DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 1-29, and 41-43), and the species including ( the election of AAV, for the viral vector recited in claim 4; the LK03 (SEQ ID NO: 2) for the single species of AAV capsid proteins recited in claim 7; the NPHS1 for the podocyte-specific promoter recited in claims 12-16; the 265 bp promoter specified in SEQ ID NO: 27 for the specific species thereof; and the CFI specified in SEQ ID NO:1 for the inhibitor of the complement system recited in claims 19-20) in the reply filed on 12/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 35-40 ,17, 23-24, and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Therefore, claims 1-16,18-22,25-29, and 41-42 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Allowable Subject Matter
Sequence search did not find any prior art with 100% identity to the claimed SEQ ID NO: 27. Therefore, SEQ ID NO: 27 is free of art.
Claim Objections
Claim 28 is objected to because of the following informalities: the claim recites in line 1 “ toclaim 1” a space should be added. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 12-15, and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 12-15 require a recombinant nucleic acid comprising a fragment or derivative of the podocyte-specific promoters, whilst claims 19-20 require a recombinant nucleic acid comprising a fragment or derivative of the inhibitor of the complement system.
Upon review of the specification, the term "derivative" in relation to a protein is defined as any substitution of, variation of, modification of, replacement of, deletion of and/or
addition of one (or more) amino acid residues from or to the sequence, providing that the resultant protein or polypeptide retains at least one of its endogenous functions. For example, a derivative of a complement inhibitor may retain the ability to inhibit the complement system. On the other hand, the “fragment “ is defined as the amino acid or nucleic acid sequence that represent a portion of a full-length polypeptide or polynucleotide. ( See instant specification on page 54 lines 6-11, and page 57 lines 10-13). While the specification shows that Applicants have provided a full description of the full length of inhibitors of the complement system by disclosing the associated SEQ ID Nos that define the exact nucleic acid sequence; however, the specification fails to disclose any nucleic acid sequences or amino acids that would specifically define the functional derivatives or fragments. Applicants have not provided sufficient description of specific nucleic acid/amino acid sequences or motifs that distinguish the said functional variants from the non-functional ones. Furthermore, Applicants have not demonstrated a reduction in practice that the claimed functional variants will perform the claimed function of encoding a functional inhibitor of the complement system.
Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
In the instant case the specification only provides sufficient description, examples, or data of SEQ ID Nos that disclose the full length of the claimed inhibitors of the complement system. But it fails to disclose the structural features of the claimed functional variants/fragment that would perform the claimed function of encoding a functional inhibitor of the complement system. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Accordingly, Applicants have not provided sufficient description of the invention to support they were in possession of all the functional variants of the claimed podocyte-specific promoters or the claimed inhibitors of the complement system. Therefore, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-16,19-22, 25-29,and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Picconi et al (Methods & Clinical Development , 2014), in view of Groendahl et al (US 2019/0255193 A1), Lachman et al ( CA 2755473 A1), and Lisowski et al ( WO 2013/029030 A1).
Regarding claims 1-6,12-16, 19-20, Groendahl et al disclose an adeno-associated viral (AAV) vector comprising a nucleotide sequence encoding Complement Factor I (CFI), an inhibitor of the complement system, or a fragment thereof, for use in the treatment or prevention of age-related macular degeneration (AMO), wherein the vectors enable delivery of CFI to the eye. ([0001]). Groendahl et al also teach that the nucleotide sequence encoding CFI or the fragment thereof can be operably linked to a chicken beta-actin (CBA) promoter, a CAG promoter, or CMV promoter. ([0027-0028]).
It is noted that Groendahl et al do not teach an AAV viral vector comprising a nucleotide sequence encoding an inhibitor of the complement that is operably linked to a podocyte-specific promoter or a viral vector that is capable of specifically transducing podocyte.
Picconi et al teach the utilization of AAV 2/9 vector containing the minimal NPHS1 promoter, which is a podocyte-specific promoter, to drive kidney-specific expression of enhanced green fluorescence protein (eGFP).( See abstract). Picconi et al disclose that tail vein injection of the rAAV serotype 2/9 piggybacked with a minimal NPHS1 promoter driving the expression eGFP gene into pregnant mice results in kidney-specific glomerular expression of the eGFP in both pups and dams that was stable up to 12 weeks post injection. (See Figs.5- 6). It should be noted that the glomerulus contains podocytes, thereby the rAAV 2/9 vector reads on a viral vector that is capable of transducing podocytes. Picconi et al demonstrate that considerable expression of eGFP was detected in the kidneys of the dams treated with a vector containing the NPHS1 promoter, while minimal off-target expression was detected in other tissues. (See Figs.7-8). To summarize, Picconi et al teach that pseudotyped rAAV 2/9 vector can produce sustained fetal kidney expression of the GFP gene following maternal tail vein injection of pregnant mice, and that by adding a podocyte-specific promoter (NPHS1 promoter), expression can be restricted to the kidneys, specifically the glomerulus. Furthermore, Picconi et al suggest employing an AAV 2/9 vector containing a podocyte-specific promoter in gene therapy for the treatment or amelioration of genetic defects associated with kidneys. (See 1st column page 6).
Lachman et al teach a therapeutic use of recombinant or plasma-derived CFI, an inhibitor of the complement system, for the prevention, treatment, or amelioration of kidney diseases associated with complement overactivation, such as atypical haemolytic uraemic syndrome (aHUS), and membranoproliferative glomerulonephritis Type 2 (MPGN2), ( Pages 3-4th pargaraph, page 5- 5th paragraph, page 6-4th paragraph).
Taken together, employing an AAV vector encoding for an inhibitor of the complement system, such as CFI, under the control of a podocyte-specific promoter, is a product of combining prior art elements according to known methods to yield predictable results. Groendahl et al disclose an AAV vector comprising a nucleotide sequence encoding an inhibitor of the complement system (i.e. CFI), but fail to suggest using a podocyte-specific promoter or an AAV vector with a tropism to podocyte. Picconi et al strongly suggest utilizing a vector with kidney tropism such as an AAv 2/9 vector with a podocyte-specific promoter, in gene therapy to repair or ameliorate genetic defects associated with kidneys. The teachings of Lachman et al provide motivation for ordinary skill in the art to use an inhibitor of the complement system, such as CFI, to treat kidney diseases associated with the overactivation of complement system. Thus, one would have been motivated to utilize the pseudotyped rAAV 2/9 vector comprising a nucleotide sequence encoding the inhibitor of the complement system that is operably linked to a podocyte-specific promoter, to restrict its expression to the kidneys, specifically the podocytes and to treat kidney’s diseases associated with complement overactivation. One would be motivated to employ the recombinant vector of Picconi to specifically deliver the CFI to podocytes rather than using the recombinant or plasma-derived CFI, as taught by Lechman et al, which would have the disadvantage of delivering this protein ubiquitously (body and brain). A person of ordinary skill in the art who had reviewed Groendahl et al could have come across Picconi and Lechman and immediately noticed the strong possibility of modifying the vector of Groendahl to comprise an rAAV 2/9 containing a podocyte-specific promoter to express CFI in podocytes. One would have been motivated to make this modification to specifically and efficiently deliver CFI transgene into the podocytes sparing other tissues.
Regarding claims 21-22, and 42, Groendahl et al teach an AAV vector comprising inhibitor of the complement sequence consisting of a polypeptide SEQ ID NO:1 that is identical to SEQ ID NO:11.
Regarding claims 7-11,and 41, following the discussion in claim 1 above, Groendahl et al in view of Picconi et al and Lachman render obvious claim 1. However, none of the cited prior art teach an AAV vector comprising LK03 capsid proteins with an amino acid sequence of SEQ ID NO: 2.
Lisowski et al disclose recombinant adeno-associated viral (AAV) comprising LK03 capsid, which consists of amino acid with SEQ ID NN:31 that is 100% identical to SEQ ID NO:2 of the instant claim. [00140]. Lisowski et al disclose that an rAAV vector comprising the LK03 capsid can be used to facilitate the expression of gene of interest in a variety of cells in a mammal, with an increased tropism to kidney cells. (See [0015], [0048], and [00199]). For example, Lisowski et al also demonstrate that an AAV comprising LK03 capsid has a high tropism to kidney cells such FRhk-4 and Hek 293 cells. ( See Figs.34,45-46)
Therefore, claims 7-11 and 41 are also a product of combining prior art elements according to known methods to yield predictable results, the predictable results being the generation of a recombinant viral construct AAV vector comprising LK03 capsid protein with amino acid sequence of SEQ ID NO: 31. Given that Lisowski et al demonstrate that an AAV vector comprising LK03 capsid has high tropism to Kidney, it would have been prima facie obvious to modify the vector of Groendahl et al to comprise an LK03 capsid proteins in order to target the AAV to Kidney. One would have been motivated to make this modification because Lisowski et al demonstrate that an AAV vector comprising LK03 capsid with SEQ ID NO:31 has a high tropism to Kidney. A person of ordinary skill in the art would have a reasonable expectation of success, when building an expression vector, that taking the LK03 capsid comprising SEQ ID 31, as described by Lisowski et al, and incorporating it in the vector encoding an inhibitor of the complement system, that the vector of claim 1 would be successfully synthesized.
Regarding claims 25-26, following the discussion above, the combined teachings of Groendahl et al , Picconi, and Lachman render obvious claim 1. Groendahl et al also disclose an AAV vector that includes a woodchuck hepatitis post transcriptional regulatory element (WPRE) that is operably linked to the nucleotide sequence encoding CFI, as well as a bovine growth hormone poly-A signal that is also operably linked to the nucleotide sequence encoding CFI. ([0242-0245]).
Regarding claim 27, following the discussion in claim 1 above, none of the cited prior art teach nucleotide sequence encoding an inhibitor of the complement system that is operably linked to a Kozak sequence.
Xu et al teach that the utilization of an AAV vector for gene therapy can be optimized by including transcriptional and post-transcriptional elements such as a promoter, enhancer, intron, and a poly(A) sequence. According to Xu et al, including such elements would improve the expression efficiency of each viral particle, allowing for fewer viral particles to be injected. (See Introduction, 2nd column 1st paragraph page 266). For example, Xu et al teach that inserting the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), a powerful viral enhancer element, between the luciferase gene and the poly(A) in an AAV construct encoding for luciferase increased luciferase expression 2- to 7-fold in vitro and 2- to 50-fold more in vivo,. (See abstract and Material and Methods section 2.1. “ adenovirus vectors” page 267). The construct of Xu et al also included the insertion of Kozak consensus sequences around the start codon of the luciferase gene, and the poly A tail derived from the bovine growth hormone,. ( See Material and Methods section 2.1. “ adenovirus vectors” page 267). Xu et al suggest that “ Inclusion of the WPRE, combined with the optimization of transcriptional regulatory elements at the stage of Ad vector design, will substantially reduce the quantity of viral particles that must be injected in order to reach a therapeutic level of transgene expression”. ( see Discussion, 1st column-last paragraph, page 270). Therefore, it would have been prima facie obvious for one of ordinary skill in the art at the time the invention was filed to combine the teachings of Groendahl, Picconi, Lachman and Xu to utilize AAV serotype 2/9 vector containing a kidney-specific promoter and specific transcriptional regulatory elements that is operably linked to nucleotide sequence encoding an inhibitor of the complement sequence to increase the transduction efficiency, and, subsequently, the expression of viral particles into the podocytes. The combined teachings of Groendahl et al , Picconi, and Lachman et al render obvious utilizing rAAV 2/9 vector and podocyte-specific promoter to produce podocyte-specific CFI expression. Xu et al teach that the inclusion of the WPRE, along with other regulatory elements such as Kozak consensus sequence and the bGH poly A sequence, substantially reduces the number of viral particles that must be injected to achieve a therapeutic level of transgene expression. Thus one would have been motivated to combine the teachings of Groendahl, Picconi, Lachman and Xu to utilize the rAAV 2/9 vector containing the podocyte-specific promoter and specific regulatory elements to specifically deliver the therapeutic protein (i.e. CFI) to the injured podocytes rather than the whole body, because such vector would allow for the specific and efficient delivery of CFI transgene into the kidney while sparing other tissues. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Regarding claims 28-29, Groendahl et al also teach an isolated cells comprising an AAV vector encoding for an inhibitor of the complement system, also disclosed a pharmaceutical composition comprising AAV vector encoding for an inhibitor of the complement system, or the isolated cell comprising AAV vector encoding for an inhibitor of the complement system in combination with a pharmaceutically acceptable carrier, diluent or excipient.( [0019-0020]).
Conclusion
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638