45, which recites “a pharmaceutical composition comprising a[n] rAAV according to claim 1 in a formulation buffer,” as set forth above, Miller anticipates each and every limitation of instant claim 1. Miller further discloses that the rAAVs taught therein may be formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier (which reads on the instantly claimed formulation buffer) for therapeutic delivery thereof (paragraphs [0084], [0085], and [00141]-[00145]).
With regard to claim 46, which reciters “the pharmaceutical composition according to claim 45, which is formulated for delivery via intracerebroventricular (IVC), intrathecal (IT), intracisternal or intravenous (IV) injection,” as set forth above, Miller discloses the pharmaceutical composition of instant claim 45. Miller further discloses that the viral particles (and therefore pharmaceutical compositions comprising the same) may be introduced to the subject intravenously, intrathecally, intraventricularly, or intracisternally (paragraph [00166]).
With regard to claim 57, which recites “an rAAV system useful for producing the rAAV according to…[claim 1 (see section Claim Objections)]…wherein the production system comprises a cell culture comprising:
a nucleic acid sequence encoding a[n] AAV capsid protein;
a vector genome; and
sufficient AAV rep functions and helper functions to permit packaging of the vector genome into the AAV capsid,”
as set forth above, Miller anticipates the rAAV of claim 1. Miller further discloses that viral vectors may be made by using a standard triple-transfection method known in the art, wherein three separate plasmids expressing the viral capsid protein, helper proteins (Rep and Cap proteins), and the transgene of interest are transfected into adherent or suspension 293 cells, and viral particles are later harvested using ultracentrifugation or chromatography followed by diafiltration/ultrafiltration and terminal sterile filtration (paragraph [00178]).
Claims 57 and 58 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/223231 A1 (hereinafter Nambiar; as cited in Applicant IDS).
With regard to claim 57, which recites “an rAAV production system useful for producing the rAAV according to any of claims [sic] 1, wherein the production system comprises a cell culture comprising:
a nucleic acid sequence encoding a[n] AAV capsid protein;
a vector genome; and
sufficient AAV rep functions and helper functions to permit packaging of the vector genome into the AAV capsid,”
the Examiner notes that the preamble of instant claim 57 is drawn to intended use (i.e. useful for producing the rAAV of claim 1), but instant claim 57 does not require the rAAV of instant claim 1. Accordingly, any rAAV production system reading on the claimed system components must anticipate the rAAV production system claimed herein. Nambiar discloses such a system, wherein said system comprises a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 2 (which is an AAV capsid protein corresponding to AAVrh.91 per page 1, line 30), a nucleic acid molecule suitable for packaging into an AAV capsid, wherein the nucleic acid molecule comprises at least one AAV inverted terminal repeat and a non-AAV nucleic acid sequence encoding a gene product operably linked to sequences which direct expression of the product in a host cell (i.e. a vector genome), and sufficient AAV rep functions and helper functions to permit packaging of the nucleic acid molecule into the rAAV capsid (page 3, lines 4-16).
With regard to claim 58, which recites “the AAV capsid [of the rAAV production system according to claim 57] is selected from a[n] AAVhu68 and AAVrh91,” as set forth above, Nambiar discloses the rAAV production system of instant claim 57, wherein the capsid of the rAAVs produced by said system is rh91 (page 1, line 30; page 3, lines 4-16).
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14, 17, and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS) as applied to claim 1 above, and further in view of US 2020/0291429 A1 (hereinafter Wilson), WO 2019/195729 A1 (hereinafter Girard), and WO 2020/223231 A1 (hereinafter Nambiar; as cited in Applicant IDS), as evidenced by WO 2018/160582 A1 (hereinafter Pennsylvania; as cited in Applicant IDS).
The disclosure of Miller is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the regulatory control sequences of instant claims 14 and 17 or the capsids of instant claims 39-41.
With regard to claim 14, which recites “the regulatory control sequences [of the rAAV according to claim 1] comprise a CMV IE enhancer, a chicken-beta actin (CB) promoter, and a chicken beta actin intron,” as set forth above, Miller discloses the rAAV of instant claim 1. Miller further discloses that said rAAV comprises a CMV enhancer (paragraphs [0060] and [0061]), a chicken beta actin promoter (paragraph [00120]), and a CBA intron (paragraph [00200]). However, Miller is silent as to specifically a CMV IE enhancer, as instantly claimed. This deficiency is cured by Wilson. Wilson discloses rAAVs comprising an AAV capsid and a vector genome packaged therein, wherein the vector genome comprises and AAV 5’ ITR, an engineered nucleic acid sequence encoding a functional hSGSH, a regulatory sequence which directs expression of hSGSH in a target cell, and an AAV 3’ ITR (abstract). Wilson further discloses that such regulatory sequences include the CMV IE enhancer (paragraphs [0058] and [0060]), as instantly claimed. Thus, the disclosure of Wilson establishes the utility of the CMV immediate-early enhancer in driving expression of hSGSH in a target cell, as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 14. Although Wilson discloses the CMV IE enhancer in the context of a hybrid promoter, this hybrid promoter nonetheless comprises the CMV IE enhancer.
With regard to claim 17, which recites “the regulatory control sequences [of the rAAV according to claim 1] further comprise a mutant WPRE element,” as set forth above, Miller discloses the rAAV of instant claim 1. Miller further discloses that said rAAV comprises a WPRE element (paragraph [00121]). However, Miller is silent as to the “mutant” WPRE element, as instantly claimed. This deficiency is cured by Girard. Girard discloses (in part) pharmaceutical compositions comprising rAAVs for the treatment of disease (abstract), wherein said rAAVs comprise a post-transcriptional regulatory element (PRE) such as WPRE (paragraph [0142]). Girard further discloses that the WPRE is important for high-level expression of native mRNA transcripts and that the WPRE may be modified to prevent expression of the viral X antigen by ablation of the translation initiation site (paragraph [0142]). Thus, it is considered that Girard discloses each and every additional limitation of instant claim 17.
With regard to claim 39, which recites “the AAV capsid [of the rAAV according to claim 1] is a Clade F AAV,” as set forth above, Miller discloses the rAAV of instant claim 1. However, Miller is silent as to the clade of the AAV capsids taught therein. This deficiency is cured by Wilson, which discloses which discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids are derived from Clade F AAVs, including AAVhu68 (paragraph [0080]). Wilson invokes Pennsylvania, which teaches that AAVhu68 is derived from Clade F AAVs (page 10, lines 32-33). Thus, it is considered that Wilson, as evidenced by Pennsylvania, discloses each and every additional limitation of instant claim 39.
With regard to claim 40, which recites “the AAV capsid [of the rAAV according to claim 1] is AAV hu68,” as set forth above, Miller discloses the rAAV of instant claim 1. However, Miller is silent as to the instantly claimed AAVhu68 capsid. This deficiency is cured by Wilson, which discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 40.
With regard to claim 41, which recites “the AAV capsid [of the rAAV according to claim 1] is AAVrh91,” as set forth above, Miller discloses the rAAV of instant claim 1. However, Miller is silent as to the instantly claimed AAVrh91 capsid. This deficiency is cured by Nambiar, which discloses that the rh91 capsid is well-suited for delivery of therapeutic rAAVs to the central nervous system (page 6, lines 3-9). Thus, it is considered that Nambiar discloses each and every additional limitation of instant claim 41.
Given that Miller discloses the rAAV of instant claim 1 (as set forth above), that Wilson also discloses therapeutic rAAVs encoding hSGSH for delivery thereof, wherein said rAAVs comprise a CMV IE enhancer and an AAVhu68 capsid derived from Clade F of AAV, Girard discloses that mutant WPRE elements eliminating expression of the viral X antigen are useful for promoting high-level expression, and that Nambiar discloses that the AAVrh91 capsid is well-suited for delivery of therapeutic rAAVs to the central nervous system, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the rAAV taught in Miller to specifically comprise the CMV IE enhancer (based on the disclosure of Wilson), as well as an AAV capsid derived from Clade F such as AAVhu68 (as disclosed in Wilson) or even AAVrh91, which is well-suited to central nervous system delivery (as disclosed in Nambiar), as well as to specifically comprise the mutant WPRE taught in Girard to predictably generate a therapeutic rAAV capable of being expressed at high levels and being delivered to the central nervous system. One would have been motivated to make such a modification in order to receive the expected benefit of expressing the transgene of the rAAV at high levels and delivering the same to the central nervous system.
Claims 47 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS) as applied to claims 1, 45, and 57 above, and further in view of US 2020/0291429 A1 (hereinafter Wilson).
The disclosure of Miller is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the dosage of instant claim 47 or the capsids of instant claim 58.
With regard to claim 47, which recites “the pharmaceutical composition according to claim 45, which is administrable at a dose [of] 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass,” as set forth above, Miller discloses the pharmaceutical composition of instant claim 45. However, Miller is silent as to the instantly claimed dosages. This deficiency is cured by Wilson, which discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that such rAAV vectors may be administered at a dose of about 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass (paragraph [0122]) to treat MPS IIIA (paragraph [0008]), as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 47.
With regard to claim 58, which recites “the AAV capsid [of the rAAV production system of claim 57] is selected from a[n] AAVhu68 and AAVrh91,” as set forth above, Miller discloses the rAAV production system of instant claim 57. However, Miller is silent as to the instantly claimed capsid species. This deficiency is cured by Wilson. Wilson discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 58.
Given that Miller discloses the rAAV of instant claim 1 (as set forth above), and that Wilson discloses therapeutic rAAVs for the treatment of MPS IIIA comprising capsid AAVhu68, wherein said treatment is administered at a dose of about 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the rAAV of Miller to comprise capsid AAVhu68 (as disclosed in Wilson) and provide the same at the dosages disclosed in WIlson to predictably provide an effective dose of a therapeutic rAAV encoding hSGSH MPS IIIA in patients in need thereof. One would have been motivated to make such a modification in order to receive the expected benefit of providing an effective dose of a therapeutic rAAV encoding hSGSH MPS IIIA in patients in need thereof.
Claims 2-4, 51, 54, 55, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS) as applied to claim 1 above, and further in view of US 2017/0191040 A1 (hereinafter Radin), WO 2021/216975 A1 (hereinafter Ramu), Gascon et al., 2020 (hereinafter Gascon), and Gould et al., 2014 (hereinafter Gould).
The disclosure of Miller is described above and applied as before (see section Claim Rejections - 35 USC § 102). However, this disclosure does not teach the specific sequences of instant claims 2-4 and 61.
With regard to claims 2-4, which respectively recite “the mature hSGSH coding sequence [of the rAAV according to claim 1] is 99% identical to SEQ ID NO: [16 (see section Claim Rejections - 35 USC § 112(b))],” “the mature hSGSH coding sequence is SEQ ID NO: 16,” and “the mature hSGSH coding sequence has the nucleic acid sequence of…SEQ ID NO: 16 or a nucleic acid sequence which is 85% identical to SEQ ID NO: 16,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix). SEQ ID NOs: 100 and 101 of Miller are disclosed to be codon-optimized at Table 4. However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 16.
SEQ ID NO: 16 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 16.
With regard to claim 61, which recites “the mature hSGSH coding sequence [of the rAAV according to claim 1] is SEQ ID NO: 35,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 96.7% and 96.8% identical to instant SEQ ID NO: 35 (see Appendix). SEQ ID NOs: 100 and 101 of Miller are disclosed to be codon-optimized at Table 4. However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 35.
SEQ ID NO: 35 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 35.
With regard to claim 51, which recites “ a nucleic acid molecule comprising an expression cassette comprising an engineered functional human N-sulfoglycoasmine sulfohydrolase (hSGSH) gene and regulatory control sequences, said expression cassette being flanked by a 5’ inverted terminal repeat (ITR) and a 3’ ITR, wherein the engineered hSGS[H] gene encodes a functional hSGSH, wherein the hSGSH coding sequence comprises a signal peptide sequence and a mature hSGSH, and wherein the mature hSGSH-coding sequence is SEQ ID NO: 16,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix). Miller further discloses that this transgene is delivered as part of an rAAV vector comprising an AAV capsid, two ITRs, and a vector genome comprising an expression cassette (paragraphs [0077], [0079], [0092], [0097], [00123], and [00125]). Furthermore, control of the transgene is disclosed to be imparted by regulatory elements within the AAV vector (comprising an expression cassette), which may also include a signal peptide (paragraph [00117]). However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 16.
SEQ ID NO: 16 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 16.
With regard to claim 54, which recites “a packaging host cell comprising a nucleic acid molecule according to claim 51,” as set forth above, Miller, Radin, Ramu, Gascon, and Gould render the nucleic acid molecule of claim 51 obvious. Miller further discloses packaging cells used to produce the viral vectors taught therein, said packaging cells comprising the AAV helper plasmid and AAV vector taught therein (paragraphs [0081] and [00140]), which itself comprises an expression cassette as set forth above (see for example paragraphs [00123], [00125], [00189], and [00190]).
With regard to claim 55, which recites “the packaging host cell according to claim 54 which further comprises AAV rep coding sequences operably linked to sequences which express rep protein in the packaging host cell, an AAV capsid coding sequences [sic] operably linked to sequences which express AAV capsid proteins in the packaging host cell, and helper virus functions necessary to permit packaging of the expression cassette and ITRs into the AAV capsid,” as set forth above Miller, Radin, Ramu, Gascon, and Gould render the packaging host cell of claim 54 obvious. Miller further discloses packaging cells used to produce the viral vectors taught therein, wherein said packaging cells provide Rep and Cap proteins in trans, as well as gene sequences from Adenovirus that help AAV replicate (paragraph [0081]). As set forth above, the rAAV vectors of Miller comprise ITRs (paragraphs [0077], [0079], [0092], [0097], [00123], and [00125]). Thus, the packaging cell line for producing said rAAV vectors must permit packaging of the expression cassette and ITRs taught therein into the AAV capsid taught therein, as instantly claimed.
Given that Miller discloses a therapeutic rAAV comprising an open reading frame encoding codon-optimized hSGSH, as well as packaging cells for producing said rAAV; that Radin and Ramu both disclose codon optimized reading frames encoding hSGSH, wherein the encoded amino acid sequence comprises 100% identity to that of instant SEQ ID NOs: 16 and 35; that Gascon discloses that codon optimization of human sulfamidase maximizes its efficiency in expression and translation for medicinal applications; and that Gould discloses in silico tools for codon-optimization, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to codon optimize the open reading frame of hSGSH (or sulfamidase as referred in Gascon) disclosed in Miller per the methods of Gould to predictably maximize expression and translation thereof for therapeutic benefit, as well as to predictably package said hSGSH open reading frame into an rAAV using packaging cells as taught in Miller. One would have been motivated to make such a modification in order to receive the expected benefit of maximize expression and translation of hSGSH from rAAVs (produced by packaging cells) for therapeutic benefit.
Claim 56 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS) in view of US 2017/0191040 A1 (hereinafter Radin), WO 2021/216975 A1 (hereinafter Ramu), Gascon et al., 2020 (hereinafter Gascon), and Gould et al., 2014 (hereinafter Gould), as applied to claims 1 and 54 above, and further in view of US 2020/0291429 A1 (hereinafter Wilson).
The combined disclosures of Miller, Radin, Ramu, Gascon, and Gould are described above and applied as before. However, these disclosures do not teach the capsid of instant claim 56.
With regard to claim 56, which recites “the packaging host cell according to claim 54, wherein the AAV capsid is selected from a AAVhu68 and AAVrh91,” as set forth above, Miller, Radin, Ramu, Gascon, and Gould collectively render the packaging host cell of claim 54 obvious. However, these disclosures are silent to the instantly claimed capsid. This deficiency is cured by Wilson. Wilson discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 56.
Given that Miller, Radin, Ramu, Gascon, and Gould collectively disclose the packaging host cell of instant claim 54, and that Wilson discloses that suitable capsids for delivering hSGSH include AAVhu68, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to package the rAAV collectively disclosed by Miller, Radin, Ramu, Gascon, and Gould into an AAVhu68 capsid (as disclosed in Wilson) to predictably generate an rAAV capable of delivering the therapeutic hSGSH to a patient in need thereof. One would have been motivated to make such a modification in order to receive the expected benefit of generating an rAAV capable of delivering the therapeutic hSGSH to a patient in need thereof.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 14-17, 39-41, 45-47, 57-58, 60, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 9, 11, 12, and 14 of U.S. Patent No. 11,555,206 B2 in view of WO 2020/117898 A1 (hereinafter Miller; as cited in Applicant IDS), US 2020/0291429 A1 (hereinafter Wilson), WO 2019/195729 A1 (hereinafter Girard), WO 2020/223231 A1 (hereinafter Nambiar; as cited in Applicant IDS), US 2017/0191040 A1 (hereinafter Radin), WO 2021/216975 A1 (hereinafter Ramu), Gascon et al., 2020 (hereinafter Gascon), and Gould et al., 2014 (hereinafter Gould), as evidenced by Vandenberghe et al., 2004 (hereinafter Vandenberghe).
Patent ‘206 is drawn to an rAAV comprising an AAV capsid and a vector genome packaged therein, wherein the vector genome comprises AAV 3’ and 5’ ITRs, an engineered nucleic acid sequence encoding a function hSGSH (corresponding to patented SEQ ID NO: 1) and a regulatory sequence directing expression of the same (recited at patented claim 1).
Patented claims 3-6 further recite that the regulatory sequence claimed therein comprises a promoter, an enhancer, an intron, or a polyA.
Patented claim 8 further recites that the AAV capsid is an AAV9 capsid, which is a Clade F capsid per Vandenberghe (see entire abstract).
Patented claim 9 further recites “a composition comprising a[n] rAAV according to claim 1 in a formulation buffer,” which may be formulated for intracerebroventricular delivery, intrathecal delivery, intracisternal delivery, or intravenous injection per patented claim 11. Furthermore, said composition may be delivered at a dose of 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass per patented claim 12.
Finally, patented claim 14 recites “a method of treating a human subject diagnosed with MPS IIIA and/or improving gait or mobility, reducing tremors, reducing spasms, improving posture, or reducing the progression of vision loss in a subject in need thereof, comprising administering to the subject a suspension of a[n] rAAV according to claim 1 in a formulation buffer at a dose of 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass.
While patent ‘206 is drawn to SEQ ID NO: 1 and the instant application is drawn to SEQ ID NO: 16 (or variants at least 85% identical thereto per instant claim 1), as set forth above, Miller anticipates the rAAV of instant claim 1. As set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix), meeting the instant limitation of at least 85% identity to instant SEQ ID NO: 16. Miller further discloses that this transgene is delivered as part of an rAAV vector comprising an AAV capsid, two ITRs, and a vector genome (paragraphs [0077], [0079], [0092], [0097], and [00123]). Furthermore, control of the transgene is disclosed to be imparted by regulatory elements within the AAV vector, which may also include a signal peptide (paragraph [00117]). Given that Miller discloses an hSGSH sequence reading on the instantly claimed hSGSH sequence, it is considered that it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to substitute the hSGSH coding sequence disclosed in Miller for the hSGSH coding sequence of the patented application, rendering the patented application and the instant application not patentably distinct, as instant claim 1 is otherwise identical to the recitation of patented claim 1.
With regard to claims 2-4, which respectively recite “the mature hSGSH coding sequence [of the rAAV according to claim 1] is 99% identical to SEQ ID NO: [16 (see section Claim Rejections - 35 USC § 112(b))],” “the mature hSGSH coding sequence is SEQ ID NO: 16,” and “the mature hSGSH coding sequence has the nucleic acid sequence of…SEQ ID NO: 16 or a nucleic acid sequence which is 85% identical to SEQ ID NO: 16,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix). SEQ ID NOs: 100 and 101 of Miller are disclosed to be codon-optimized at Table 4. However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 16.
SEQ ID NO: 16 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 16.
With additional regard to claim 4, which recites “the mature hSGSH coding sequence [of the rAAV according to claim 1] has the nucleic acid sequence of SEQ ID NO: 16 or a nucleic acid sequence which is 85% identical to SEQ ID NO: 16,” as set forth above, Miller discloses SEQ ID NOs: 100 and 101, which encode codon optimized hSGSH (Table 4) and are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix). Thus, it is considered that Miller discloses each and every limitation of instant claim 4.
With regard to claim 5, which recites “the signal peptide sequence [of the rAAV according to claim 1] is a native signal sequence having [the] nucleic acid sequence of SEQ ID NO: 31 or a sequence at least about 95% identical thereto which encodes SEQ ID NO: 32,” as shown in the alignments of the Appendix, SEQ ID NOs: 100 and 101 comprise 85.2% identity to instant SEQ ID NO: 31. The Examiner notes that the instant claim language of “at least about 95% identical thereto” has been interpreted in light of the definition in the specification. Per the instant specification, the term “about” refers to a variant of + 10% from the reference integer and values therebetween (page 63, lines 32-33). Therefore, the recitation of “at least about 95%” is not indefinite but does embrace values ranging from 85%-100% sequence identity. Thus, it is considered that Miller discloses each and every limitation of instant claim 5.
With regard to claim 14, which recites “the regulatory control sequences [of the rAAV according to claim 1] comprise a CMV IE enhancer, a chicken-beta actin (CB) promoter, and a chicken beta actin intron,” as set forth above, Miller discloses the rAAV of instant claim 1. Miller further discloses that said rAAV comprises a CMV enhancer (paragraphs [0060] and [0061]), a chicken beta actin promoter (paragraph [00120]), and a CBA intron (paragraph [00200]). However, Miller is silent as to specifically a CMV IE enhancer, as instantly claimed. This deficiency is cured by Wilson. Wilson discloses rAAVs comprising an AAV capsid and a vector genome packaged therein, wherein the vector genome comprises and AAV 5’ ITR, an engineered nucleic acid sequence encoding a functional hSGSH, a regulatory sequence which directs expression of hSGSH in a target cell, and an AAV 3’ ITR (abstract). Wilson further discloses that such regulatory sequences include the CMV IE enhancer (paragraphs [0058] and [0060]), as instantly claimed. Thus, the disclosure of Wilson establishes the utility of the CMV immediate-early enhancer in driving expression of hSGSH in a target cell, as instantly claimed. Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 14. Although Wilson discloses the CMV IE enhancer in the context of a hybrid promoter, this hybrid promoter nonetheless comprises the CMV IE enhancer. The Examiner notes that both a promoter and enhancer are also recited at patented claims 3 and 4.
With regard to claim 15, which recites “the regulatory control sequences [of the rAAV according to claim 1] further comprise one or more of a Kozak sequence, an intron, an enhancer, a TATA signal and a polyA sequence,” as set forth above, Miller anticipates the rAAV of instant claim 1. Miller further discloses that the rAAV taught therein comprises a chicken beta actin intron (paragraph [00200]). Thus, it is considered that Miller discloses each and every limitation of instant claim 15. The Examiner notes that an intron is also recited at patented claim 5. Furthermore, Wilson discloses that the constructs taught therein further comprise a rabbit polyA sequence (paragraph [0062]). The Examiner notes that such polyA sequences are also recited at patented claim 6.
With regard to claim 16, which recites “the regulatory control sequences [of the rAAV according to claim 15] comprise one or more of a chicken beta actin intron, [and] a rabbit globin polyadenylation sequence,” as set forth above, Miller further discloses that the rAAV taught therein comprises a chicken beta actin intron (paragraph [00200]). Thus, it is considered that Miller discloses each and every limitation of instant claim 16. The Examiner notes that an intron is also recited at patented claim 5.
With regard to claim 17, which recites “the regulatory control sequences [of the rAAV according to claim 1] further comprise a mutant WPRE element,” as set forth above, Miller discloses the rAAV of instant claim 1. Miller further discloses that said rAAV comprises a WPRE element (paragraph [00121]). However, Miller is silent as to the “mutant” WPRE element, as instantly claimed. This deficiency is cured by Girard. Girard discloses (in part) pharmaceutical compositions comprising rAAVs for the treatment of disease (abstract), wherein said rAAVs comprise a post-transcriptional regulatory element (PRE) such as WPRE (paragraph [0142]). Girard further discloses that the WPRE is important for high-level expression of native mRNA transcripts and that the WPRE may be modified to prevent expression of the viral X antigen by ablation of the translation initiation site (paragraph [0142]). Thus, it is considered that Girard discloses each and every additional limitation of instant claim 17.
With regard to claim 39, which recites “the AAV capsid [of the rAAV according to claim 1] is a Clade F AAV,” as set forth above, patented claim 8 further recites that the AAV capsid is an AAV9 capsid, which is a Clade F capsid per Vandenberghe (see entire abstract).
With regard to claim 40, which recites “the AAV capsid [of the rAAV according to claim 1] is AAV hu68,” as set forth above, Miller discloses the rAAV of instant claim 1. However, Miller is silent as to the instantly claimed AAVhu68 capsid. This deficiency is cured by Wilson, which discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 40.
With regard to claim 41, which recites “the AAV capsid [of the rAAV according to claim 1] is AAVrh91,” as set forth above, Miller discloses the rAAV of instant claim 1. However, Miller is silent as to the instantly claimed AAVrh91 capsid. This deficiency is cured by Nambiar, which discloses that the rh91 capsid is well-suited for delivery of therapeutic rAAVs to the central nervous system (page 6, lines 3-9). Thus, it is considered that Nambiar discloses each and every additional limitation of instant claim 41.
With regard to claim 45, which recites “a pharmaceutical composition comprising a[n] rAAV according to claim 1 in a formulation buffer,” as set forth above, patented claim 9 recites identical limitations. While the sequences of the two compositions differ, Miller cures this deficiency by disclosing SEQ ID NOs: 100 and 101 (Table 4), as set forth above. Furthermore, Miller discloses that the rAAVs taught therein may be formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier (which reads on the instantly claimed formulation buffer) for therapeutic delivery thereof (paragraphs [0084], [0085], and [00141]-[00145]). Thus, it is considered that Miller also discloses each and every limitation of instant claim 45.
With regard to claim 46, which reciters “the pharmaceutical composition according to claim 45, which is formulated for delivery via intracerebroventricular (IVC), intrathecal (IT), intracisternal or intravenous (IV) injection,” as set forth above, these limitations are also recited at patented claim 9.
With regard to claim 47, which recites “the pharmaceutical composition according to claim 45, which is administrable at a dose [of] 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass,” as set forth above, these limitations are also recited at patented claim 12.
With regard to claim 51, which recites “ a nucleic acid molecule comprising an expression cassette comprising an engineered functional human N-sulfoglycoasmine sulfohydrolase (hSGSH) gene and regulatory control sequences, said expression cassette being flanked by a 5’ inverted terminal repeat (ITR) and a 3’ ITR, wherein the engineered hSGS[H] gene encodes a functional hSGSH, wherein the hSGSH coding sequence comprises a signal peptide sequence and a mature hSGSH, and wherein the mature hSGSH-coding sequence is SEQ ID NO: 16,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 97.4% and 97.3% identical to instant SEQ ID NO: 16 (see Appendix). Miller further discloses that this transgene is delivered as part of an rAAV vector comprising an AAV capsid, two ITRs, and a vector genome comprising an expression cassette (paragraphs [0077], [0079], [0092], [0097], [00123], and [00125]). Furthermore, control of the transgene is disclosed to be imparted by regulatory elements within the AAV vector (comprising an expression cassette), which may also include a signal peptide (paragraph [00117]). However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 16.
SEQ ID NO: 16 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 16.
With regard to claim 54, which recites “a packaging host cell comprising a nucleic acid molecule according to claim 51,” as set forth above, Miller, Radin, Ramu, Gascon, and Gould render the nucleic acid molecule of claim 51 obvious. Miller further discloses packaging cells used to produce the viral vectors taught therein, said packaging cells comprising the AAV helper plasmid and AAV vector taught therein (paragraphs [0081] and [00140]), which itself comprises an expression cassette as set forth above (see for example paragraphs [00123], [00125], [00189], and [00190]).
With regard to claim 55, which recites “the packaging host cell according to claim 54 which further comprises AAV rep coding sequences operably linked to sequences which express rep protein in the packaging host cell, an AAV capsid coding sequences [sic] operably linked to sequences which express AAV capsid proteins in the packaging host cell, and helper virus functions necessary to permit packaging of the expression cassette and ITRs into the AAV capsid,” as set forth above Miller, Radin, Ramu, Gascon, and Gould render the packaging host cell of claim 54 obvious. Miller further discloses packaging cells used to produce the viral vectors taught therein, wherein said packaging cells provide Rep and Cap proteins in trans, as well as gene sequences from Adenovirus that help AAV replicate (paragraph [0081]). As set forth above, the rAAV vectors of Miller comprise ITRs (paragraphs [0077], [0079], [0092], [0097], [00123], and [00125]). Thus, the packaging cell line for producing said rAAV vectors must permit packaging of the expression cassette and ITRs taught therein into the AAV capsid taught therein, as instantly claimed.
With regard to claim 56, which recites “the packaging host cell according to claim 54, wherein the AAV capsid is selected from a AAVhu68 and AAVrh91,” as set forth above, Miller, Radin, Ramu, Gascon, and Gould collectively render the packaging host cell of claim 54 obvious. However, these disclosures are silent to the instantly claimed capsid. This deficiency is cured by Wilson. Wilson discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 56.
With regard to claim 57, which recites “an rAAV system useful for producing the rAAV according to…[claim 1 (see section Claim Objections)]…wherein the production system comprises a cell culture comprising:
a nucleic acid sequence encoding a[n] AAV capsid protein;
a vector genome; and
sufficient AAV rep functions and helper functions to permit packaging of the vector genome into the AAV capsid,”
as set forth above, Miller anticipates the rAAV of claim 1. Miller further discloses that viral vectors may be made by using a standard triple-transfection method known in the art, wherein three separate plasmids expressing the viral capsid protein, helper proteins (Rep and Cap proteins), and the transgene of interest are transfected into adherent or suspension 293 cells, and viral particles are later harvested using ultracentrifugation or chromatography followed by diafiltration/ultrafiltration and terminal sterile filtration (paragraph [00178]). Thus, it is considered that Miller discloses each and every limitation of instant claim 57.
With regard to claim 58, which recites “the AAV capsid [of the rAAV production system of claim 57] is selected from a[n] AAVhu68 and AAVrh91,” as set forth above, Miller discloses the rAAV production system of instant claim 57. However, Miller is silent as to the instantly claimed capsid species. This deficiency is cured by Wilson. Wilson discloses rAAV vectors encoding hSGSH, as set forth above (abstract). Wilson further discloses that suitable capsids include AAVhu68 (paragraph [0080]). Thus, it is considered that Wilson discloses each and every additional limitation of instant claim 58.
With regard to claim 60, which recites “a method of treating a human subject diagnosed with MPS IIIA and/or improving gait or mobility, reducing tremors, reducing spasms, improving posture, or reducing the progression of vision loss in a subject in need thereof, comprising administering to the subject a suspension of a[n] rAAV according to claim 1 in a formulation buffer at a dose of 1 x 109 GC per gram of brain mass to about 1 x 1013 GC per gram of brain mass,” patent ‘206 recites identical limitations at patented claim 14.
With regard to claim 61, which recites “the mature hSGSH coding sequence [of the rAAV according to claim 1] is SEQ ID NO: 35,” as set forth above, Miller discloses delivery of transgenes at Table 4, including codon optimized SGSH corresponding to SEQ ID NOs: 100 and 101, which are respectively 96.7% and 96.8% identical to instant SEQ ID NO: 35 (see Appendix). SEQ ID NOs: 100 and 101 of Miller are disclosed to be codon-optimized at Table 4. However, Miller is silent as to a sequence comprising 100% identity to instant SEQ ID NO: 35.
SEQ ID NO: 35 encodes mature hSGSH, which comprises an amino acid sequence that is 100% identical to the hSGSH amino acid sequence disclosed in Radin (SEQ ID NO: 39 taught therein at Table 6-see Appendix) and Ramu (SEQ ID NO: 18 taught therein at page 25-see Appendix). Both Radin and Ramu disclose that the sequences taught therein may be codon optimized for improved expression, such as in a plant (paragraphs [0006] and [0052] of Radin) or in a human cell (page 72 of Ramu). Such codon optimization of hSGSH is known in the art. Gascon discloses a medicinal product for the treatment of MPSIIIA, wherein said medicinal product comprises the cDNA of the human sulfamidase gene with codon optimization in order to maximize its efficiency in expression and translation of the human sulfamidase protein, which has yielded robust results in preclinical efficacy studies (page 390, column 1, paragraph 2; page 390, column 2, paragraph 1; page 391, column 2, paragraph 2). Methods of codon optimization are known in the art.
Gould discloses in silico tools for codon-optimization (Table 1). Such tools include web-based applications, tools that allow for user-based preference in designing a codon-optimized sequence based on various factors, including codon context bias, RNA secondary structure, specific codon and/or motif preference, and others (Table 2; pages 2-4). Thus, Gould discloses a finite number of platforms that can be utilized to codon-optimize the open reading frame of hSGSH, thereby producing a finite number of codon-optimized hSGSH open reading frames, including instant SEQ ID NO: 35.
Given that Miller discloses an hSGSH sequence reading on the instantly claimed hSGSH sequence, it is considered that it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to substitute the hSGSH coding sequence disclosed in Miller for the hSGSH coding sequence of the patented application, rendering the patented application and the instant application not patentably distinct, as instant claim 1 is otherwise identical to the recitation of patented claim 1.
Furthermore, given that Miller discloses a therapeutic rAAV comprising an open reading frame encoding codon-optimized hSGSH, as well as packaging cells for producing said rAAV; that Radin and Ramu both disclose codon optimized reading frames encoding hSGSH, wherein the encoded amino acid sequence comprises 100% identity to that of instant SEQ ID NOs: 16 and 35; that Gascon discloses that codon optimization of human sulfamidase maximizes its efficiency in expression and translation for medicinal applications; and that Gould discloses in silico tools for codon-optimization, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to codon optimize the open reading frame of hSGSH (or sulfamidase as referred in Gascon) disclosed in Miller per the methods of Gould to predictably maximize expression and translation thereof for therapeutic benefit, as well as to predictably package said hSGSH open reading frame into an rAAV using packaging cells as taught in Miller. One would have been motivated to make such a modification in order to receive the expected benefit of maximize expression and translation of hSGSH from rAAVs (produced by packaging cells) for therapeutic benefit.
Finally, given that Wilson, Girard, and Nambiar respectively disclose suitable AAV capsids for use in therapeutic rAAVs to treat MPS IIIA, mutant WPRE sequences useful for therapeutic applications, and AAV capsids useful for treatment of the central nervous system, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to substitute the hSGSH coding sequence disclosed in Miller for the hSGSH coding sequence of the patented application, as well as to further design the rAAV of Miller per the teachings of Wilson, Girard, and Nambiar to predictably generate an rAAV useful for therapeutic applications in treating MPS IIIA, as in patent ‘206. One would have been motivated to make such a modification in order to receive the expected benefit of generating an rAAV useful for therapeutic applications in treating MPS IIIA, as in patent ‘206, thereby rendering the patented application and the instant application not patentably distinct.
Allowable Subject Matter
Claims 35, 36, 59, and 62 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims, as well as if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
Claims 35, 36, 59, and 62 all depend from rejected instant claims 1 or 57. However, the sequences recited at claims 35, 36, 59, and 62 are free of the prior art based on a thorough search of both the patent and non-patent literature. While individual portions of the instantly claimed vector sequences were known in the art prior to the effective filing date of the instant application, not all intervening sequences were known in the art and therefore, overall, the instantly claimed vector sequences are considered to be free of the prior art.
Conclusion
Claims 1-5, 14-17, 39-41, 45-47, 57-58, 60, and 61 are rejected.
Claims 35, 36, 59, and 62 are objected to.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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