DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-47 are pending.
The present application is a U.S. national stage of application No. PCT/JP2021/040410, filed on November 2, 2021 which claims priority to Japanese Application No. 2020- 184495, filed November 4, 2020.
Applicant cannot rely upon the foreign priority papers to overcome this rejection because a translation of said papers has not been made of record in accordance with 37 CFR 1.55. See MPEP § 201.15. Hence, the effective filing date of the application is November 2, 2021.
Information Disclosure Statement
Information disclosure statements filed 5/4/2023, 10/18/2024. 6/6/2025 and 8/22/2025 have been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures.
Specifically, Figures 4, 10, Figure 12, Figure 16-22 contain sequences that are not identified by sequence identifier numbers. If the sequences can be found in the sequence listing it would be remedial to insert the appropriate SEQ ID NO:s. If not, a substitute paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, CRF and letter stating that the contents of the sequence listing and the CRF are the same and contain no new matter is required. The nature of the non-compliance did not preclude the examination on the merits of the instant application, the results of which follow.
Claim Objections
Claims 6, 20, 24 and 26 are objected to because of the following informalities: in claim 6, “plasmid” requires its own article. The recitation here is to two separate limitations and not a compound noun and hence each require their own article. In claim 6, it should be “the”.
This is true of 5’ITR and 3’ITR of claim 20 but it is noted that the previous claim does not establish that the ITRs are specifically 5’ and 3’ just that there are two ITRs. As to claim objections, the ITRs require an article. As to clarity this is presented below.
Claims 21, 22, 24, 26 are objected to for referring to genes as proteins. The claims should consistently use language associated with the molecule. For example, in claim 21, the helper gene encodes at least one of E1A, E1B, E2A, E4 and VA.
Claims 24 and 26 refer to rep and cap which are abbreviations. However, on the first occurrence the full spelling should be made.
Claim 46 requires an article prior to “load”. Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
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.
Claim 4 recites the limitation "the host cell that is competent" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 6 is unclear as it recites that the nucleic acid “or” plasmid comprises a nucleic acid sequence of a gene of interest. If one has it the other should and therefore it is not clear how one OR the other can comprise a component wherein the steps do not include adding or deleting the nucleic acid sequence of a gene of interest.
Claim 14 is vague and indefinite in that the recitation of “a sequence of a gene of at least a part of a whole genome of the virus”. It is unclear how a gene is of at least a part of a whole genome. The virus comprises a number of genes but it is not clear how there is a gene of at least a part of whole genome.
Claim 17 is vague in reciting “other”. The term “other” is a relative one not defined by the claim, no single set of conditions is recognized by the art as being “other” and because the specification does not provide a standard for ascertaining the requisite degree, the metes and bounds of this claim cannot be established. There was no first moiety or original moiety to understand what this was the other moiety to.
Claims 19, 23, 25, 27 and 47 are vague and indefinite in that the metes and bounds of the term “derived from” are unclear. It is unclear the nature and number of steps required to obtained a “derivative” of the serotypes. The term implies a number of different steps that may or may not result in a change in the functional characteristics of the viral proteins and sequences from the source that it is “derived from”.
Claim 20 recites that “the method” comprises a terminator from upstream between 5’ITR and 3’ITR. The method cannot comprise these components. Rather, it appears the components are part of something in the method such as the nucleic acid. As well, it is unclear what is intended from terminator from upstream. It is unclear what reference is “from upstream”. Finally, the claim recites 5’ITR and 3’ITR without reference. Therefore, there are several components that lack proper reference which renders unclear the metes and bounds of the claim.
Claims 30-36 recite the limitation "the host cell" in claim 1. There is insufficient antecedent basis for this limitation in the claim. There are apparently two sets of host cells in claim 1 as understood from the claims (see for example claim 32) as there is a host cell of part A) and part B). This indicates that “a host cell of A)” is not the same as “a host cell of B)”. By reciting the host cell, it is not clear to which the claim refers.
The term “desired” in claim 47 is a relative term which renders the claim indefinite. The term “desired” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what makes a nucleic acid desired such that the metes and bounds of the claim can be determined. This claim is drawn to viral vectors but further discusses viral particles comprising nucleic acids from the plasmid and it is not clear from where the particles are obtained.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims read on components that are claimed so broadly as to lack adequate description. The following components are not adequately described.
Claims 1, 2, 3, 15 require a “nucleic acid sequence for producing a virus vector” or comprise “a method for creating a virus vector plasmid”. However, neither the method nor the sequence has structure. This function/method is “for producing a virus vector” and the structure is in claim 1 broadly any nucleic acid sequence and in claims 2 and 3, no sequence except as being a plasmid as set forth below. . The claims except for claim 10-13 do not limit the virus for which the virus vector is produced. Rather any number of virus vector plasmids are intended by the scope. But, to this end, the description does not provide the details for all but AAV.
Claims 2, 3, 15 recite that the plasmid comprises “a sequence which is replicated in hay bacillus” or that “promote plasmid replication in hay bacillus”. This again is a function in search of a structure. Claim 3 further recites that a host cell comprising “the plasmid” is placed under a condition where the plasmid is amplified. The conditions are undefined in the claim and present a required functional property with out provided the structure of this condition.
Claim 28 and 41 recites that a producer cell introduced with the plasmid alone to produce virus vector wherein the plasmid as claimed cannot provide the results.
Claim 40 requires that the CCC purity of “a plasmid” is 80% or greater. This is a desired outcome that is not accompanied by a means to accomplish this outcome.
Claim 47 requires less than 2% of the particles comprise “a nucleic acid derived from the plasmid” that are not “desired”.
The written description requirement for genus claims may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with known or disclosed correlations between function and structure, or by a combination of such characteristics sufficient to show that the applicant was in possession of the claimed genus. To this end, the disclosure teaches a narrow set of structures that appear to meet these requirements.
Starting with a nucleic acid for producing a virus vector, this is a large group of nucleic acids without any structural or specific functional properties. An indication of what is intended is found in dependent claim 18. Claim 18 provides components that could be used to produce an AAV virus which are rep and cap and helper genes, although the art teaches that these components require E4orf6, E2a and VA (see Yang, abstract and page 5, ¶1). Additional component required for rAAV production for therapeutic purposes include ITR sequences flanking on the 5’ and 3’ end of a gene of interest. The disclosure demonstrates a plasmid comprising these elements.
PNG
media_image1.png
518
688
media_image1.png
Greyscale
As to the nucleic acid that promotes plasmid replication in hay bacillus, this again is a function with a limited structural designation. The disclosure teaches that it is an origin of replication functional in hay cells.
Examples of a sequence which is replicated in hay bacillus include a plasmid or a portion or replication origin point thereof or a variant thereof and the like, which are known to operate the rolling-circle-type replication mechanism, the theta-type replication mechanism, the oriC replication mechanism, or the replication mechanism using a phage or the like.
Hence, it seems an origin of replication is all that is actually required of this limitation and nothing specific to hay bacillus. As to sequences intended to constitute a virus, there are various descriptions but it would seem that a replication and capsid gene between a 5’ ITR and a 3’ ITR are necessary as well as helper genes (see page 5).
As to producer cells, the claims require that the plasmid alone can be used to create the virus vector. Again, given the lack of components provided for the plasmid, this is a limited descriptive element wherein the claims broadly and incompletely claim the claim. However, the producer cell as well lacks adequate description wherein the disclosure uses teaches producer cells that are mammalian cells that appropriately produce AAV. These include,
[0201] In one embodiment, the vector plasmid of the present disclosure is introduced into a producer cell to produce a virus vector. Examples of a producer cell include, but are not limited to, 911 cells, PER.C6 cells, E1-transformed amniocytes, E1-transformed A549 cells, GH329: HeLa cells, HEK293 cells, IT293SF cells, HEK293T, HEK293F, Vero cells, CHO cells, Sf9 cells, Freestyle™ 293-F, Expi293-F™, Expi293 inducible, Expi293 NGT-Viral Production Cells 1.0, Viral Production Cells 2.0, AAVpro® 293T Cell Line, Lenti-X™ 293T Cell Line, FreeStyle™ CHO-S cells, ExpiCHO-S™, and the like. Any known suitable producer cell can be selected depending on the type of the virus vector that is produced.
As to claim 40, the CCC purity of a plasmid is a desired outcome. Looking to the disclosure, this appears to be an inherent consequence of producing the vector in hay bacillus, the purity exceeds 80%. There are no other means of achieving this as disclosed.
For both plasmids pGETS103-AAV-Helper-RC2 and pGETS103-RC2, the CCC purity was higher in hay bacillus than in Escherichia coli. The guidance of the FDA specifies that the CCC purity shall exceed 80%. Since a plasmid produced using hay bacillus was observed to have a high CCC purity, said plasmid can reduce the burden of the purification operation for improving the CCC purity and the manufacturing costs. It is believed that CCC purity is also associated with safety, functionality, and transfection efficiency of a plasmid DNA. A plasmid DNA with a high CCC purity is highly useful.
Finally, claim 47 recites that the composition of claim 45 which are viral vectors wherein virus vector particles from comprising plasmid nucleic acids that are not “desired” are in less than 2% of the viral particles. As set forth above, it is not clear how to define desired vs non-desired nucleic acids. Furthermore, the description of this composition if amended to read on particles wherein the non-desired nucleic acids are in less than 2% of the composition is a desired goal wherein the disclosure does not provide description of how to obtain this composition.
To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
Specifically, The claims lack adequate description to link structure to these required functions. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements. Furthermore, it is aptly noted that the Federal Circuit has decided that a generic statement that defines a genus of substances by only their functional activity, i.e., the ability to specifically bind a polypeptide and inhibit its function, does not provide an adequate written description of the genus. See the Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The claims recite nucleic acids and producer cell and cells in large and incomplete terms but require specific functions of these sequences. The disclosure is limited to methods and sequences for producing AAV vectors wherein the nucleic acid sequence for producing a virus is a sequence comprising rep/cap, helper genes and ITR sequences flanking a gene of interest. As to sequences for replication in hay bacillus, this is an origin of replication for hay. CCC purity is the consequence of the replication in hay and does not in itself have any structure. As to producer cells, they are AAV mammalian producer cells.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 6-14, 29, 30 and 37-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williams et al (U.S. application 20210010021) as evidenced by Carnes and Williams (U.S. Patent 7,943,377) and Gallagher et al (Biotage, 2024 copyright, pages 1-6).
As recited in claim 1, Williams et al teach plasmids that comprise nucleic acid sequences for producing a virus vector. For example,
[0092] In one embodiment, the present technology provides a method for improving AAV vector viral transducing unit production from a covalently closed circular plasmid comprising the following steps: a) providing a covalently closed circular plasmid comprising: i) a 1 kb or larger bacterial replication-selection region comprising a Pol I-dependent origin of replication and an antibiotic selectable marker, and ii) an insert comprising a eukaryotic region selected from the group consisting of AAV vector, AAV rep cap vector, Ad helper vector, and Ad helper rep cap vector;
Reference is made to Carnes in ¶0007 and this reference teaches placing a host cell under conditions in which the plasmid is amplified (see figure 2 of Carnes).
As recited in claim 6, the construct has a transgene (see Table 7).
As recited in claims 7-9, there are at least 10 units in the plasmid.
As recited in claim 10-13, the virus is AAV (see ¶0068)).
In some vectors only the ITR sequences with a transgene and therefore a sequence of a gene for AAV is missing as recited in claim 14.
Williams teaches amplified plasmid in E. coli (see ¶0007) as recited in claim 30 wherein the amplified plasmid is purified (as shown in detail by Carnes and described in Williams on ¶0295) as recited in claim 29. The plasmid is part of a composition as recited in claims 37 and 38 wherein the method of Williams et al (see ¶0007) relies on a method used in U.S Patent 7,943,377. This method indicates a purity of plasmid purification (col 16, lines 42-50) that is pure which indicates 100% purity and means no endotoxin (as evidenced by Gallagher, ¶4) as recited in claim 39. The plasmid is a CCC (see abstract) and given the 100% purity the composition of claim 40 is met.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-4, 6-18, 24-27, 29, 30, 37-40 and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williams et al (U.S. application 20210010021) as evidenced by Carnes and Williams (U.S. Patent 7,943,377) and Gallagher et al (Biotage, 2024 copyright, pages 1-6) in view of Wang et al (CN 112472690).
Wang et al teach as recited in claim 2 and 3, a method for creating a virus vector plasmid which is replicated in hay bacillus (also known as colon bacillus).
[page 5, ¶2] pAAV-MCS plasmid uses BamHI and HindIII double enzyme cutting; purifying; preparinglinearized plasmid with sticky end; using T4 ligase, ligase cutting plasmid and CNPase CDS product, transferring to colon bacillus competent DH5 α cell, incubating for one hour at 37 degrees centigrade in the LB culture medium; centrifuging; taking the precipitate; after re-suspending, uniformly coating on the agarose solid flat with ampicillin antibiotic; culturing overnight at 37 degrees centigrade; extracting monoclonal; screening positive clone by using colony PCR method; and confirming the construction of recombinant plasmid by sequencing method.
Colon bacillus is another name for hay bacillus. This teaches use of competent bacillus which overlaps that of Williams. Based on Wang et al one could have used the colon bacillus of Wang using the full set of steps as presented above to make the plasmid such that it could be used in producing viral vectors.
Wang teaches that the cells used are competent (see page 5, ¶2).
As set forth above, claim 15 is encompassed by the passage provided from Wang et al.
As shown in Williams, the remaining claims are taught.
Williams teaches that the helper plasmid is larger than 10 kB (see Table 9) as recited in claim 16.
As recited in claim 17, Williams teaches ITR with transgene (see Table 7).
As recited in claim 18, rep and cap are included in the plasmid (Williams ¶0044)
As recited in claims 24-27, rep and cap sequences any of a number of AAV2 and AAV9 respectively are considered (see e.g. ¶0042) of Williams et al.
As to claim 47, it appears that this intends that only desired nucleic acids are in the vector. As only desired nucleic acids have bene used to transduce the host, they will alone be part of the viral particle absent evidence to the contrary.
Claims 1, 4, 6-13, 20, 28, 30, 41-45 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over any of Bennett (U.S. Patent 9,249,425) in view of Groff et al (US 20170191070).
Claim 1 is drawn to a method of creating a virus vector plasmid and is limited to introducing a nucleic acid into a host cell thus the plasmid which is then amplified. Bennett et al teach proviral plasmids hence plasmids for producing viral vectors.
Bennett while inherently does, does not explicitly teach that the plasmids are placed under conditions where the plasmid is amplified. While Bennett does omit this from the teaching, it is an inherent part of plasmid production For example, the same plasmid backbone pJ201 of Bennett is also use by ¶0123 of Groff which teaches the amplification step.
[0081] The expression cassette of the complementing plasmid can be cloned into a plasmid for expression in E. coli, such as a multicopy plasmid. Depending on the origin of replication of the plasmid, the copy number can vary. Plasmids, such as the pUC vector, pBluescript vector, pGEM vectors, pJ201 vectors, and derivatives thereof that reach very high copy numbers (e.g., about 300-1000 or more copies) within a bacterial cell can be used. Alternatively, lower copy number plasmids, such as the pBR322 vector, pACYC vector, pSC101 vector and derivatives thereof that are presents at about 5-20 copies per bacterial cell can be used.
Groff teaches methods of amplification (see ¶0129).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to amplify the plasmid in bacterial host cells given that this is necessary to provide plasmid. Such a modification would have resulted in a method encompassed by claim 1. As noted above: 1) Bennett et al teach construction of a proviral plasmid that is used to produce viral vectors 2) Groff teaches similar plasmids that are amplified in bacterial host cells. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow plasmid production for adequate use.
Groff teaches that use of such vector for amplification occurs using competent cells (see e.g. ¶0096) as recited in claim 4.
The proviral plasmids of Bennett comprise ITR and a gene of interest for producing a viral vector (see abstract) as recited in claim 6.
As recited in claim 7-9, there are according to Bennett at least 10 units in the plasmid (figure 1 and col 2, lines 4-38).
As recited in claims 10-13, Bennett teaches the method is designed for producing AAV (see e.g. col 1, line 53-57).
As recited in claim 20 and shown in figure 5, the inserted ORG which is inserted between the ITRs comprises a terminator sequence.
As provided for by Groff, the host cell as set forth in claim 30 can be coli (see abstract).
Bennett teaches introducing the plasmid into producer cells to from the virus (see col 15, line 31-41) as recited in claim 41. It is the only plasmid introduced as required of claim 42. However, as recited in claim 43, the plasmid is integrated into the genome (see col 10, lines 57-60).
Bennett teaches a virus and composition comprising the virus (see col 12, line 19-25). This is as recited in claims 44 and 45.
This passage (see e.g. ¶0038 and 0042) teaches that the plasmid alone provides necessary requirements to produce the viral vector as recited in claim 28.
As to claim 47, it appears that this intends that only desired nucleic acids are in the vector. As only desired nucleic acids have bene used to transduce the host, they will alone be part of the viral particle absent evidence to the contrary.
Claim 2, 3, 15-19, 21, 22, 24-27, 29, 31, 37, 38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Bennett (U.S. Patent 9,249,425) in view of Groff et al (US 20170191070) as applied to claims 1, 4, 6-13, 20, 28, 30, 41-45 and 47 above, and further in view of Strong et al (US 20060242725).
Strong et al teach as recited in claim 2 and 3, a method for creating a virus vector plasmid which is replicated in hay bacillus (also known as Bacillus subtilis).
[0099] The nucleic acid, e.g., plasmid vector, viral vector or linear DNA molecule, of the present disclosure can contain other elements, in addition to the osteoblast-specific nuclear entry polynucleotide sequence and promoter polynucleotide sequence, to direct expression and the gene (nucleic acid) of interest or RNA molecule to be delivered. For example, it can be desirable to include a bacterial origin of replication (such as oriC) for replication of the plasmid in Escherichia coli, or the origin of replication of Bacillus subtilis for replication therein, or the origin of replication of Pseudomonas aeruginosa for replication therein, etc.) so that the plasmid can be maintained and replicated in a bacterial host.
A viral vector comprising a bacterial origin of replication is a plasmid. The plasmid introduced into hay bacillus would create a virus vector plasmid.
Bennett does not teach that this viral vector can replicate in hay bacillus as recited in claim 15. However, Strong et al teaches that viral vectors can be propagated in hay bacillus wherein the ability to accomplish this is afforded by an origin of replication.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to use hay bacillus as taught by Strong et al to make the plasmids used by Bennett. Such a modification would have resulted in a method encompassed by claim 2, 3 and 15-27. As noted above: 1) Bennett teaches use of plasmids for AAV production wherein the plasmids can be grown in cells for amplification as taught by Groff et al; 2) Strong et al teach that the plasmids as used by Bennett et al are amplified in cells to produce the plasmid. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow means to produce the plasmid such that it is amplified for use.
The dependent claims 16-27 have details taught by Bennett and these are set forth below. As shown in figure 3, the vector is larger than 10 kB as recited in claim 16.
As recited in claim 17, Bennett et al teach ITR surrounding a transgene (see abstract).
As recited in claim 18, rep and cap are included in the plasmid (see e.g. col 11, line 19-21)
The ITRs are from AAV2 (see col 5, line 55-60) as recited in claim 19.
As recited in claim 21, the helper genes comprise E2A at least (see e.g. col 14, line 31) and fully E1A, E4 and VA (see col 11, line 22-24) as recited in claim 22.
As to claims 24-27 rep and cap can be from any of a number of AAV (see col 12, line 26-40 in light of col 13, line 10-15).
This latter passage teaches that the plasmid alone provides necessary requirements to produce the viral vector as recited in claim 28.
Strong teaches that polynucleotides are purified from host cells by their removal of host cell polynucleotides (see e.g. ¶0063) which applied to Bennett in view of Groff allows for isolation of the plasmid (see Strong, ¶0063).
As the disclosure teaches production in hay bacillus means that purity is 100% and the specification of Bennett et al shows CCC (see figure 3). Hence producing the CCC in the cells of Strong et al would meet the limitations of claim 40.
Claims 1, 4, 6-14, 28-30, 37, 38, 41-45 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Colosi et al (U.S. application 20020052485) in view of Liu et al (U.S. 20170266273).
Colosi teaches methods of producing rAAV with AAV plasmids, The plasmids provide a transgene and ITR sequences. Colosi teaches a second plasmid that is a helper plasmid and a third that encodes Rep and Cap (see ¶0044). The steps of producing the plasmid in cells is not provided. However, Liu et al provide methods of such wherein competent coli cells are transduced with the AAV plasmids and the plasmids purified (see e.g. ¶0038).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to use hay bacillus as taught by Strong et al to make the plasmids used by Bennett. Such a modification would have resulted in a method encompassed by claim 2, 3 and 15-27. As noted above: 1) Colosi teaches use of plasmids for AAV production wherein the plasmids can be grown in cells for amplification as taught by Liu et al; 2) Wang et al teach that the plasmids as used by Colosi et al are amplified in cells to produce the plasmid. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow means to produce the plasmid such that it is amplified for use.
As recited in claims 6-9, one of the plasmids described in Colosi comprise a gene of interest (see e.g. ¶0007). Descriptions of construction of another plasmid, pladeno5, demonstrates at least 10 units are used to produce the nucleic acid (¶0105).
As set forth above, the virus of Colosi produced is AAV as required in claims 10- 13.
Colosi teaches plasmids that do not comprise a sequence of a gene as recited in claim 14. These include for example pladeno5 (see e.g.,. ¶0105).
Producer cells as required of claim 28 are used to produce the virus wherein plasmids alone are used (see e.g. ¶0116 see Colosi).
Colosi et al teach that the plasmids are introduced into produced cells and thus form a virus vector as recited in claim 41. The methods alternatively use only plasmids (see e.g. ¶0116) wherein pHLP which encodes rep/cap, pladeno5 (helper genes) and pVmLacZ (transgene) as recited in claim 42. However, alternative methods include integrated sequences (see e.g. ¶ 0124) as recited in claim 43. Both lead to virus and compositions comprising thereof as recited in claims 44 and 45.
As to claim 47, it appears that this intends that only desired nucleic acids are in the vector. As only desired nucleic acids have bene used to transduce the host, they will alone be part of the viral particle absent evidence to the contrary.
Claim 2, 3, 15-27, 31, 39 and 40, are rejected under 35 U.S.C. 103 as being unpatentable Colosi et al (U.S. application 20020052485) in view of Liu et al (U.S. 20170266273) as applied to claims 1, 4, 6-14, 28-30, 37, 38, 41-45 and 47 above, and further in view of Wang et al (CN 112472690).
Wang et al teach as recited in claim 2 and 3, a method for creating a virus vector plasmid which is replicated in hay bacillus (also known as colon bacillus).
[page 5, ¶2] pAAV-MCS plasmid uses BamHI and HindIII double enzyme cutting; purifying; preparinglinearized plasmid with sticky end; using T4 ligase, ligase cutting plasmid and CNPase CDS product, transferring to colon bacillus competent DH5 α cell, incubating for one hour at 37 degrees centigrade in the LB culture medium; centrifuging; taking the precipitate; after re-suspending, uniformly coating on the agarose solid flat with ampicillin antibiotic; culturing overnight at 37 degrees centigrade; extracting monoclonal; screening positive clone by using colony PCR method; and confirming the construction of recombinant plasmid by sequencing method.
Colon bacillus is another name for hay bacillus. This teaches use of competent bacillus which overlaps that of Colosi. Based on Wang et al one could have used the colon bacillus of Wang using the full set of steps as presented above to make the plasmid such that it could be used in producing viral vectors.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to use hay bacillus as taught by Wang et al to make the plasmids used by Colosi. Such a modification would have resulted in a method encompassed by claim 2, 3 and 15-27. As noted above: 1) Bennett teaches use of plasmids for AAV production wherein the plasmids can be grown in cells for amplification as taught by Groff et al; 2) Strong et al teach that the plasmids as used by Bennett et al are amplified in cells to produce the plasmid. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow means to produce the plasmid such that it is amplified for use.
As set forth above, claim 15 is encompassed by the passage provided from Wang et al.
As shown in Colosi, the remaining claims are taught. Colosi teaches that the helper plasmid is larger than 10 kB as recited in claim 16.
As recited in claim 17, Colosi teaches ITR with transgene (¶0007).
As recited in claim 18, rep and cap are included in the plasmid (¶0044)
The ITRs are from any of a variety of AAV (see ¶0038) as recited in claim 19.
This helper plasmid encodes VA, E2A and E4 (see e.g. ¶0018) as recited in claims 21-23, adenovirus serotype 2 provides the necessary components.
As recited in claims 24-27, rep and cap sequences any of a number of AAV are considered (see e.g. ¶0042) of Colosi et al.
As recited in claim 39, Wang teaches that the plasmid prep is endotoxin free (see page 5, ¶3). As the disclosure teaches production in hay bacillus means that purity is 100% and the specification of Colosi et al shows CCC (see figure 6). Hence producing the CCC in the cells of Wang et al would meet the limitations of claim 40.
Claims 5 and 46 are rejected as being unpatentable are rejected under 35 U.S.C. 103 as being unpatentable over Bennett (U.S. Patent 9,249,425) in view of Groff et al (US 20170191070) as applied to claims 1, 4, 6-13, 20, 28, 30, 41-45 and 47 above, or Colosi et al (U.S. application 20020052485) in view of Liu et al (U.S. 20170266273) as applied to claims 1, 4, 6-14, 28-30, 37, 38, 41-45 and 47 or Williams et al (U.S. application 20210010021) as evidenced by Carnes and Williams (U.S. Patent 7,943,377) and Gallagher et al (Biotage, 2024 copyright, pages 1-6) as applied to claims 1, 6-14, 29, 30 and 37-40 and further in view of Kashida et al (Polymer J, 2016, pages 781-786) and Grieger et al (Molecular Therapy vol. 24 no. 2, 287–297, 2016).
The references above (Bennett and Groff et al or Colosi and Liu et al or Williams) do not teach that the nucleic acid is acyclic as required of claim 5. However, Kashida et al teach that acyclic artificial sequences “have several advantages, including facile chemical synthesis and resistance to nuclease-mediated cleavage” (abstract and col 2, page 781).
There are several advantages of acyclic scaffolds over other XNAs. First, the synthetic costs of acyclic XNA are often low due to their simple structures. Second, chemical modification is usually facile, allowing XNAs with novel structures to be easily prepared. Third, because their chemical structures are very different from natural nucleic acids, they are highly resistant to nucleases. In addition, acyclic XNAs with phosphodiester bonds are usually highly water-soluble, in contrast to neutral XNAs. Furthermore, acyclic XNAs are candidates for genetic material in the ‘pre-RNA world’ because of their simple structures.30,31
Incorporation of acyclic nucleic acids given the benefits recited above. Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate these nucleic acids. Such a modification would have resulted in a method encompassed by claim 2 wherein an AAV sequence with ITRs meets the requirement for tandem repeats. As noted above: Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow advantages of reduced cost, facile modifications as candidates for gene therapy.
As to claim 46, which appears to indicate that the full versus empty particles are at least 65% full. Purificaiton methods are known in the art which allow for enrichment of full vesrsus empty capsids (see abstract, Grieger et al).
This user-friendly process can be completed within 1 week, results in high full to empty particle ratios (>90% full particles), provides postpurification yields (>1×1013 vg/l) and purity suitable for clinical applications and is universal with respect to all serotypes and chimeric particles.
Double Patenting
A rejection based on double patenting of the "same invention" type finds its support in the language of 35 U.S.C. 101 which states that "whoever invents or discovers any new and useful process ... may obtain a patent therefor ..." (Emphasis added). Thus, the term "same invention," in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957); and In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
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. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-47 are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-6, 8, 11, 12, 14,15, 17, 19-21 and 23-30 of copending application 19/042,220.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are generic to all that is recited in claims 1-6, 8, 11, 12, 14,15, 17, 19-21 and 23-30 of copending application 19/042,220. That is, the cited claims of copending application 19/042,220 anticipate and fall entirely within the scope of the rejected claims of the instant application. Specifically, copending application 19/042,220 is drawn to related methods using related nucleic acids to make virus vector and virus vector plasmids. The copending claims are narrower as to characteristics of the vectors.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the copending application 19/042,220, then two different assignees would hold a patent to the claimed invention of copending application 19/042,220, and thus improperly there would be possible harassment by multiple assignees.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
Claims 32-36 appear to be free of the art as the art does nto teach use of two distinct species to produce and then amplify a palsmid.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARIA MARVICH/Primary Examiner, Art Unit 1634