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 .
Applicant’s amendments to the claims and arguments filed on November 11, 2025 have been received and entered. Claims 68, 78, 80, 86, 89 and 90 have been amended, while claims 1-67, 74, , 77, 79, 82-85, 93-96 have been canceled. Claims 68-73, 75-76, 78, 80-81, 86-91 and 92 are pending.
Election/Restrictions
Applicant’s election of joint and osteoarthritis as species for location of interest and condition in the reply filed on June 18, 2024 was 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)). Upon further consideration election of species requirement is withdrawn and all the non-elected species are hereby rejoined with the elected species.
Priority
This application is a Divisional of application no 16/326, 488 filed on February 19, 2019, which is a 371 of PCT/US17/47589 filed on 08/18/2017 that claims priority from US provisional application no 62/377,297 filed on 08/19/2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/11/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claims 68-73, 75-76, 78, 80-81, 86-91 and 92 are under consideration.
Maintained-Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 68-73, 75-76,78, 80-89 and 90 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for A method of delivering IL-1Ra polypeptide in a subject in need thereof, said method comprising administering directly into cartilage in a human subject in need thereof, a composition comprising an effective amount of recombinant sc adeno-associated virus (rAAV) comprising a capsid and a nucleic acid vector comprising a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 2 encoding codon optimized IL-1Ra polypeptide operably linked to a promoter , wherein the codon-modified IL-1Ra gene is expressed in a therapeutically effective amount in chondrocyte, does not reasonably provide enablement for administering rAAV via any other route. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Applicant assert that claims have been amended as suggested in scope rejection therefore the rejection should be withdrawn. Applicants’ arguments have been fully considered, but are not found persuasive.
In response as stated in the previous office action, instant specification enables to a method comprising administering directly into a location of cartilage in a human subject in need thereof, a composition comprising an effective amount of recombinant sc adeno-associated virus (rAAV). As stated in prior office action, the art teaches conventional single-strand AAV vectors provided only marginal levels of transgene expression intra-articularly (see Watson et al Gene Therapy (2013) 20, 670–677, page 670, col. 2, para. 2). The art further teaches it is only self-complementary (sc; double-stranded) AAV vectors could provide higher enhancement of gene expression, with rapid onset in synovial and capsular cells in vitro and in vivo (see page 670, col. 1, para. 2). The guidance provided in the specification is limited to intra articular administration of 1x1012 vg particle of sc-rAAV encoding IL-1Ra one time or multiple time to human subject suffering of osteoarthritis (examples 1-2). Watson investigated scAAV.GFP or hIL-1Ra packaged in serotypes 1, 2, 5, 8 or 9 at doses in 10-fold increments ranging from 102 to 104 viral genomes (vg) per cell. It is further disclosed that transgene expression from vectors packaged in serotypes 8 and 9, however, was significantly lower, at near background levels (see page 671, col. 1, para. 2). Watson teaches only AAV serotypes 2 and 5 were capable of mediating effective intra-articular gene transfer in the equine joint following injection of 2 1011 vg, scAAV vectors packaged in both serotypes elevated the steady state levels of hIL-1Ra in the synovial fluids to ~1 ng ml-1, a level shown to have beneficial effects in other model systems Watson (Human Gene Therapy, 2018, 29, 101-111) reported “although intra-articular transgene expression occurred over a wide range, no correlation was found between synovial fluid eqIL-1Ra content and therapeutic benefit. This is attributed to the mode of action of IL-1Ra as a competitive inhibitor of the IL-1 type 1 receptor. Due to the potency of IL-1 signaling, IL-1Ra must be present in 100- to 1,000- fold excess over IL-1 to completely inhibit its activity (see page 110, col. 2, last para. to page 111, col. 1, para. 1). Applicant has provided any argument and/or evidence contrary to the teaching of Watson.
It should be noted that claims 68-69, 71-76. 78-80, 86-90 are not limited to scAAV nor do claims recite the capsid serotype or resulting expression or level of IL-1Ra in any tissue or synovial fluid following delivery of any of the codon optimized sequence having at least 95% sequence identity to SEQ ID NO 2. In the instant case, neither prior art not instant specification provides any specific guidance to overcome this art recognized unpredictability with respect to using single-strand AAV comprising hIL-1Ra packaged in any and all different serotypes including serotypes 8 and 9, and therefore, one of skill in the art would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because transport barriers for vector selection, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for treatment, and identifying the best route to deliver IL-1Ra into chondrocyte known to be critical and unpredictable parameter in achieving more favorable AAV gene therapy outcomes for the treatment of OS or RA as supported by the observations in the art record.
Maintained-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.
Claims 68, 70, 72-73, 75-76, 78, 81, 86-89, 90-91 and 92 remain rejected under 35 U.S.C. 103 as being unpatentable over Ghivizzani et al (USPGPUB 20080187576, dated 08/07/2008) as evidenced by Evans (WO/1995/16353, dated 6/22/201995), Fath et al (PLoS One 2011, 6e17596, 1-14), Bancel et al (USPGPUB 20140141067, 05/22/2014).
Claims are drawn to a method comprising administering to a human subject into a location of interest a composition comprising a recombinant adeno-associated virus (rAAV) comprising a capsid and a nucleic acid vector comprising a codon modified IL-lRa gene comprising a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 2 over the length of SEQ ID NO: 2. Dependent claims limit the rAAV to a scAAV, wherein the nucleic acid sequence that is at least 90% identical to SEQ ID NO: 2 is operably linked to a promoter and wherein the capsid comprises at least a portion of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, or combinations thereof.
Claim interpretation: instant rejection is applied to the extent claims are directed to a method of administering/ delivering a codon-modified IL-lRa gene comprising a nucleic acid sequence that is at least 95% identical to the SEQ ID NO: 2 over the length ( SEQ ID NO: 2 is a codon modified sequence) to a location of cartilage and not necessarily any therapeutic effect.
With respect to claim 68, Ghivizzani teaches a method comprising administering to a mammal (a human subject (para. 46)) into a location of cartilage (joint, see para. 21, claim 1 and 4 of 576) a composition comprising a recombinant adeno-associated virus (rAAV) comprising a capsid (see para. 25) and a nucleic acid vector comprising a modified IL-lRa gene (see para. 178, example 6 and claim 6 of ‘576).
Regarding claim 70, Ghivizzani teaches that the rAAV is self-complementary rAAV (see example 6), para. 178.
With respect to claim 72, Ghivizzani teaches method, wherein the nucleic acid sequence of IL-1Ra gene that express a biologically-active IL-1Ra polypeptide is operably linked to a promoter (see claim 1, 9 of ‘576).
Regarding claim 73, Ghivizzani teaches the method, wherein the capsid comprises at least a portion of AAV2, AAV3, AAV5, AAV7 and AAV8 (see para. 97, 100).
With respect to claim 74, Ghivizzani teaches method, wherein the composition is administered to the joint, synovium, sub synovium, joint capsule, tendon, ligament, cartilage or a peri-articular muscle of said mammal (see claim 4 of ‘576).
Regarding claim 75, Ghivizzani teaches the method, wherein the composition is administered via direct intraarticular injection (see claim 5-6 of ‘576 and para. 74-75).
With respect to claim 76, Ghivizzani teaches that the human subject in the method is diagnosed with arthritis, osteoarthritis, neuromuscular disease, autoimmune disorder, or a joint injury or defects (see claim 8 of ‘576).
Regarding claims 78-81, Ghivizzani teaches a method of delivering an IL-lRa peptide to a synoviocyte, comprising contacting the synoviocyte with a composition comprising a self-complementary recombinant adeno-associated virus (scAAV) comprising a AAV2 capsid and anucleic acid plasmid comprising IL-lRa gene to produce IL-1RA (see para. 96 fig 1).
Regarding claim 86-87, Ghivizzani teaches that method of directly delivering scAAV encoding IL-1ra to cartilage to treat or ameliorate of one or more symptoms of injuries of cartilage (see claim 4 of ‘576, para 26).
Regarding claim 88, Ghivizzani teaches the method, wherein the capsid comprises at least a portion of AAV2, AAV3, AAV5, AAV7 and AAV8 (see para. 97, 100).
With respect to claim 89, Ghivizzani teaches a method further comprising co-administering second therapeutic molecule-encoding nucleic acid segment (see para. 33, claim 13 of ‘576).
Regarding claim 90, Ghivizzani teaches the method may ameliorates the symptoms of osteoarthritis or rheumatoid arthritis in a human (see claim 2 of ‘576).
With respect to claim 91, Ghivizzani teaches the method, wherein the sc-rAAV comprises: a. an engineered AAV capsid; and b. a vector packaged within the capsid, said vector comprising a modified IL-1 Ra gene operably linked to a promoter (see para. 46, 97, 101, 107, 112).
Regarding claim 92, Ghivizzani teaches a method of providing IL-1 Ra peptide to an area of inflammation in a subject, said method comprising: directly injecting scAAV.IL-1Ra into an inflamed knee joints (see fig. 3), wherein said sc-rAAV comprises: a. an engineered AAV capsid of serotype 2, 5, 7 or 8; a vector packaged within the capsid, said vector comprising a IL-1 Ra gene operably linked to a promoter (see para. 46, 97, 101).
Ghivizzani differs from claimed invention by not disclosing that the nucleic acid vector comprising a codon optimized IL-lRa gene comprising a nucleic acid sequence that is at least 90% or 95% identical to SEQ ID NO: 2 or a codon modified IL-1Ra gene encoding IL-1Ra protein as set forth in SEQ ID NO: 6.
Before the effective filing date of instant application, it is noted that IL-1Ra cDNA and protein sequence was known in prior art as set forth in SEQ ID NO: 3 that has 100% sequence identity to SEQ ID NO: 6 as evident from the teaching of Evans (See below).
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Additionally, it was routine to codon optimize a gene sequence for enhancing expression in mammalian cell culture. Fath et al disclose optimizing various candidate genes’ coding regions taking the following sequence-based parameters into account (i) Codon choice, (ii) increase in GC-content, (iii) avoiding UpA- and introducing CpG-dinucleotides, (iv) removing destabilizing RNA elements, (v) removing cryptic splice-sites, (vi) avoiding intragenic poly(A)-sites, (vii) removing direct repeats, (viii) avoiding RNA secondary structures, and (ix) deleting internal ribosomal entry sites (See page 2, col. 1, last para.). Bancel teaches a codon optimized modified IL-1Ra gene sequence comprising nucleic acid sequence as set forth in SEQ ID NO: 11161 that has about ~93% local homology with SEQ ID NO: 2 and about 88% sequence identity over the full length of the sequence. Regarding claim 70, Bancel et al further discloses that the modified IL-1Ra gene sequence comprising nucleic acid sequence as set forth in SEQ ID NO: 11161 that has about 90% local homology with SEQ ID NO: 5 (see sequence search below). Bancel teaches codon optimization tools, algorithms and services are well known in the art including services from GeneArt (Life Technologies), DNA2.0 (Menlo Park Calif.) and/or proprietary methods.
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Ghivizzani by substituting IL-1Ra coding sequence with another codon optimized IL-1Ra from the native human IL-1Ra coding sequence as set forth in Evan as suggested by Fath and Bancel, with a reasonable expectation of success, before effective filing date of instant invention, in order to improve IL-1Ra expression and resulting therapeutic outcome. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to optimize IL-1Ra coding sequence with reasonable expectation of success in achieving the predictable results as the Artisan was well aware of the required structures, the results of optimized coding sequence of IL-IRa in achieving the predictable results. It is noted that while Applicant’s specific sequences as set forth in SEQ ID NO: 2 is not specifically taught, absent evidence of any unexpected and/or superior results, there is nothing in the art to demonstrate that the artisan would not expect to codon optimize the known human IL-Ra coding sequence as such an optimization would fall into the general requirements for codon optimized sequence of IL-1Ra that is at least 95% sequence identify to another codon optimized sequence set forth in SEQ ID NO: 2 as suggested in Bancel. Hence, it would appear that Applicant's contribution to the art is simply to claim codon optimized coding sequences in an obvious method to the Artisan before the effective filing of the instant application. Furthermore, KSR has already stated that motivation need not be specific, and only in the case of an infinite number of variants is a specific variant non-obvious. Given that one of ordinary skill in the art was well aware of the results of codon optimization, the requirements for codon optimization of IL-1Ra, and was already able to codon optimized IL-1Ra, before the effective filing date of instant invention. Hence, it is prima facie obvious to one of ordinary skill in the art to codon optimize the IL-1Ra as suggested in prior art to express IL-1Ra at higher level in method to improve gene therapy for treating RA or OA. One who would have practiced the invention would have had reasonable expectation of success because codon optimization of to improve gene expression was already known in the art in an obvious manner to produce improved gene product, as the Artisan had already recognized the usefulness of codon optimized of IL-1Ra. Thus, it would have only required routine experimentation to modify the method of Ghivizzani to optimize the coding sequence of modified IL-1Ra as suggested in Fath and Bancel using the techniques and software known in art, as required by instant invention. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 68, 71 remain rejected under 35 U.S.C. 103 as being unpatentable over Ghivizzani et al (USPGPUB 20080187576, dated 08/07/2008) as evidenced by Evans (WO/1995/16353, dated 6/22/201995), Fath et al (PLoS One 2011, 6e17596), Bancel et al (USPGPUB 20140141067, 05/22/2014), and Husain et al (Gene Therapy (2009) 16, 927–932), Hildinger et al (US 20070042462,02/22/2007).
The teaching of Ghivizzani as evidenced by Evans, Fath and Bancel have been discussed above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that the vector comprises (i) a SV40 and bovine growth hormone (bGH) polyadenylation sequence; and/or SV40 splice donor (SD) and splice acceptor (SA) sites.
However, before the effective filing date of instant application use of SV40 SD-SA region, SV40 polyA and BGH polyA in an AAV was considered routine and conventional as evident from the teaching of Husain (see figure 1) and Hildinger (see para. 250).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Ghivizzani by substituting IL-1Ra coding sequence with another codon optimized IL-1Ra from the native human IL-1Ra coding sequence as set forth in Evan and suggested by Fath and Bancel, with a reasonable expectation of success, before effective filing date of instant invention, in order to improve IL-1Ra expression and resulting therapeutic outcome. Said modification amounting to combining prior art elements according to known methods to yield predictable results. It would be further obvious to include SV40 SD-SA region, SV40 polyA and BGH poly A in an AAV disclosed in Ghivizzani for optimal gene delivery to a human subject. One who would have practiced the invention would have had reasonable expectation of success of codon optimization and incorporation of SD/SA sites and polyA sequence as it was already known in the art to improve gene expression and produce gene product in an obvious manner, as the Artisan already recognized the usefulness of codon optimized IL-1Ra sequence. Thus, it would have only required routine experimentation to substitute the coding sequence of modified IL-1Ra as disclosed in Ghivizzani with a codon optimized sequence as disclosed as suggested in Bancel using the techniques and software known in art and disclosed in Fath. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 68, 70, 72-73, 75-76, 78 81, 86-89, 90-91 and 92 remain rejected under 35 U.S.C. 103 as being unpatentable over Ghivizzani et al (USPGPUB 20080187576, dated 08/07/2008) as evidenced by Evans (WO/1995/16353, dated 6/22/201995), Fath et al (PLoS One 2011, 6e17596), Bancel et al (USPGPUB 20140141067, 05/22/2014) and further in view of Goodrich et al (Molecular Therapy–Nucleic Acids (2013) 2, e70;1-10, IDS).
The teaching of Ghivizzani as evidenced by Evans, as evidenced by Evans, Fath and Bancel have been discussed above and relied in same manner here. The combination of references differs from claimed invention by not disclosing delivering codon optimized IL-1ra coding sequence expresses IL-Ira inhibits inflammation through blocking IL-1.
Goodrich et al teach a method comprising contacting the chondrocyte or synoviocyte with a composition comprising a self-complementary recombinant adeno-associated virus (scAAV) comprising a AAV2 capsid and a nucleic acid plasmid comprising IL-lRa gene operably linked to a CMV or CBh promoter to produce IL-1Ra (see fig. 2) (limitation of claims 78-81). It is further disclosed that codon optimized IL-Ra sequence delivered via scAAV directly to inflamed knee joint shows reduced inflammation (see page 4, col. 2, para. 2, page 7, col. 2, para. 4-5, abstract). Goodrich et al teach a scAAV virus vector comprising a nucleic acid vector comprising the modified IL-lRa gene: a promoter operably linked to the modified IL-1Ra gene, wherein promoter is a CMV promoter or Cbh (see page 8, col. 1, para. 1-3). Goodrich et al teach that the vector is a scAAV2.5 IL-1ra (see figure 4, 6 and page 8, col. 1, para. 3-4).
Accordingly, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Ghivizzani/ Goodrich by substituting IL-1Ra coding sequence with another codon optimized IL-1Ra from the native human IL-1Ra coding sequence as set forth in Evan and suggested by Fath and Bancel, with a reasonable expectation of success, before effective filing date of instant invention, in order to improve IL-1Ra expression and resulting therapeutic outcome. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use optimized human IL-1Ra sequence with reasonable expectation of success in achieving the predictable results as the Artisan was well aware of the required structures, the results of optimized coding sequence of IL-IRa. It is noted that while Applicant’s specific sequences as set forth in SEQ ID NO: 2-5 are not specifically taught, absent evidence of any unexpected and/or superior results, there is nothing in the art to demonstrate that the artisan would not expect to codon optimize the IL-1Ra sequence known in prior Goodrich and Bancel. Hence, it would appear that Applicant's contribution to the art is simply to claim codon optimized coding sequences, which is obvious to the Artisan before the effective filing of the instant application. Furthermore, KSR has already stated that motivation need not be specific, and only in the case of an infinite number of variants is a specific variant non-obvious. Given that one of ordinary skill in the art was well aware of the results of codon optimization, the requirements for codon optimization of IL-1Ra, and was already able to codon optimize IL-1Ra construct that is packaged in the AAV2capsid as evident from Goodrich to reduce inflammation, before the effective filing date of instant invention. One of skill in the art would have been expected to have a reasonable expectation of success because prior art reported experimentation to substitute the wild type coding sequence with a codon optimized coding sequence of IL-1Ra as disclosed in Goodrich to improve the therapeutic outcome. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicant disagree with the rejection arguing claim 68 is not obvious over the combination of Ghivizzani and Bancel. Contrary to the Office's assertion that Bancel suggests that the known human IL-1Ra coding sequence can be codon optimized to generate a IL-1Ra sequence with at least 95% sequence identity to SEQ ID NO: 2 (Office Action, page 12), in view of the teachings of Bancel, there is no reason to codon optimize Ghivizzani's IL-1Ra sequence used for treating osteoarthritis and rheumatoid arthritis. Fath is silent on any IL- 1Ra gene or codon-optimization for expression in any tissue, much less in a cartilage tissue. Accordingly, there would be no reason to combine Ghivizzani's methods and compositions for treating osteoarthritis and rheumatoid arthritis with Fath's broad optimization of genes for expression in immortal cell lines. As such, Fath and Ghivizzani do not render obvious a codon- modified IL-1Ra gene comprising a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 2 administered to a location of cartilage, wherein the codon-modified IL-1Ra gene is expressed in a therapeutically effective amount. Further, as stated in the Applicant's previous Response, just because codon-modification is possible, one of ordinary skill in the art would not presume that a codon-modified sequence will result in increased expression (see, e.g., Dronadula, Polakova and Passetti, each of which were submitted previously). As such, claims 78 and 92 and all claims that depend therefrom likewise would not have been obvious over Ghivizzani, Bancel, Fath and Evans. Therefore, all claims would not have been obvious over Ghivizzani, Bancel, Evans and Fath, and this rejection may be withdrawn. Applicants’ arguments have been fully considered, but are not found persuasive.
As an initial matter as stated in previous office action, applicant’s argument that prior art fails to teach or suggest specific sequence that are at least 90% identical to SEQ ID NO: 2 as set forth in SEQ ID NO: 3, 4 or 5 is found persuasive, because claims recite finite number of sequences showing biological effect that may be non-obvious from a innumerable number of choice from the claim limitation, therefore, previous rejection of claims 69 and 80 were withdrawn. Applicant’s argument pertaining to rejection of claim 69 and 80 thereby moot.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have further engaged in selective reading of the teachings of Ghivizzani to formulate the grounds for not teaching the codon optimized IL-1Ra sequence. It should be noted that the ultimate goal of codon optimization is to have reliable expression and increased protein yields (see Fath, page 2, col. 2, and art of record Goodrich et al page 9. Col. 1, para. 1). As previously indicated, Bancel/ Goodrich both in describe sequence of the gene of interest may be codon optimized including IL-1Ra.
In response to applicant's argument that Fath is directed to expression of a broad selection of 50 optimized candidate genes in HEK293T cells, CHO cells and insect cells (Fath, "Abstract". However, Fath is silent on any IL- 1Ra gene or codon-optimization for expression in any tissue, much less in a cartilage tissue., the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, both Fath and Bancel references describe codon optimization methods are known in the art and may be useful in efforts to achieve one or more of several goals. These goals include to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that may impair gene construction or expression, customize transcriptional and translational control regions, insert or remove protein trafficking sequences, remove/add post translation modification sites in encoded protein (e.g. glycosylation sites), add, remove or shuffle protein domains, insert or delete restriction sites, modify ribosome binding sites and mRNA degradation sites, to adjust translational rates to allow the various domains of the protein to fold properly, or to reduce or eliminate problem secondary structures within the mRNA (see para. 144 of Bancel). A variety of codon optimization tools, algorithms and services that includes services from GeneArt and/or proprietary methods (see para. 144 and page 8, col. 1, para. 1 and Goodrich page 9 col. 1, para. 1) for this purpose, are well-known in the art. Thus, Bancel/ Fath/Goodrich. cure the deficiency in Ghivizzani to codon optimize the coding sequence using known method to improve gene expression. Additionally, Goodrich explicitly teaches IL-1Ra codon optimized sequence could be generated from software, GeneOptimizer (Life Technologies, Grand Island, NY), which provides algorithms that optimize codon usage in a particular species to enhance protein production (see page 9, col. 1, para. 1). In view of foregoing, it is apparent one of ordinary skill in the art seeking to increase expression of IL-1Ra in a cartilage tissue would be motivated to generate several codons optimized sequence to select the ones showing higher expression in cartilage tissue as in Goodrich, with reasonable expectation of success.
Further as stated in previous office action, Examiner in part relying on that KSR stated “only in the case of an infinite number of variants, it is a specific set of variant non-obvious.” That is not the case here (emphasis added). Examiner has already withdrawn rejection pertaining to more specific sequence. The rejected claims are not limited to any particularly effective set of variants amongst a large number of possibilities. Given that one of ordinary skill in the art was well aware of the results of codon optimization of IL-1Ra (see Goodrich), the requirements and known proprietary methods and software for codon optimization (such as one disclosed in Goodrich. and Bancel), and was already able to make codon optimized sequence. Absent evidence to an unexpected superior result with any specific variant of IL-1Ra sequence, it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of human IL-1Ra as disclosed in Evans using method disclosed in prior art by codon optimizing to obtain the one of the pluralities of variant embraced by the breadth of claim, with reasonable expectation of success.
On pages 11-12 of the applicant’s argument, applicant re-iterates and rely on their previous arguments pertaining that have been discussed in preceding section. The arguments are substantially the same as those addressed in the foregoing response.
In response to applicant's argument that Goodrich fails to teach any codon-modified human IL-1Ra, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As stated before, the rejected claims are broad and encompass innumerable number of codons optimized human IL1Ra sequences. Before the effective filing date of instant application, human IL-1Ra cDNA and protein sequence were known in prior art as set forth in SEQ ID NO: 3 that has 100% sequence identity to SEQ ID NO: 6 as evident from the teaching of Evans. Given that one of ordinary skill in the art was well aware of the results of codon optimization, the requirements for codon optimization of IL-1Ra, and was already able to codon optimize IL-1Ra construct that is packaged in the AAV2 capsid as evident from Goodrich to reduce inflammation, before the effective filing date of instant invention. One of skill in the art would have been expected to have a reasonable expectation of success to generate a large number of human codons optimized IL-1Ra sequence because prior art reported experimentation to substitute the wild type coding sequence with a codon optimized coding sequence of IL-1Ra as disclosed in Goodrich, in order to improve the therapeutic outcome.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments on record are not compelling and do not overcome the rejection of record.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 68-73, 75-76, and 80 were 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. Applicant’s amendments to the claims obviate the basis of the rejection.
Examiner’s note: Applicant’s representative is requested to contact Examiner to resolve the pending issues to put instant application in the condition for allowance.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632