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 .
Applicant’s amendment filed on 12/18/2025 has been entered.
Amended claims 1, 3-13 and 20-26 are pending in the present application.
Applicant elected previously without traverse of Group I, which is drawn to a rAAV vector comprising a nucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver.
Applicant also elected previously the following species: (i) myelin oligodendrocyte glycoprotein (MOG) as a species of first autoimmune disease therapeutic molecule; (ii) SEQ ID NO: 15 as the distinct species of MOG; (iii) a mammalian cell-specific promoter as a species of a promoter; and (iv) a peptide as a species of a further encoded second distinct therapeutic molecule.
Claims 20-26 were withdrawn previously from further consideration because they are directed to a non-elected invention. Claims 6-7 were also withdrawn previously from further consideration because they are directed to non-elected species.
Accordingly, amended claims 1, 3-5 and 8-13 are examined herein with the above elected species.
Response to Amendment
1. The rejection under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (US 6,630,348; IDS) was withdrawn in light of currently amended independent claim 1, particularly with the limitation “wherein the nucleic acid segment encodes a mammalian myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG)”.
2. The rejection on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,297,444 was withdrawn since the ‘444 patent has a later filing date than the instant pending application and, likely, a later expiration date.
Claim Objections
Claims 1 and 3-5 are objected to because of the term “myelin basis protein (MBP)”. It should be - - myelin basic protein (MBP) - -.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Amended claim 11 is 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. This is a new ground of rejection necessitated by Applicant’s amendment.
Amended claim 11 recites the limitation "the subject" in line 3 of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation, and in claims 1 and 10 from which claim 11 is dependent upon, there is no recitation of any subject. Accordingly, which particular subject does the limitation refer to? Clarification is requested because the metes and bounds of the claim are not clearly determined.
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.
Amended claims 1, 3 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over High et al (US 2003/0130221; IDS) in view of Luth et al (J. Clin. Invest. 118:3403-3410, 2008; IDS), Kerlero de Rosbo et al (Eur. J. Immunol. 27:3059-3069, 1997; IDS), and Fissolo et al (J. Neuroinflammation 9:139, 2012; http://www.jneuroinflammation.com/content/9/1/139, 13 pages; IDS). This is a slightly modified rejection necessitated by Applicant’s amendment.
The instant claims are directed to a recombinant AAV vector comprising a polynucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver, wherein the nucleic acid segment encodes a mammalian myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG).
With respect to the elected species, High et al teach that hepatic/liver-directed expression of a therapeutic transgene induces immunological tolerance to the expression product of the therapeutic transgene using at least a recombinant AAV vector/particle comprising a therapeutic transgene operably linked to a liver-specific promoter (see at least the Abstract; Summary of the Invention; particularly paragraphs 20-22, 24, 38-39, 42, 48-50, 57, 62; and examples 1-7). High et al stated “The therapeutic polypeptide can be substantially any polypeptide or protein that can elicit a desired therapeutic effect” (paragraph 22); “A therapeutic polypeptide as described herein can be a biologically active peptide, protein fragment or full-length protein that can bring forth a desired therapeutic response” (paragraph 50); “The polynucleotide encoding one or more proteins of interest can be operatively associated with a variety of different promoter/regulator sequences” (first sentence of paragraph 57); “Accordingly, it is preferred that the polynucleotide described herein is operably linked to a liver-specific promoter” (paragraph 21); “For example, a synthetic promoter comprised of liver specific promoter and enhancer elements or the ApoE/hAAT enhancer/promoter combination may be used to direct high level expression to the liver” (paragraph 57); “Preferably, the vector is an adeno-associated virus vector” (last line of paragraph 21); “AAV vectors can be produced in a helper virus-free system, are devoid of any viral gene products, and have reduced immunogenicity compared to other viral vectors” (paragraph 62); and “The methodology of the present invention can be used prophylactically, to minimize the symptoms or risks associated with various diseases or disorders. Thus, a tolerized subject challenged with a therapeutic nucleic acid (to effect transgenic expression) or a therapeutic polypeptide directly does not exhibit a medically significant neutralizing/inhibitory antibody response and can ideally prevent or ameliorate symptoms associated with a disease or disorder" (paragraph 42). Example 4 demonstrated that in a hemophilia model sustained expression of F.IX is associated with induction of immune tolerance and that the tolerance induction is antigen-specific.
High et al do not teach a recombinant AAV vector comprising at least a therapeutic transgene encoding myelin oligodendrocyte glycoprotein (MOG) operably linked to a liver-specific promoter for inducing immunological tolerance at least to MOG.
Before the effective filing date of the present application (4/24/2014), Luth et al already demonstrated that ectopic expression of neural autoantigen myelin basic protein (MBP) in a transgenic mouse liver suppresses experimental autoimmune neuroinflammation in a mouse model for the human neuroinflammatory disease multiple sclerosis EAE by inducing MBP-specific CD4+CD25+Foxp3+ Tregs which are important mediators of immune tolerance to self-antigens and Treg inactivation may cause autoimmune disease (see at least the Abstract and Figs. 1-5). Luth et al also demonstrated that ectopic MBP expression in the liver via transient gene expression facilitated by hydrodynamics-based gene transfer with MBP-encoding vector and/or adenoviral gene transfer of MBP suppresses EAE (page 3405, left col, first full paragraph; Fig. 1 F-G). Luth et al stated “Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases” (last sentence of the Abstract); and “[t]he method of Treg expansion described here may be promising because gene delivery to hepatocytes is becoming a realistic therapeutic option (27). Moreover, the MBP-specific Tregs induced by hepatic MBP expression featured extraordinary suppressive efficacy, both in abrogating the proliferation even of a 20-fold excess of MP-stimulated conventional T cells in vitro (Figure 5) and in suppressing EAE in vivo after the transfer of as few as 2 x 104 converted T cells (Figure 4). Of note, even transient hepatic expression of autoantigen induced robust control of autoreactive lymphocytes (Figure 1, F and G). Thus, targeting of autoantigen expression to the liver may indeed be an attractive approach to induce active tolerance to autoantigens and protect from autoimmune disease and the usefulness of this approach to serve as therapy for human autoimmune disease should be explored" (page 3409, left col., first full paragraph).
Additionally, Kerlero de Rosbo et al taught that the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in multiple sclerosis (MS) over that to myelin basic protein (MBP), proteolipid protein or myelin-associated glycoprotein, suggesting a prevalent role for the autoimmune response to MOG in the pathogenesis of MS in patients (see at least the Abstract).
Before the effective filing date of the present application (4/24/2014), Fissolo et al also demonstrated the beneficial effects (e.g., anti-inflammatory and neuroprotective effects) of MOG-DNA vaccines which were intramuscularly administered into a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), in both prophylactic and therapeutic settings (see at least the Abstract and Figure 1). Fissolo et al found that vaccination with DNA encoding MOG protects against EAE induction as well as ameliorates ongoing EAE, via induction CD4+CD25+FoxP3+ regulatory T cells and upregulation of genes with neuroprotective functions (see sections titled “Vaccination with DNA encoding MOG protects against EAE induction” and “MOG-DNA vaccination ameliorates ongoing EAE”). Fissolo et al also stated “vaccination with DNA encoding MBP was also associated with a significant reduction in disease severity, although to a lesser degree compared with MOG-encoding DNA vaccines” (page 5, left col, bottom of last paragraph).
It would have been obvious for an ordinary skilled artisan to modify the teachings of High et al by also preparing a recombinant AAV vector comprising at least a therapeutic transgene encoding a human myelin oligodendrocyte glycoprotein (MOG) or a biologically active fragment thereof operably linked to a liver-specific promoter for inducing immunological tolerance at least to MOG that is useful for minimizing the symptoms or risks associated with MS in a patient, as well as the same modified recombinant AAV vector that further comprises a second therapeutic transgene encoding a human myelin basic protein (MBP) or a biologically active fragment thereof, in light of the teachings of Luth et al, Kerlero de Rosbo et al and Fissolo et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Luth et al already demonstrated that ectopic expression of neural autoantigen myelin basic protein (MBP) in a transgenic mouse liver, and ectopic MBP expression in the liver via transient gene expression facilitated by hydrodynamics-based gene transfer with MBP-encoding vector and/or adenoviral gene transfer of MBP suppress experimental autoimmune neuroinflammation in a mouse model for the human neuroinflammatory disease multiple sclerosis EAE. Additionally, Kerlero de Rosbo et al also taught that the autoimmune response to MOG plays a prevalent role in the pathogenesis of MS in patients. Moreover, Fissolo et al also demonstrated successfully the beneficial effects (e.g., anti-inflammatory and neuroprotective effects) of MOG-DNA vaccines which were intramuscularly administered into a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), in both prophylactic and therapeutic settings.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of High et al, Luth et al, Kerlero de Rosbo et al and Fissolo et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified recombinant AAV vector resulting from the combined teachings of High et al, Luth et al, Kerlero de Rosbo et al and Fissolo et al as set forth above is indistinguishable and encompassed by the composition of the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejection in the Amendment filed on 12/18/2025 (pages 6-10) have been fully considered but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued basically that one of ordinary skill in the art would not combine the cited reference to arrive at the claimed rAAV vectors at least because the rAAV vectors disclosed in the cited references are used for different purposes. For example, High which focuses on the treatment of hemophilia, provides only an early, general disclosure regarding promoting central tolerance by expressing an antigen (e.g., a wild-type Factor IX that does not already exist in the subject’s body because the subject is deficient in wild-type Factor IX) in a subject’s liver; while the present claims relate to promoting a tolerant immune response to a subject’s immune reactivity to a pre-existing MOG, MBP, or PLP proteins. Nor does High discuss multiple sclerosis, reducing immune reactivity to a pre-existing antigen, or that MOG, PLP, or MBP are therapeutic polypeptides. Applicant also argued that neither Luth nor Fissolo relate to rAAV nucleic acid vectors as claimed, but are rather directed to transient systems for introducing genes to a target cell. Specifically, Luth discloses ectopic expression of MBP in the liver, using MBP delivered via adenovirus vectors and hydrodynamics-based gene transfer, prophylactically suppresses development of EAE in some but not all mice (Luth, FIG.1). Fissolo relates to DNA vaccination (using naked DNA encoding MOG), which was found to prophylactically suppress development of EAW in some but not all mice (Fissolo, FIG. 1) and to transiently reverse EAE progression to some degree; however, the trend seems to indicate that the therapeutic effects are wearing off by day 28. Applicant also argued that based on the disclosure of Fissolo, the skilled artisan would not have selected MBP or PLP as a candidate protein in the context of MS due to the statement “therapeutic treatment with plasmids encoding MOG, but not with MBP or PLP, resulted in amelioration of ongoing EAE” (Fissolo at Discussion). In contrast, Applicant argued that AAV produces longer-term, lower levels of expression for at least 35 days, as demonstrated by the present application (e.g., FIGs. 6A-6C, 14A, 14B, 15A, 15B); and based on the difference in expression kinetics, one skill in the art would not have had the motivation to combine the cited references to arrive at the claimed rAAV nucleic acid vectors, let alone a reasonable expectation of success in generating a rAAV vector to express MOG, PLP, or MBP in the liver of a subject in need thereof based on the disclosure of Luth and Fissolo. Applicant also argued that even in the context of High, which reports AAV as one of several potential vectors (including DNA vectors and adenovirus) for general expression in the liver, Luth and Fissolo would not provide adequate teachings or motivation to constitute a reasonable expectation of success. Applicant further argued that Kerlero de Rosbo does not relate to rAAV nucleic acid vectors as claimed, and no teaching or suggesting that MOG should be a therapeutic protein, let alone a rAAV nucleic acid as claimed.
First, since the above rejection was made under 35 U.S.C. 103 none of the cited references have to teach every limitation of the instant claims. For example, the primary High reference does not have to teach or suggest using MOG, PLP, and/or MBP as therapeutic polypeptides, or multiple sclerosis. Similarly, none of Luth, Kerlero de Rosbo, and Fissolo have to teach or suggest the use of a recombinant AAV vector for expressing a neural autoantigen such as MBP, MOG, or PLP. It is also apparent that Applicant considered each of the cited references in total isolation one from the others, without taking into consideration the specific combined teachings of High, Luth, Kerlero de Rosbo and Fissolo as set forth in the above 103 rejection.
Second, the instant claims are simply drawn to a recombinant AAV vector comprising a polynucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver, wherein the nucleic acid segment encodes a mammalian myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG).
Third, High teaches that hepatic/liver-directed expression of a therapeutic transgene induces immunological tolerance to the expression product of the therapeutic transgene using at least a recombinant AAV vector/particle comprising a therapeutic transgene operably linked to a liver-specific promoter. High also discloses that a therapeutic polypeptide can be any polypeptide or protein that can elicit a desired therapeutic effect, not necessarily limited to coagulation factors such as Factor VIII and Factor IX. Moreover, High stated explicitly “AAV vectors can be produced in a helper virus-free system, are devoid of any viral gene products, and have reduced immunogenicity compared with other viral vectors….Therefore, an AAV vector is preferred even though any vector that can help achieve efficient hepatic gene transfer is useable” (paragraph [0062]); and exemplary recombinant AAV vectors were constructed and used in all Examples. Importantly, Luth already demonstrated that ectopic expression of neural autoantigen myelin basic protein (MBP) in a transgenic mouse liver (a long-term expression of the neural autoantigen MBP) suppresses experimental autoimmune neuroinflammation in a mouse model for the human neuroinflammatory disease multiple sclerosis EAE by inducing MBP-specific CD4+CD25+Foxp3+ Tregs which are important mediators of immune tolerance to self-antigens and Treg inactivation may cause autoimmune disease. Additionally, Luth also demonstrated that ectopic MBP expression in the liver via transient gene expression facilitated by hydrodynamics-based gene transfer with MBP-encoding vector and/or adenoviral gene transfer of MBP suppresses EAE. Moreover, Fissolo also disclosed that vaccination with DNA encoding MOG protects against EAE induction as well as ameliorates ongoing EAE, via induction CD4+CD25+FoxP3+ regulatory T cells and upregulation of genes with neuroprotective functions; while Kerlero de Rosbo taught that the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in multiple sclerosis (MS) over that to myelin basic protein (MBP), proteolipid protein or myelin-associated glycoprotein, suggesting a prevalent role for the autoimmune response to MOG in the pathogenesis of MS in patients. Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of High by also preparing a recombinant AAV vector comprising at least a therapeutic transgene encoding a human myelin oligodendrocyte glycoprotein (MOG) or a biologically active fragment thereof operably linked to a liver-specific promoter for inducing immunological tolerance at least to MOG that is useful for minimizing the symptoms or risks associated with MS in a patient, as well as the same modified recombinant AAV vector that further comprises a second therapeutic transgene encoding a human myelin basic protein (MBP) or a biologically active fragment thereof, in light of the teachings of Luth, Kerlero de Rosbo and Fissolo as presented above with a reasonable expectation of success. Please also note that the primary High reference already taught clearly that AAV is a preferred vector due to its reduced immunogenicity compared to other viral vectors. Please refer to the above 103 rejection for details.
Fourth, Fissolo et al stated clearly “Unexpectedly, one of the antigenic controls, MBP, had also a positive effect on EAE disease course, albeit it did not modify the onset of disease” (page 10, right column); “vaccination with DNA encoding MBP was also associated with a significant reduction in disease severity, although to a lesser degree compared with MOG-encoding DNA vaccines” (page 5, left col, bottom of last paragraph); and “A DNA vaccine encoding the full-length MBP molecule (BHT-30009) has been used in clinical trials to evaluate safety in MS patients [9,10]. DNA vaccines were found to be safe and demonstrated efficacy reducing brain MRI lesion activity” (page 10, paragraph bridging left and right columns). Thus, at least based on the teachings of Fissolo alone an ordinary skill in the art would readily recognize at least that in addition to MOG, MBP is also a useful therapeutic polypeptide for reducing EAE disease severity.
Fifth, before the effective filing date of the present application (04/24/2014) the prior art at least in the form of Xiao article (J. Virol. 70:8098-8108, 1996; IDS) already demonstrated an efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector, with a transgene expression persisted for more than 1.5 years (see Abstract).
B. Applicant argued that the claimed composition has surprisingly beneficial properties. Applicant argued that the application represents the first disclosure of a composition capable of (i) initial and continuous induction of antigen-specific Tregs after administration of a gene therapy in animals exhibiting MS symptoms, and (ii) reversal of MS symptoms, and prevention of symptom onset, for 35 or more days (e.g., FIGs. 7B, 8, 10, and 13A-13C). Additionally, the claimed therapy exhibited a complete prevention of onset of symptoms after its administration to mice, and the administration conferred survival for at least 135 days, as shown in FIG. 3B of Keeler (Keeler et al. Gene therapy-induced antigen-specific Tregs inhibit neuro-inflammation and reverse disease in a mouse model of Multiple Sclerosis, Molecular Therapy (2017); IDS). These findings garnered praise from immunologists in a leading neurology news publication (Robinson, Inducing tolerance to a myelin protein reverses MS symptoms in a mouse model, Neurology Today (2019)). Applicant also argued that both the instant application (e.g., Example 4) and Keeler (a publication from the inventor’s lab which includes additional data related to AAV-MOG with a promoter driving liver expression) demonstrate reversal of EAE using only a single dose of AAV-MOG. This is very different than the results demonstrated in Luth and Fissolo, with Fissolo had data related to reversal of EAE, but the MOG-DNA was injected twice and the reversal effect of the mean clinical score was modest and only observed for about 27 days, at which point the mean clinical score began to rise again, consistent with the beginning of a relapse (FIGs. 1D-1F of Fissolo). Accordingly, the properties of the claimed rAAV nucleic acid vector are “unexpectedly superior” to those of the treatments described in the cited references.
First, once again the instant claims are simply drawn to a recombinant AAV vector comprising a polynucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver, wherein the nucleic acid segment encodes a mammalian myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). The instant claims are not drawn to a prophylactic or a treatment method in a subject in need thereof., let alone one that requires a particular prophylactic and/or therapeutic efficacy.
Second, please note that any “unexpected” result must be commensurate with the scope of the claims. In this instance, the examiner noted that the therapeutic and/or prophylactic effects in the present application and/or the post-filing Keeler reference were obtained at least via the use of a recombinant AAV8 viral particle containing the full-length coding sequence of the neural protein MOG.
Third, the modified recombinant AAV vector resulting from the combined teachings of High et al, Luth et al, Kerlero de Rosbo et al and Fissolo et al as set forth above is indistinguishable and encompassed by the composition of the presently claimed invention. Please note that the patentability of composition claims depends on the claimed structure and not on the use or purpose of the structure, and stating an intended use is not sufficient to structurally distinguish from the prior art. Please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Fourth, please note that the standard under 35 USC 103 is a “reasonable” expectation of success. Please also refer to the Patent Board Decision dated 01/12/2022 for similar composition claims in the parent application of 15/306,163. The encouraging words by a single expert in the field was also not found by to be sufficient to overcome a strong prima facie case of obviousness with respect to the claimed product.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over High et al (US 2003/0130221; IDS) in view of Luth et al (J. Clin. Invest. 118:3403-3410, 2008; IDS), Kerlero de Rosbo et al (Eur. J. Immunol. 27:3059-3069, 1997; IDS), and Fissolo et al (J. Neuroinflammation 9:139, 2012; http://www.jneuroinflammation.com/content/9/1/139, 13 pages; IDS) as applied to claims 1, 3 and 8-13 above, and further in view of Devaux et al (WO 95/06727; IDS).
The combined teachings of High et al, Luth et al, Kerlero de Rosbo et al and Fissolo et al were presented above. However, none of the cited references teaches explicitly that the encoded MOG comprising at least 20 amino acid contiguous sequence of SEQ ID NO: 15 (elected species), including at least 95% identical to the sequence of SEQ ID NO: 15 (the 247-amino-acid sequence of human MOG).
Before the effective filing date of the present application (4/24/2014), Devaux et al already disclosed a nucleic acid molecule having a nucleotide sequence encoding human MOG, an autoantigen related to demyelinating autoimmune diseases, having SEQ ID NO: 2 (encoded by the nucleotide sequence of SEQ ID NO: 1) that is 100% identical to the sequence of SEQ ID NO: 15 of the present application for preparation of recombinant human MOG and/or antigenic fragments that are useful in the treatment of autoimmune diseases (see at least the abstract; SEQ ID NOs. 1-2; and attached sequence searches below).
It would have been obvious for an ordinary skilled artisan to further modify the combined teachings of High et al, Luth et al, Kerlero de Rosbo et al and Fissolo et al by also using at least an encoded MOG having the sequence of SEQ ID NO: 15 and/or biologically active protein fragments thereof for MS treatment, in light of the teachings of Devaux et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Devaux et al already disclosed a nucleic acid molecule having a nucleotide sequence encoding human MOG, an autoantigen related to demyelinating autoimmune diseases, having SEQ ID NO: 2 that is 100% identical to the sequence of SEQ ID NO: 15 of the present application for preparation of recombinant human MOG and/or antigenic fragments that are useful in the treatment of autoimmune diseases.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of High et al, Luth et al, Kerlero de Rosbo et al, Fissolo et al and Devaux et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified recombinant AAV vector resulting from the combined teachings of High et al, Luth et al, Kerlero de Rosbo et al, Fissolo et al and Devaux et al as set forth above is indistinguishable and encompassed by the composition of the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejection in the Amendment filed on 12/18/2025 (page 10) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically that Deveaux merely discloses a MOG sequence and does not cure the defects of High, Luth, Kerlero de Roso and Fissolo as discussed above. Accordingly, withdrawal of the above 103 rejection is requested.
Please refer to the examiner’s same responses to Applicant’s arguments on the deficiencies of High, Luth, Kerlero de Roso and Fissolo above. The Deveaux reference was cited primarily to supplement the combined teachings of High, Luth, Kerlero de Roso and Fissolo for the limitations recited in dependent claims 4-5.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s acting SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
WO9506727-A2;
SEQ ID NO: 1
Alignment Scores:
Length: 1080
Score: 1306.00 Matches: 247
Percent Similarity: 100.0% Conservative: 0
Best Local Similarity: 100.0% Mismatches: 0
Query Match: 100.0% Indels: 0
Gaps: 0
Qy 1 MetAlaSerLeuSerArgProSerLeuProSerCysLeuCysSerPheLeuLeuLeuLeu 20
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 184 ATGGCAAGCTTATCAAGACCCTCTCTGCCCAGCTGCCTCTGCTCCTTCCTCCTCCTCCTC 243
Qy 21 LeuLeuGlnValSerSerSerTyrAlaGlyGlnPheArgValIleGlyProArgHisPro 40
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 244 CTCCTCCAAGTGTCTTCCAGCTATGCAGGGCAGTTCAGAGTGATAGGACCAAGACACCCT 303
Qy 41 IleArgAlaLeuValGlyAspGluValGluLeuProCysArgIleSerProGlyLysAsn 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 304 ATCCGGGCTCTGGTCGGGGATGAAGTGGAATTGCCATGTCGCATATCTCCTGGGAAGAAC 363
Qy 61 AlaThrGlyMetGluValGlyTrpTyrArgProProPheSerArgValValHisLeuTyr 80
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 364 GCTACAGGCATGGAGGTGGGGTGGTACCGCCCCCCCTTCTCTAGGGTGGTTCATCTCTAC 423
Qy 81 ArgAsnGlyLysAspGlnAspGlyAspGlnAlaProGluTyrArgGlyArgThrGluLeu 100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 424 AGAAATGGCAAGGACCAAGATGGAGACCAGGCACCTGAATATCGGGGCCGGACAGAGCTG 483
Qy 101 LeuLysAspAlaIleGlyGluGlyLysValThrLeuArgIleArgAsnValArgPheSer 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 484 CTGAAAGATGCTATTGGTGAGGGAAAGGTGACTCTCAGGATCCGGAATGTAAGGTTCTCA 543
Qy 121 AspGluGlyGlyPheThrCysPhePheArgAspHisSerTyrGlnGluGluAlaAlaMet 140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 544 GATGAAGGAGGTTTCACCTGCTTCTTCCGAGATCATTCTTACCAAGAGGAGGCAGCAATG 603
Qy 141 GluLeuLysValGluAspProPheTyrTrpValSerProGlyValLeuValLeuLeuAla 160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 604 GAATTGAAAGTAGAAGATCCTTTCTACTGGGTGAGCCCTGGAGTGCTGGTTCTCCTCGCG 663
Qy 161 ValLeuProValLeuLeuLeuGlnIleThrValGlyLeuValPheLeuCysLeuGlnTyr 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 664 GTGCTGCCTGTGCTCCTCCTGCAGATCACTGTTGGCCTGGTCTTCCTCTGCCTGCAGTAC 723
Qy 181 ArgLeuArgGlyLysLeuArgAlaGluIleGluAsnLeuHisArgThrPheAspProHis 200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 724 AGACTGAGAGGAAAACTTCGAGCAGAGATAGAGAATCTCCACCGGACTTTTGATCCCCAC 783
Qy 201 PheLeuArgValProCysTrpLysIleThrLeuPheValIleValProValLeuGlyPro 220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 784 TTTCTGAGGGTGCCCTGCTGGAAGATAACCCTGTTTGTAATTGTGCCGGTTCTTGGACCC 843
Qy 221 LeuValAlaLeuIleIleCysTyrAsnTrpLeuHisArgArgLeuAlaGlyGlnPheLeu 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 844 TTGGTTGCCTTGATCATCTGCTACAACTGGCTACATCGAAGACTAGCAGGGCAATTCCTT 903
Qy 241 GluGluLeuArgAsnProPhe 247
|||||||||||||||||||||
Db 904 GAAGAGCTACGAAATCCCTTC 924
WO9506727-A2;
SEQ ID NO:2
Query Match 100.0%; Score 1306; DB 1; Length 247;
Best Local Similarity 100.0%;
Matches 247; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MASLSRPSLPSCLCSFLLLLLLQVSSSYAGQFRVIGPRHPIRALVGDEVELPCRISPGKN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MASLSRPSLPSCLCSFLLLLLLQVSSSYAGQFRVIGPRHPIRALVGDEVELPCRISPGKN 60
Qy 61 ATGMEVGWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKDAIGEGKVTLRIRNVRFS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATGMEVGWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKDAIGEGKVTLRIRNVRFS 120
Qy 121 DEGGFTCFFRDHSYQEEAAMELKVEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DEGGFTCFFRDHSYQEEAAMELKVEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQY 180
Qy 181 RLRGKLRAEIENLHRTFDPHFLRVPCWKITLFVIVPVLGPLVALIICYNWLHRRLAGQFL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RLRGKLRAEIENLHRTFDPHFLRVPCWKITLFVIVPVLGPLVALIICYNWLHRRLAGQFL 240
Qy 241 EELRNPF 247
|||||||
Db 241 EELRNPF 247