DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions. Claims 1-20 are pending.
This application is a divisional of U.S. Patent Application No. 16/229,491, filed on December 21, 2018, which is a continuation of U.S. 14/438,571 filed 4/24/2015, now U.S. Patent 10,398,787, which is a 371 of PCT/EP2013/072450 filed 10/25/2013 which claims priority to parent applications PCT/EP2012/071297 filed 10/26/2012 and PCT/EP2013/064054 filed 7/3/2013.
Information Disclosure Statement
An IDS filed 7/15/2022 has been identified and the documents considered. The 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. In the case that only an English abstract was identified, this is indicated.
Drawings
Figures are objected to under 37 CFR 1.83(a) because they fail to show any details as described in the specification. Figure 3C in the drawings 10/3/2022 has an error shown below.
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The box that was present is omitted but leaves the letters not fully formed. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). A proposed drawing correction or corrected drawings are required in reply to the Office action to avoid abandonment of the application. The objection to the drawings will not be held in abeyance.
Claim Observation
Claim 12 requires that the vector is transduced into the subject at a dose lower than 2x1012 vg/kg which designation is typically reserved for viral doses. It therefore sems that applicants intended that claim 12 depend from claim 11. It will be thus considered.
As to the rejection under 35 USC, first paragraph, the claims have been evaluated under this statute as if they are drawn to in vivo use. While, claim 1 can be interpreted as reading on in vivo or in vitro use the remaining claims cannot. The in vitro use of claim 1 is allowable and hence the rejection will focus on issues of enablement for in vivo use only.
Claim Objections
Claims 9 18 is objected to because of the following informalities: claim 18 re-abbreviates AAV. Once the claims are allowed, the abbreviation should be provided for on the first occurrence and thereafter the term recited by the abbreviation. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The dependent claims are included in the rejection as they do not otherwise overcome the basis of the rejection.
The term “codon optimized” in claim 1 is a relative term which renders the claim indefinite. The term “optimized” 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. Sequences are codon optimized for a specific organism. While the claim recites a liver cell, the codon optimization does not indicate to what organism the sequence is optimized.
The term “based” in claim 13 (and claim 14, 19 and 20) is a relative term which renders the claim indefinite. The term “optimized” 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. Hence, it would not be clear what the vector scope is at the point of use as it is only recited as based in piggy-bac or transposon vectors.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 1-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating hemophilia A or hemophilia B in a subject in need thereof by a method of intravenously administering an AAV9 vector comprising a serpin enhancer with the nucleic acid sequence of SEQ ID NO:8, a transthyretin promoter (TTR), an MVM intron, a codon optimized transgene and a termination signal wherein the codon optimized transgene is respectively hFVIII with a B domain deletion and hFIX-R338L, does not reasonably provide enablement for any other embodiment. 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and in re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to (claim 1) a method of expressing a protein in a liver cell, (claim 9) a method for obtaining levels of a coagulation factor in the plasma of a subject wherein the method is for hemophilia (claim 15) and a method of treating hemophilia in a subject (claim 16). Each of the methods use a vector comprising a serpin enhancer with the nucleic acid sequence of SEQ ID NO:8, a promoter, an MVM intron codon optimized transgene and a termination signal.
2) Scope of the invention. The scope of the invention is broad in that method of claim 1 is not limited as to vector or promoter or whether the cell is in vitro or in vivo. The method of introducing will be specific for methods of introducing into cells in vivo or in vitro. For in vivo the methods of introducing are much more complicated than simply introducing a vector to a cell. It would be introduced to a subject and yet the route and means of introducing are not specified. As well, expression is required but the promoter is not specified. Hence, it is not clear how expression can naturally result as some promoters are constitutive and some inducible. Furthermore, the transgene is codon optimized but to what the claim does not indicate and hence the transgene sequence is one of many genes with one of many variations. Finally, as to claim 1, the goal is expression only which lacks direction as to transgene, cell and outcome.
As to claim 9, the issues of introducing as regards, vector and mode of introducing are not limited. The codon optimization is unspecified as to what organ or tissue or system the transgene is optimized. This is further complicated by requiring therapeutic threshold levels of FVIIII or FIX but not indicating what the outcome is. The subject is any wherein the only subject requiring these effects is one with Hemophilia A or B. These issues arise for claim 16 but are further compounded by simply requiring an active ingredient for hemophilia.
3) Number of working examples and guidance. In example 1, the disclosure teaches construction of an AAV encoding FIX-388L codon optimized and under control of the TTR promoter. This and a similar construct encoding FIX codon optimized were injected into a mouse tail vein and FIX 338L found to be at increased expression. In example 2, use of AAV9 and MVM intron in hemophiliac B mice models had no immune tolerance and increased expression over constructs without MVM and AAV9. As well, bleeding phenotype was corrected. In example 3, FVIII with a deleted B domain were injected into SCID mice. Expression was assayed and found to be at sufficient levels. In example 4, the vector used in the studies was amended to piggy-bac transposon and transposase for expression of FVIII. These were tested in hepatocytes and found to yield high expression of FVIII. As well, mice were injected with the transposon and transposase and shown not to induce tumor development. In example 5, FIX under the above conditions with PB was measured in hemophilia B mice were used to demonstrate hFIX levels and activity. The example states that “these results indicate that stable transposition is necessary for sustained expression” and “The transposon plasmid comprising the MVM intron yielded significantly higher hFIX levels and activity” as compared to non MVM/AAV9 levels. The following passage is unclear as it is not clear how the transfection is “liver-directed”. “Similarly, liver-directed co-transfection of the pB_hFIXco transposon with 5 MVM intron and mPB plasmid resulted in a significant =12-fold higher (p<0.001) hFIX protein and activity level that stabilized in the supra-physiologic range (Fig. 12F: 13290 ± 990 ng/ml hFIX and 313 + 7% normal clotting activity).”
In example 6, the serpin enhancer led to 3-6-fold increase in hFVIII levels when expression from AAV9ss-TTR-MVM-hFVIIIcopt-SC40pA (hFVIIIcopt is a b domain deleted hFVIII). The conclusion is that the combination of Serpin enhancer and hFVIIIcopt leads to synergistic effect of hFVIII levels which appears to mean simply expression levels not therapeutic effects. In example 6, AAV9 expression with the described vectors of example 3 were tested. In example 7, the same effect with hFIX is shown. Finally, in example 8, efficacy of the PB transfected mice was assessed and terminal repeat mutants. Hence, the vectors were ultimately defined as to those that provided high levels of expression in mice.
4) State of the art. The vector claimed are to be used to mediate increased expression of proteins that are dysfunctional in patients with hemophila A and B. These are respectively FVIII and FIX. Therapy prior to development of gene therapy was to provide blood infusions but these methods did not provide enough of the factors and most subjects died in childhood (see Franchini and Mannucci, Orphanet J of Rare Disease, 2012, page 2, col 1). Therapy progressed to providing factors in cryoprecipitated plasma. However, safety issues arose (see Franchini and Mannucci, page 2, col 2) wherein cloning of FIX and FVII provided the impetus for gene therapy (abstract).
The major challenges of current treatment regimens, such the short half-life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia.
The ultimately defined vector is based in either AAV9 or on a piggybac transposon. The vector also includes in addition to genes coding for FIX and FVIII include the serpin enhancer and MVM intron used with a TTR promoter and the genes are codon optimized as well as modified FVIII and FIX. The TTRm is known with FVIII as demonstrated by Cuoto et al (US Patent 6,200,560 col 10, line 19-30). Furthermore, the TTR promoter with a serpin enhancer with FIX produced therapeutic levels of FIX as shown by Vandenriessche et al (WO 2009071679, page 11, ¶1). Use of the Serpin enhancer of SEQ ID NO:8 provided liver specific expression Chuah et al (US 20110184049, abstract).
To date, HA and HB have been under considerable analysis. (Jones and George, Annual Reviews Medicine, 2023, pages 231-247, see page 232).
HA and HB AAV vectors in clinical development are distinguished by outcomes, including level of transgene derived factor activity, durability of expression, heterogeneity between recipients, and annualized bleeding rate (ABR). To date, only adult men with endogenous factor levels ≤2% and without advanced liver disease have received gene therapy. While there has been repeated proof-of-concept success in HA and HB gene therapy, the goal of stable factor expression adequate to eliminate or nearly eliminate bleeding in all patients has not yet been achieved.
Jones and George also demonstrate that the claimed modifications were known well before the filing date, this reference dates to 1985.
Because full-length F8 cDNA (7 kb) exceeds the packing capacity of AAV vectors (∼4.7 kb), AAV-based gene therapy approaches for HA use B-domain deleted FVIII variants. While the B domain comprises 40% of F8 cDNA, it is not necessary for clotting activity (18).
And F9 since 2009,
The F9 cDNA (1.6 kb) is easily packaged within an AAV vector. Early studies of AAV-based gene therapy for HB utilized wild-type FIX (22–25). However, current AAV approaches for HB use the FIX-R338L (FIX-Padua) variant, which is a naturally occurring missense mutation that results in approximately eightfold-enhanced FIX activity relative to wild-type FIX (26–29). The 338L substitution results in an enhanced interaction between activated FIX-R338L and activated FVIII, but it does not change FIX-R338L activation or inactivation compared to wild-type FIX (30).
5) Unpredictability of the art. Base claims 1, 9 and 16 require either expression in the liver cell or means of addressing high therapeutic concentrations of FIX or FVIII in the blood of a subject. The subject can only be one with hemophilia. Claim 16 is thereto directed to treating hemophilia. However, none of these claims limit the mode of delivery either by mechanism or actual vector. To the contrary, the vector is critical to overcome the art recognized obstacles i.e. organ barriers, failure to persist, side-effects in other organs, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered (Pang et al, Clinical and Applied Thrombosis/Hemostasis, 2024, pages 1-20 see especially, pages 12, col 2-14). In short, pang teaches
Despite the advancement of multiple gene therapies for hemophilia A and B through various phases of clinical trials, large-scale studies have identified a spectrum of challenges, including immunogenicity, thrombotic risks, potential gene integration, and prohibitive costs. 13 Consequently, gene therapy strategies warrant further refinement by the scientific and clinical communities.
AAV has risen to the top even with these detailed issues (Jones and George, Annual Reviews Medicine, 2023, pages 231-247, see page 232). Limitations that are to be overcome include anti-AAV antibodies. And while transit is to the liver, this can lead to hepatotoxicity both issues are reviewed by Jones and George, page 236-237. However, applicants show their results with AAV9 and Jones and George teach,
However, depending on the AAV vector, observed transgene expression varies 10–100-fold (23, 25, 27, 56, 58–60). Therefore, it is not possible to target individual patient factor threshold needs. Further, studies in a clonal population of mice chimeric with human hepatocytes demonstrated up to sevenfold variability in transduction efficiency alone (81).These data are consistent with the presence of multiple biological variables impacting each step between vector infusion and steady state transgene expression (10) and underscore the reality that the field will likely have to tolerate interpatient variability of transgene expression in the near future.
Considering piggy bac Pang teaches (page 14, col 1-2)
The clinical translation of non-viral gene delivery technologies is hindered by significant challenges related to inferior transfection performance, as demonstrated by empirical studies showing 2–3 log reductions relative to viral vector sys tems.113 Physical delivery modalities (e.g. electroporation, sonoporation) transiently enhance membrane permeability via controlled energy deposition, achieving in vitro transfection efficiencies of up to 40% by facilitating cytosolic nucleic acid entry. However, inefficiencies in intracellular trafficking and barriers to nuclear membrane translocation impede clinical translation, with fewer than 5% of preclinical candidates progressing to phase 1 trials.
Sato details some of these issues and in a post filing publication (Sato et al, Pharmaceutics, 2020, pages 1-20, see especially page 2).
Notably, in a typical situation where naked plasmid DNA is placed within tissues, delivery inside a cell is rare unless appropriate gene delivery-assisted reagents (i.e., liposomes and nanoparticles) or apparatuses (i.e., electroporator and gene gun) are used [5].
Non-viral vectors carrying transgenes have been applied locally (via direct introduction) or systemically (via tail-vein injection) to modify target cells in situ for evaluating the function of a gene of interest (GOI), creating models for human disease and basic research toward gene therapy [2,6,7]. Despite several attempts to increase transfection efficiency, chromosomal integration of non-viral vectors into the host genome was difficult. Consequently, this may negatively affect the long-term expression of the GOI as a result of the degradation of plasmids present episomally in the cells’ cytoplasm, and/or dilution during cell proliferation. Thus, low transfection and poor integration rates associated with non-viral vectors have been some of the limiting factors for their use in in vivo gene delivery experiments.
The mechanism of PB is to integrate genes into the chromosome (see Figure 1 of Sate et al, page 3). This mechanism requires transposase activity, claims that do not require the transposase omit a critical element, see Satoe et al, page 2)
In 1995, Fraser et al. [12] showed for the first time that the PB transposon, which was originally isolated from insect cells, is only active when co-transfected with a PB transposase expression vector.
Furthermore, expression systems so associated has only been demonstrated in animals. As safeguards, the system is inducible wherein animal systems are based on transfection through hydrodynamics gene delivery (HGD) system, which is one of the most common methods for in vivo gene delivery through high-speed injection of large volumes of plasmid DNA-containing solution and under control of a tet promoter and thus inducible by doxycycline (Sate, page 4). Instead of use for treatment, PB has been limited to developing models of disease in animals (Sate, abstract)., modes of delivery
Hence, the art demonstrates that the in vivo use for therapy requires specific vectors, modes of delivery and in order to be expressed specific expression controls sequences. As to the latter, one cannot simply as be recited for example in claim 1 as “expressing the transgene protein product in the liver cell”. It is either an induced process or else a natural event of the vector. But the claim requires expression as a consequence. As well, claim 9 requires a specific level of expression which is also provided for in claim 10 and claim 17. These levels are desired outcomes that are not accompanied by means of achieving the required levels. What happens in actuality is that the vector expresses protein to whatever levels, the vector and system allow.
Finally, claim 16 requires an “active” ingredient. However, there is no indication as to what constitutes an active ingredient by name or structure. The term simply is provided for with no representative active ingredients. The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the composition itself. Naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. When one is unable to envision the detailed constitution of a complex chemical compound having a particular function, such as an active ingredient, so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred. Rather, it is an attempt to preempt the future before it has arrived.
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.”
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 1-12 and 15-18 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-4 of U.S. Patent 10,398,787.
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. The safe harbor for non-statutory double patenting only applies for applications filed as divisional applications. In this case, the instant application is a not a divisional of U.S. application 14/438,571 no U.S. Patent 10,398,787. And the instant claims are drawn to a method of using a vector encompassed by claims 1-4 of U.S. Patent 10,398,787. Both claims recite a transgene encoding FIX (instant claim 2). It is noted that claim 3 is relevant only if FVIII is selected but the selection is not required and hence claim 3 is simply a limitation on claim 2. Claims 4-8 read on the FIX R338L recited in U.S. Patent 10,398,787 and claims 6-8, the promoter. Claims 9-12 read on treating a subject with a vector that anticipates that of U.S. Patent 10,398,787. Similarly, claims 12-18 recite such a method.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the U.S. Patent 10,398,787, then two different assignees would hold a patent to the claimed invention of U.S. Patent 10,398,787, and thus improperly there would be possible harassment by multiple assignees.
Conclusion
The vector used in the method has been previously found allowable. 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 on 8 am - 5 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARIA MARVICH/
Primary Examiner, Art Unit 1633
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