DETAILED ACTION
Applicant’s response to the Restriction/Election of Species requirement received on 1/20/26 has been entered. Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 37, 42-44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are pending in the instant application.
Applicant’s election of Group I, and the species 1(c)-no splice or inactivated splice regulatory element, species 2(i)- insertion site 581-593, species RGDLSTP as the species of n-mer peptide, and species 4(b)-eukaryotic cell is acknowledged. The applicant does not state that the election of an invention or the election of species were made with traverse. While applicant does state that they disagree with the restriction between Groups I and II, they do not traverse the restriction requirement with any actual arguments. As such, applicant’s election of Group I and the elections of species set forth above are considered to have been made without traverse. However, upon further consideration, the election of species requirement for the n-mer peptide and the election of species requirement for the splice regulatory element are both withdrawn.
Claims 37 and 42-43 are therefore withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/20/26. Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are therefore currently under examination based on the species of an insertion site which is 581-593, and a cell which is a eukaryotic cell. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/11/22, 4/17/25 (4), and 1/20/26 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Claim Objections
Claims 15, 57, 62, and 71 are objected to because of the following informalities: claim 15 contains a grammatical error in which an extra comma is present between muscle cell and specificity; claim 57 has a typographical error which recites “as viral rep” instead of “a” viral rep”; claim 62 has a typographical error which reads “apolypeptide” instead of “a polypeptide”; claim 71 repeats the phrase “and combinations thereof” at the end of the claim. Appropriate correction is required.
Claim Interpretation
Claims 1, 4, 9, 21, 22, 25, 34, 44, 51, 57, 62, 65, 67, 70 and 71 all recite one or more limitations which are preceded by the term “optionally”. The term “optionally” has been interpreted as an alternative embodiment of the claim which is not required as it may or may not be present. As such, limitations following the term “optionally”, have been interpreted as embodiments which are not required elements of the claimed structures or methods. In so far as certain dependent claims further limit an feature which is optional in the claim upon which it depends, it is noted that unless the dependent claim specifically states that the optional element is required to be present in the composition or method, the dependent limitations are not required to meet the limitations of the parent claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 30, 61, and 70 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception which is a product of nature without significantly more.
Claim 30 recites a polypeptide which is produced by the vector of claim 1. Note that claim 1 recites a vector that encodes an AAV capsid protein. While claim 1 recites that the capsid may “optionally” be an engineered capsid, the use of the term “optionally” has been interpreted as an alternative embodiment which is not required. As such, the polypeptide encoded by the vector of claim 1 encompasses a wild type AAV capsid polypeptide, which is a naturally occurring polypeptide present in all naturally occurring AAV virions. Further, there is no evidence of record that expression of the AAV capsid polypeptide from the vector in any way changes the fundamental structure of the polypeptide such that it is markedly different than the AAV capsid polypeptide found in nature. In addition, this judicial exception is not integrated into a practical application as claim 30 is simply a product claim. The claim further does not include additional elements that are sufficient to amount to significantly more than the judicial exception because all that is required for claim 30 is the polypeptide.
Claim 61 recites a polypeptide which is produced by the vector system of claim 44. The vector system of claim 44 requires as an element a vector comprising a cell-specific capsid polynucleotide. The vector system of claim 44 further comprises a number of “optional” elements which are not required but which in an alternative embodiment may be present. One of these “optional” elements is a cargo that encodes a gene-modification molecule, a non-gene modification polypeptide, or a non-gene modification RNA. Thus, one of polypeptides produced by the vector system is a gene-modification molecule, or a non-gene modification polypeptide. Claim 61, therefore, encompasses any naturally occurring polypeptide which is involved in gene-modification, such as a nuclease, or any naturally occurring polypeptide that is not involved in gene modification, such as the vast majority of polypeptides encoded by and produced in a cell, such as insulin, cytokines, albumin, hemoglobin etc. Further, there is no evidence of record that expression of the polypeptide from the vector system in any way changes the fundamental structure of the polypeptide such that it is markedly different than the polypeptide found in nature. In addition, this judicial exception is not integrated into a practical application as claim 30 is simply a product claim. The claim further does not include additional elements that are sufficient to amount to significantly more than the judicial exception because all that is required for claim 61 is the polypeptide.
Claim 70 recites a pharmaceutical composition comprising a polypeptide produced by the vector system of claim 44. As discussed above in regards to claim 61, the vector system of claim 44 further comprises a number of “optional” elements which are not required but which in an alternative embodiment may be present. One of these “optional” elements is a cargo that encodes a gene-modification molecule, a non-gene modification polypeptide, or a non-gene modification RNA. Thus, one of polypeptides produced by the vector system is a gene-modification molecule, or a non-gene modification polypeptide. Claim 70, therefore, encompasses any naturally occurring polypeptide which is involved in gene-modification, such as a nuclease, or any naturally occurring polypeptide that is not involved in gene modification, such as the vast majority of polypeptides encoded by and produced in a cell, such as insulin, cytokines, albumin, hemoglobin etc. Further, there is no evidence of record that expression of the polypeptide from the vector system in any way changes the fundamental structure of the polypeptide such that it is markedly different from the polypeptide found in nature. In addition, this judicial exception is not integrated into a practical application as claim 70 is a product claim. The claim further does not include additional elements that are sufficient to amount to significantly more than the judicial exception because while the composition is referred to as “pharmaceutical” composition, the only other element in the composition is a pharmaceutically acceptable carrier, which the specification discloses may be water or a salt solution. However, water or a salt solution is not taught in either the prior art or the specification to affect the structure or functionality of the polypeptide and as such does not amount to significantly more.
Claim Rejections - 35 USC § 112
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 3-4, 67, 69-71 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 3 recites that the vector of claim 1 comprises “minimal splice elements”. The term “minimal” is relative term of degree. It is unclear what constitutes “minimal splice elements” in regards to the claimed vector. Are the “minimal splice elements” present in the vector only those naturally associated with an AAV capsid encoding sequence, such that the vector does not comprise additional splice regulatory elements, or does “minimal splice elements” encompass the presence of less than all the naturally occurring splice elements associated with an AAV capsid sequence, or perhaps “minimal splice element” denotes the presence of splice elements which are truncated or modified from a naturally occurring splice sequence. Thus, the metes and bounds of the claim cannot be determined as it is unclear what types or number of splice regulatory elements may be present in the vector to qualify as “minimal splice elements”. In the interests of compact prosecution, claim 3 has been given its broadest reasonable interpretation where the “minimal splice elements” may encompass the presence of splice elements in the AAV capsid encoding sequence which are necessary for AAV capsid splicing.
Claim 4 recites a vector of claim 1 further comprising “a modified splice regulatory element, wherein the modification inactivates the splice regulatory element, optionally wherein the modified splice regulatory element is a polynucleotide sequence sufficient to induce splicing between a rep protein polynucleotide and the capsid protein polynucleotide, and optionally wherein the polynucleotide sequence sufficient to induce splicing is a splice acceptor or a splice donor”. The optional limitation where the modified splice regulatory element is “sufficient to induce splicing” conflicts with the preceding limitation that the modification inactivates the splice regulatory element. Thus, the metes and bounds of the claim cannot be determined as it is unclear which types of modifications to the splice regulatory element are actually encompassed by the claims.
Claim 67 lacks proper antecedent basis for “the cargo polynucleotide”. Claim 67 depends on claim 65, which recites an engineered virus particle comprising a cell-specific capsid encoded by a cell-specific capsid polynucleotide of the vector system of claim 44. Claim 65, does not itself recite a “cargo polynucleotide”, and further does not include all the limitations of claim 44 as claim 65 only recites that the virus particle comprises a cell-specific capsid encoded by a cell-specific capsid polynucleotide of the vector system of claim 44. As such, antecedent basis in not present in claim 65 for “cargo polynucleotide”.
Claim 69 recites in part, “ a vector system as claim 44 in a cell”. This limitation is confusing as appears to be missing one or more words. As written, it is not clear what is meant by vector system “as claim 44” such that the metes and bounds of the claim cannot be determined. It is suggested that applicant amend claim 69 to recite, “as set forth in claim 44”.
Claims 70 and 71 recites in part, “an engineered virus particle a cell-specific capsid and optionally a cargo”. This phrasing is confusing as it is unclear whether the virus particle and the cell-specific capsid and optionally a cargo are all separate alternative of the claim missing the required punctuation, i.e. commas or semi-colons, between the elements, or whether the phrase is missing one or more words to indicate that the virus particle comprises the capsid and the cargo. As such, the metes and bounds of claims 70 and 71 cannot be determined.
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 2, 4, 9, 11-16, 18-20, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 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 an engineered AAV capsid polypeptide comprising an RGDnmer peptide selected from a peptide set forth in Tables 4, 5, or 6 inserted between amino acids 588-589 of wild type AAV9 or an equivalent position in a wild type AAV of a different serotype, where the encoded engineered AAV capsid exhibits increased tropism for muscle cells, a polynucleotide encoding the engineered AAV capsid, an AAV comprising said engineered capsid, a vector encoding said engineered AAV capsid, a vector system comprising said vector, and a eukaryotic cell comprising said vector,
does not reasonably provide enablement for making and using any vector comprising any engineered AAV capsid protein comprising any targeting peptide which imparts increased specificity for any cell type, or for any engineered “cell-specific” AAV capsid which exhibit cell specific targeting when incorporated into an AAV particle for any type of cell, or for a vector encoding n AAV capsid protein which does not comprise any splice regulatory elements. 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 or use the invention commensurate in scope with these claims.
As set forth in MPEP 2164.01(a), there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: A) the breadth of the claims; B) the nature of the invention; C) the state of the prior art; D) the level of one of ordinary skill; E) The level of predictability in the art; (F) the amount of direction provided by the inventor; G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) and Ex parte Forman, 230 USPQ 546,547 (BPAI 1986).It is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others. The examiner’s analysis must consider all the evidence related to each of these factors, and any conclusion of nonenablement must be based on the evidence as a whole. In re Wands 858 F.2d at 737, 740, 8 USPQ2d at 1404, 1407. Further, a conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). MPEP 2164.01(a). In regards to the full scope of the claimed invention, it is noted that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991).
The claimed vectors comprise a nucleotide sequence encoding an engineered AAV capsid protein which comprises an n-mer target peptide of at least three amino acids inserted between two codons, which based on the elected species is an insertion site between two codons corresponding to amino acids 581-593. The claims further limit the n-mer motif to peptide comprising 3-15 amino acids, or more specifically to 6 or 7 amino acids, or to a peptide where the first three amino acids are RGD, or most specifically to any one of the peptides recited in Tables 1-6. Certain claims further recite where the engineered AAV capsid has increased specificity, increased muscle cell specificity, or has muscle-specific tropism. Certain claims further recite a “cell-specific” AAV capsid polypeptide. The broadest claim thus encompass an engineered AAV capsid with any n-mer peptide insertion, or any other capsid modification, that can increase cell specificity for any cell type, or which can render the AAV capsid “cell-specific” for any cell type.
The specification is focused exclusively on the identification of AAV capsid proteins comprising a targeting peptide which are capable of conferring muscle cell tropism to an AAV virus comprising the capsid. The specification does not disclose the use of the engineered/modified AAV capsid for targeting AAV particles comprising the capsid to cells other than muscle cells. The specification thus clearly identifies the “use” of the disclosed engineered AAV capsid protein for generating a modified AAV virus with muscle specific tropism. Applicant is reminded that 35 U.S.C. 112(a) requires that the specification provide, “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”. Further, while the specification provides general guidance for modifying the capsid protein of AAV, particularly AAV9, in a number of specific positions, to include putative heterologous targeting peptides, the specification’s working examples are limited to the generation and testing of a library of AAV comprising AAV9 capsid proteins in which a putative targeting 7-mer peptide has been inserted into the capsid protein between amino acids 588-589. The specification teaches that AAV virus comprising an AAV9 capsid modified at position 588 by insertion of 7 amino acid n-mer sequences including the peptides listed in Tables 1-6 passed a score of “100” as a threshold for muscle cell tropism. The specification does not however provide a discussion of what a score of “100” represents. In Table I, it appears to be related to the “sum of muscle mRNA”. However, as no baseline mRNA control is shown, or level of statistical relevance for a score of “100”, it is unclear what level of muscle infection, or muscle specific infection, this data represents. From Tables I-III, the majority of putative targeting peptides have scores barely above 100. It is noted, however, that the highest scoring peptides, for example Variant ID Nos 1-13 in Table I, are all RGDnmers with scores above 300. Table IV-VI, which list the highest ranked peptides for muscle expression in the context of the AAV9 capsid with target peptide insertion at position 588, again show that all the highest ranked peptides are RGDnmers. Thus, based on the disclosure and working examples, it appears that at least the AAV9 capsids with RGDnmers listed in Tables IV-VI inserted at position 588 appear to exhibit increased muscle tropism. However, as the specification fails to provide sufficient guidance as to the relevance of scores from Tables I-III which are near 100, or even 200, it is unclear whether AAV9 or any other serotype comprising the breadth of targeting peptides recited as Table I for example, inserted between positions 588-589 can in fact confer or increase muscle specific tropism to AAV9 or any other AAV serotype. The specification also does not provide any working examples which demonstrate that any of the targeting peptides recited in Table I, for example, when inserted between positions 588-589, are capable of selectively transducing or have increased transduction any other types of cells, such as fibroblasts, neurons, pancreatic cells, or epithelial cells etc. Further, neither the specification nor the working examples provide any teachings or specific data which indicate that any of the AAV capsids modified with one of the n-mer peptides disclosed in Tables I-VI are “cell-specific”. At best, the working examples show an increase in transduction of muscle cells using certain peptides obtained through screening. However, the data provided still shows that AAV comprising even the peptides with the strongest scores for muscle expression still exhibit expression in other cell types-particularly cell types present in the liver, lung, brain, and abdomen see Figures 4 and 12. Thus, upon consideration of the breadth of the claims, the guidance provided by the specification, and the working examples provided, the disclosure fails to provide sufficient specific guidance and/or evidence that the use of any n-mer peptide of at least three amino acids, when inserted between positions 588-589 of AAV or an equivalent position in any other AAV serotype would result in a functional capsid protein capable of redirecting the targeting of an AAV virus comprising the capsid to muscle cells, muscle tissue, or any other type of cell.
Turning to the state of the prior art at the time of filing, it is noted that the prior art teaches that there are several methods for increasing the tropism of an AAV for a target tissue, many such modifications such as conjugation of ligands to the capsid can cause viral instability, higher immunogenicity, and reduced infectivity (Ying et al. (2010) Gene Therapy, Vol. 17, 980-990, see page 980). Ying et al. teaches that genetic modification of the capsid nucleic acid sequence by oligonucleotide insertions, particularly oligonucleotides encoding small targeting peptides, are able to circumvent some of these problems, and that insertions adjacent to amino acids 587 or 588 are well tolerated and most successful (Ying et al., page 980). However, Ying et al. teaches that an inherent problem of genetic modification of the AAV capsid is the design of the targeting peptide, due both to incomplete knowledge in the art regarding cell surface receptors and their ligands, and unpredictability with regards to the toleration and performance of ligand peptides identified by phage display with the AAV capsid structure (Ying et al., page 980). Ying et al. teaches that they were able to identify two specific target peptide capable of increasing heart transduction and expression of modified AAV2 using three rounds of in vivo screening of an AAV2 peptide library and two additional peptides with putative increased heart cell targeting using four rounds of in vitro screening of the AAV2 library in heart cells (Ying et al., pages 981-983) However, it is clear from Table I that the majority of peptides identified in the first round of both types of screenings were not present in subsequent rounds (Ying et al., page 982, Table I). Ying et al. also teaches that the in vitro selected peptides did not in fact significantly increase AAV2 targeting to cardiac tissue when tested in vivo (Ying et al., page 983). Finally, Ying et al. clearly shows that even their 2 best targeting peptides from the in vivo screen, while demonstrating a statistically significant increase in cardiac tissue targeting of AAV2, continued to exhibit transduction of other tissues (Ying et al., page 984). Korbelin et al., like Ying et al., also utilized in vivo screening of an AAV2 target peptide library where a 7mer peptide was inserted at position 588, and found after 5 rounds of in vivo screening only 1 peptide which provided a significant increase in pulmonary targeting with a decrease in the targeting of other tissue types (Korbelin et al. (2016) Molecular Therapy, Vol. 24(6), 1050-1061, see page 1053, Figure 2, and page 1059). Korbelin et al., however, also shows that the AAV2 comprising this peptide, despite a substantial increase in pulmonary targeting, continues to transduce heart tissue (Korbelin et al., page 1055, Figure 4b). Thus, the prior art at the time of filing teaches the unpredictability and difficulty in generating modified AAV capsid with targeting peptides that confer increased specificity to a desired tissue, and further demonstrate that even peptides that confer substantially increased specificity to a target tissue continue to exhibit transduction of other tissue types and thus are not “cell-specific”.
In regards to making and using a vector encoding an AAV capsid protein which does not comprise any splice regulatory elements as recited in claims 2, 4, and 56, it is noted that while the specification does state that the invention can include a vector encoding an AAV capsid protein that “does not comprise splice regulatory elements”, the specification does not provide any guidance as to how to remove or inactivate all of the splice regulatory elements associated with the nucleotide sequence encoding an AAV capsid, or provide any guidance or description of a nucleotide sequence encoding an AAV capsid without any splice regulatory elements that is capable of expressing a functional capsid protein. At the time of filing, it was well understood by the skilled artisan that the AAV capsid protein comprises three separate capsid subunit proteins, VP1, VP2, and VP3, which associate to form the AAV capsid, and that a single AAV nucleotide sequence comprising three partially overlapping reading frames generates all three capsid subunits using alternative splicing (see for example Farris et al. (2008) Human Gene Therapy, Vol. 19, 1421-1427). Farris et al. teaches that capsid production is a rate-limiting step for AAV viral particle production, and teaches that enhancing the splicing of the VP1, VP2, and VP3 mRNA by using a non-consensus AAV donor splice element can improve the expression levels of the complete capsid protein and thus increase viral production (Farris et al., pages 1422-1423 and Figure 1). Farris et al. further teaches that there is a delicate balance in the expression of three subunits and that it is important when modifying splice regulatory elements in the capsid nucleotide sequence to not disrupt the delicate balance between the three capsid proteins (Farris et al., page 1422). Becerra et al. further demonstrates that removal of a splice donor in the nucleotide sequence for the capsid produces unspliced transcripts that do not effectively synthesize the capsid proteins in vitro or in vivo (Becerra et al. (1988) J. Virol., Vol. 62(8), 2745-2754, see pages 2746 and 2751). Thus, the state of the prior art with regards to splice regulatory elements in vectors encoding AAV capsid teaches that splice regulatory elements are essential in the generation of mRNA generation and VP1, VP2, and VP3 subunit expression, and that maintaining the balance of expression of the capsid subunits is important.
Therefore, in view of the state of the prior art at the time of filing and in particular the art-recognized unpredictability in modifying AAV capsid proteins, including the modification of the AAV capsid to comprise a targeting peptide, the art recognized unpredictability in obtaining a peptide which confers increased tropism to a desired cell type, the art recognized importance of splice regulatory elements for expressing AAV capsid from a vector, the lack of guidance in the specification for n-mer peptides which confer increased tropism to any type of cell, the limitation of the working examples to insertion of target peptides at position 588 of the AAV9 capsid for increasing the tropism of an AAV capsid for muscle cells, the lack of guidance for any peptide capable of conferring cell-specific AAV transduction where other non-target cells are not transduced, the lack of guidance for removing all splice regulatory elements from a vector comprising a nucleotide sequence encoding the three subunits of AAV capsid while retaining the capacity to express a functional AAV capsid, and the breadth of the claims, it would have required undue experimentation to make and/or use the scope of vectors encoding a capsid proteins, and in particular capsid proteins comprising an n-mer peptide insert, encompassed by the instant claims as written.
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, 7, 9, 11-15, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 57, 59, 61-62, 65, 67, and 69 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/189244 (April, 2018), hereafter referred to as Grimm et al.
As noted above, limitations following the term “optionally” in the claims have been interpreted as being not required. As such, “optional” elements recited by a claim do not need to be taught by the cited prior art.
Grimm et al. teaches the vectors comprising a polynucleotide encoding an engineered AAV capsid polypeptide in which a targeting peptide has been inserted between positions 588 and 589 of AAV capsid serotype AAV2 or AAV9 (Grimm et al., pages 25-28, and 30-31). Grimm et al. further teaches that the targeting peptide comprises RGDCFC or RGDCFCA (Grimm et al., also SEQ ID NOS 3, and 9). In particular, Grimm et al. further teaches an AAV vector encoding the AAV2 rep gene together with the capsid gene coding for the engineered AAV capsid (Grimm et al., paragraph 158). On page 19, Grimm et al. teaches that the vector can further comprise a polyA site such as SV40 polyA sequence downstream of the polynucleotide encoding the engineered AAV capsid and a single promoter for expression of the capsid where the promoter may be a CMV promoter (Grimm et al., page 19). Specifically Grimm on page 19 states:
More preferably, in the vector of the invention, the polynucleotide is operatively linked to expression control sequences allowing expression in eukaryotic cells or isolated fractions thereof. Expression of said polynucleotide comprises transcription of the polynucleotide, preferably into a translatable mRNA. Regulatory elements ensuring expression in eukaryotic cells, preferably mammalian cells, are well known in the art. They, preferably, comprise regulatory sequences ensuring initiation of transcription and, optionally, poly-A signals ensuring termination of transcription and stabilization of the transcript. Additional regulatory elements may include transcriptional as well as translational enhancers. Possible regulatory elements permitting expression in eukaryotic host cells are the AOX1 or GALI promoter in yeast or the CMV-, SV40-, RSV-promoter (Rous sarcoma virus), CMV-enhancer, SV40- enhancer or a globin intron in mammalian and other animal cells. Preferably, the regulatory element comprises the AAV p40 promoter. Moreover, inducible expression control sequences may be used in an expression vector encompassed by the present invention. Suitable expression control sequences are well known in the art. Beside elements which are responsible for the initiation of transcription such regulatory elements may also comprise transcription termination signals, such as the SV40-poly-A site, the tk-poly-A site, or the AAV poly-A site downstream of the polynucleotide (emphasis added by the examiner).
Note that Grimm et al. on page 15 clearly teaches, “[t]he polynucleotide of the present invention encodes a variant AAV capsid polypeptide of the present invention. Preferably, the polynucleotide comprises a sequence encoding an AAV capsid polypeptide as specified herein, wherein a nucleic acid sequence encoding a specific combination of (i) a strain-specific capsid polypeptide and (ii) a peptide inserted into said capsid polypeptide, preferably replacing the nucleic acid sequence encoding the naturally occurring capsid polypeptide”. Thus, the polynucleotide present in the vector, which is taught in page 19 to be operably linked to a promoter and, optionally, to a polyA sequence, is a polynucleotide encoding a variant AAV capsid polypeptide. Grimm et al. further teaches cells, particularly packaging cells for producing engineered AAV viral particles, or human comprising said vectors and comprising the modified AAV capsid polypeptide, and AAV viral particles comprising the modified AAV capsid polypeptides (Grimm et al., pages 2, 9, 12-13).
Thus, by teaching all the elements of the claims as written, Grimm et al. anticipates the instant invention as claimed.
Claims 1, 7, 9, 11-15, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 57, 59, 61-62, 65, 67, and 69-71 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017.
Li et al. teaches AAV comprising a modified capsid protein with enhanced transduction of muscle cells, including skeletal, and cardiac muscle cells, and reduced transduction of the liver (Li et al., paragraphs 186). Li et al. teaches that the capsid can be modified by inserting 1-10 or more amino acids into amino acid position 585-590 of AAV2 or the corresponding positions of other AAV, including specifically amino acid positions 588-589 of AAV9 (Li et al., paragraphs 188-190, and 232). More specifically, Li et al., teaches the insertion of peptide comprising an RGD motif following the amino acid position 587 of AAV2, where the RGD motif can function as an integrin receptor binding motif (Li et al., paragraph 208). Specific RGD peptide motifs taught by Li et al. include CDCRGDCFC and CRGDGWC (Li et al., paragraph 216). Li et al. teaches vectors encoding the modified capsid protein, mammalian cells comprising said vectors, and pharmaceutical compositions comprising the vector or AAV particle (Li et al., paragraphs 20, 90,185, 244-246, and 491). Li et al. further teaches that the vector encoding the modified capsid and further encode an AAV rep gene (Li et al., paragraph 247). In addition, Li et al. teaches that the vector encoding the modified capsid also comprises an SV40 polyadenylation sequence (Li et al., paragraph 475). Li et al. further teaches that the modified AAV administer to a subject in vivo for the treatment of muscular dystrophy, including Duchenne or Becker muscular dystrophy (Li et al., paragraphs 266 and 289). Li et al. also teaches that the AAV comprises muscle specific promoter/enhancer elements to express a therapeutic protein such as a mini- or micro-dystrophin (Li et al., paragraphs 270 and 285).
Thus, by teachings all the elements of the claims as written, Li et al. anticipates the instant invention as claimed.
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 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017, in view of Farris et al. (2008) Human Gene Therapy, Vol. 19, 1421-1427.
Li et al. teaches AAV comprising a modified capsid protein with enhanced transduction of muscle cells, including skeletal, and cardiac muscle cells, and reduced transduction of the liver (Li et al., paragraphs 186). Li et al. teaches that the capsid can be modified by inserting 1-10 or more amino acids into amino acid position 585-590 of AAV2 or the corresponding positions of other AAV, including specifically amino acid positions 588-589 of AAV9 (Li et al., paragraphs 188-190, and 232). More specifically, Li et al., teaches the insertion of peptide comprising an RGD motif following the amino acid position 587 of AAV2, where the RGD motif can function as an integrin receptor binding motif (Li et al., paragraph 208). Specific RGD peptide motifs taught by Li et al. include CDCRGDCFC and CRGDGWC (Li et al., paragraph 216). Li et al. teaches vectors encoding the modified capsid protein, mammalian cells comprising said vectors, and pharmaceutical compositions comprising the vector or AAV particle (Li et al., paragraphs 20, 90,185, 244-246, and 491). Li et al. further teaches that the vector encoding the modified capsid and further encode an AAV rep gene (Li et al., paragraph 247). In addition, Li et al. teaches that the vector encoding the modified capsid also comprises an SV40 polyadenylation sequence (Li et al., paragraph 475). Li et al. further teaches that the modified AAV administer to a subject in vivo for the treatment of muscular dystrophy, including Duchenne or Becker muscular dystrophy (Li et al., paragraphs 266 and 289). Li et al. also teaches that the AAV comprises muscle specific promoter/enhancer elements to express a therapeutic protein such as a mini- or micro-dystrophin (Li et al., paragraphs 270 and 285).
Li et al. differs from the invention of claim 3 by not specifically teaching that the vector encoding the modified capsid comprises “minimal” splice regulatory elements. Note that “minimal splice regulatory elements” has been given its broadest reasonable interpretation as encompassing the presence of splice regulatory elements necessary for capsid expression-see the rejection of claim 3 under 35 U.S.C. 112(b) above. Farris et al. supplements Li et al., by teachings that the AAV capsid protein comprises three separate capsid subunit proteins, VP1, VP2, and VP3, which associate to form the AAV capsid, and that a single AAV nucleotide sequence comprising three partially overlapping reading frames generates all three capsid subunits using alternative splicing (Farris et al., pages 1421-1423). Farris teaches that capsid production is a rate-limiting step for AAV viral particle production, and teaches that enhancing the splicing of the VP1, VP2, and VP3 mRNA by using a non-consensus AAV donor splice element instead of the naturally occurring AAV donor splice element can improve the expression levels of the complete capsid protein and thus increase viral production (Farris et al., pages 1422-1423 and Figure 1). Farris et al. further teaches that there is a delicate balance in the expression of three subunits and that it is important when modifying splice regulatory elements in the capsid nucleotide sequence to not disrupt the delicate balance between the three capsid proteins (Farris et al., page 1422).
Thus in view of the teachings of Farris as to the importance of splice regulatory elements in the AAV capsid encoding sequence to ensure the proper balance of expression of the three capsid subunits, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize a capsid encoding sequence in the vector taught by Li et al. which includes either the naturally occurring splice regulatory elements, or the improved splice regulatory element taught by Farris et al. in order to ensure proper expression of all three capsid subunits, VP1, VP2, and VP3 to produce a functional AAV capsid with a reasonable expectation of success.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,920,150, hereafter referred to as the ‘150 patent, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017.
The ‘150 patent claims recite vector/vector systems, capsid polypeptides, cell comprising the vectors, AAV particles comprising the capsid and methods of administering the vector or AAV particle which are both broader than the instant claims. ‘150 patent claims do recite in certain dependent claims the majority of the limitations set forth in the narrower instant claims with the exception that the ‘150 patent claims do not specifically recite additional particular of the capsid vector, such as the presence of a polyA, a rep protein, a promoter, or the presence or absence of a splice regulatory element. However, it is noted that the ‘150 patent claims do encompass these embodiment and do broadly recite in claim 12 that the vector comprises one more regulatory element operatively linked to the capsid or cargo sequence.
Specifically, the ‘150 patent claims recite engineered AAV capsids, or AAV viral particles, or vector systems comprising engineered AAV capsids where the capsid comprises an RGD motif which is 3-18 amino acids in length and which more specifically is a peptide sequence set forth in Table I of the instant application (’150 claims 1, 3 and 12-13), and where the RGD motif is inserted between amino acids 588-589 (‘150 claims 5 and 17). The ‘150 patent claims also recites cells comprising the engineered AAV capsids (’150 claims 21-26), pharmaceutical compositions comprising the cells or the engineered AV, and methods of administering the pharmaceutical composition to treat disease (‘150 claims 22, and 27-30) . Thus, while not identical in scope, the ’150 patent claims encompass the instant claimed products and methods.
As noted above, while claim 12 of the ‘150 patent claim does recite the presence of one or more regulatory sequences in the vector, the ‘150 patent claims do not specifically recite that the regulatory sequence is a polyA sequence or a promoter, or that the vector further encodes a rep protein. However, such embodiments are encompassed by the ‘150 patent claims and further the inclusion of such elements in an AAV vector encoding a modified capsid were known in the prior art. Li et al. , for example, teaches similar AAV vectors encoding a modified AAV capsid comprising a targeting peptide and which further encode an AAV rep gene (Li et al., paragraph 247). In addition, Li et al. teaches that the vector encoding the modified capsid can also comprises an SV40 polyadenylation sequence (Li et al., paragraph 475). Li et al. further teaches that the modified AAV administer to a subject in vivo for the treatment of muscular dystrophy, including Duchenne or Becker muscular dystrophy and that the AAV comprises muscle specific promoter/enhancer elements to express a therapeutic protein such as a mini- or micro-dystrophin (Li et al., paragraphs 270 and 285). Therefore, in view of the recitation in the ‘150 patent claims that the vector further comprises one or more regulatory elements, and the motivation for including elements such as a polyA sequence, promoter, and a rep coding sequence in a vector encoding a modified AAV capsid as provided by Li et al., it would have been obvious to the skilled artisan to the modify the vector recited in the ‘150 patent claims to include these elements with a reasonable expectation of success.
Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26, and 31-41 of copending application 17/707,944, hereafter referred to as the ‘944 application, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017. Note that claims in the ‘944 application has been allowed. At such time as a patent is issued in the ‘944 application, this rejection with no longer be a provisional rejection.
The ‘944 application composition claims are both broader than the instant claims; however, the ‘944 application claims recite in certain dependent claims the majority of the limitations set forth in the narrower instant claims. Specifically, the ‘944 application recites engineered AAV capsids, or AAV viral particles, or vector systems comprising engineered AAV capsids where the capsid comprises an RGD motif and which includes specific peptides set forth in instant Table 1 (’944 claims 1 and 13), and where the RGD motif is inserted between amino acids 588-589 (‘944 claims 3 and 17). The ‘944 application claims also recites cells comprising the engineered AAV capsids (‘944 claims 24-26), and methods of administering the cells or AAV to treat disease (‘944 claims 40-41).
It is further noted that ‘944 claim 13 does recite the presence of regulatory sequences in the vector. However, the ‘944 claims do not specifically recite that the regulatory sequence is a polyA sequence or a promoter, or that the vector further encodes a rep protein. However, such embodiments are encompassed by the ‘944 application claims and further the inclusion of such elements in an AAV vector encoding a modified capsid were known in the prior art. Li et al. , for example, teaches similar AAV vectors encoding a modified AAV capsid comprising a targeting peptide and which further encode an AAV rep gene (Li et al., paragraph 247). In addition, Li et al. teaches that the vector encoding the modified capsid can also comprises an SV40 polyadenylation sequence (Li et al., paragraph 475). Li et al. further teaches that the modified AAV administer to a subject in vivo for the treatment of muscular dystrophy, including Duchenne or Becker muscular dystrophy and that the AAV comprises muscle specific promoter/enhancer elements to express a therapeutic protein such as a mini- or micro-dystrophin (Li et al., paragraphs 270 and 285).
Therefore, in view of the recitation in the ‘944 application claims that the vector further comprises regulatory elements, and the motivation for including elements such as a polyA sequence, promoter, and a rep coding sequence in a vector encoding a modified AAV capsid as provided by Li et al., it would have been obvious to the skilled artisan to the modify the vector recited in the ‘944 application claims to include these elements with a reasonable expectation of success.
Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7-10, 15-34, and 36 of copending application 17/707,951, hereafter referred to as the ‘951 application. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘951 application composition claims are broader and narrower than the instant claims; however, the ‘951 application claims recite in certain dependent claims all of the limitations set forth in the narrower instant claims. Specifically, the ‘951 application recites engineered AAV capsids, or AAV viral particles, or vector systems comprising engineered AAV capsids where the capsid comprises an RGD motif including an RGD motif set forth in Table I (’951 claim 1), and where the RGD motif is inserted between amino acids 588-589 (‘951 claim 1). The ‘951 application also recites cells comprising the engineered AAV capsids (‘951 claim 21), and methods of delivering an AAV particle comprising the engineered capsid to a subject to treat disease (‘951 claims 22-24). In addition, the ’951 claims specifically teach that vector further comprises a rep sequence and a promoter sequence operably linked to the capsid sequence (‘951 claim 25), a polyA sequence (‘951 claim 31), and inactivated splice regulatory elements (‘951 claim 32). Thus, while not identical in scope, the ‘951 patent claims render obvious the instant claimed products and methods.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 7, 9, 11-16, 18-22, 25, 30-32, 34, 44, 48, 51, 53-54, 56-57, 59, 61-62, 65, 67, and 69-71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-8, 11, 13, 16, 18-19, 21, 23, 31-35, 37-39, 42, 44-45, 47-48, 52, 58-59, 61-62, 64, 74, 77, and 88-89 of copending application 17/764,509, hereafter referred to as the ‘509 application, in view of US Patent Application Publication 2020/0325456 (October 15, 2020), hereafter referred to as Li et al., with an effective filing date of 12/19/2017.
The ‘509 application composition claims are broader than the instant claims; however, the ‘509 application claims recite in certain dependent claims all the limitations set forth in the narrower instant claims, with the exception of the presence of a polyA sequence. Specifically, the ‘509 application recites engineered AAV capsids, or AAV viral particles, or vector systems comprising engineered AAV capsids where the capsid comprises an RGD motif which is SEQ ID NO:13 (’549 claims 5 and 35), and where the RGD motif is inserted between amino acids 588-589 (‘509 claims 11 and 45). The ‘509 application also recites cells comprising the engineered AAV capsids (‘509 claims 74 and 88). The ‘509 application claims further include limitations where the cargo is operatively linked to promoter (‘509 claim 23), where the nucleotide sequences in the vector do not have splice regulatory elements (‘509 claim 47), and where the vector encoding the capsid further encodes a rep protein (‘509 claim 48).
It is also noted that ‘509 claim 32 further recite that the vector comprises additional regulatory elements. While the ‘509 claims do not specifically recite that the regulatory element is a polyA sequence, this embodiment is clearly encompassed by the ‘509 claims. The inclusion of such regulatory elements in an AAV vector encoding a modified capsid was known in the prior art. Li et al. , for example, teaches similar AAV vectors encoding a modified AAV capsid comprising a targeting peptide and which further encode an AAV rep gene (Li et al., paragraph 247). In addition, Li et al. teaches that the vector encoding the modified capsid can also comprises an SV40 polyadenylation sequence (Li et al., paragraph 475).
Therefore, in view of the recitation in the ‘590 application claims that the vector further comprises one or more regulatory elements, and the motivation for including elements such as a polyA sequence in a vector encoding a modified AAV capsid as provided by Li et al., it would have been obvious to the skilled artisan to the modify the vector recited in the ‘509 application claims to include a polyA sequence with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634